Sirolimus (sirolimus)

Commercially available sirolimus tablets and oral solution are not bioequivalent. However, the manufacturer states that because 2 mg doses of sirolimus given as conventional tablets and as the oral solution have been shown to be therapeutically equivalent, such formulations may be interchangeable on a mg-per-mg basis at doses that do not exceed 2 mg. It is not known whether the commercially available sirolimus tablets and the oral solution are therapeutically equivalent at doses exceeding 2 mg.

Sirolimus is administered orally as tablets or oral solution. To minimize variability in systemic exposure to sirolimus, the drug should be given once daily, consistently with or without food. Grapefruit juice reduces cytochrome P-450 (CYP) 3A4 (CYP3A4)-mediated metabolism of sirolimus and should not be administered with or used for dilution of the drug.

Sirolimus tablets should not be crushed, chewed, or split; the oral solution should be used in patients who are unable to take the tablets.

For dilution and administration of sirolimus oral solution, the prescribed amount of oral solution should be withdrawn from the bottle using the amber oral dose syringe supplied by the manufacturer and then the correct amount of the drug emptied into a glass or plastic container that holds at least 2 ounces (1/4 cup or 60 mL) of water or orange juice. Other liquids, including grapefruit juice, should not be used for dilution. The diluted oral solution should be stirred vigorously and drunk at once. The container should be refilled with an additional volume (minimum of 4 ounces (1/2 cup or 120 mL)) of water or orange juice, stirred vigorously, and then drunk at once.

Sirolimus therapy should be initiated as soon as possible following renal transplantation as part of an initial immunosuppressive regimen that includes both cyclosporine and corticosteroids. At 2-4 months following transplantation, gradual discontinuance of cyclosporine and adjustment of the sirolimus dosage to achieve recommended blood concentrations of the drug are recommended in patients at low to moderate immunologic risk. In patients at high immunologic risk (defined as Black ethnicity, repeat transplant following loss of a previous allograft for immunologic reasons, and/or recipients with a high level of PRAs (peak PRA level over 80%)), the manufacturer recommends that sirolimus be used in combination with cyclosporine and corticosteroids for the first 12 months following renal transplantation.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Cyclosporine; Sirolimus/Adagrasib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Adagrasib may decrease the metabolism and increase the absorption of cyclosporine and sirolimus by inhibiting CYP3A4 and P-glycoprotein (P-gp).(1)

CLINICAL EFFECTS: Concurrent use of adagrasib may result in elevated levels of and toxicity from cyclosporine and sirolimus.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of adagrasib states that concurrent administration of sensitive narrow therapeutic index P-glycoprotein substrates or sensitive CYP3A4 substrates (e.g. cyclosporine, sirolimus) with adagrasib should be avoided.(1)

DISCUSSION: Concurrent adagrasib (600 mg twice daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of digoxin by 1.5-fold and 1.9-fold, respectively.(1) In a study, adagrasib (400 mg twice daily) increased the AUC and Cmax of a single dose of midazolam by 21-fold and 4.8-fold, respectively. In a study, adagrasib (600 mg twice daily) increased the AUC and Cmax of a single dose of midazolam by 31-fold and 3.1-fold, respectively.(1)

Immunosuppressive; Immunomod/Cladribine Onc Inj (10 Mg/5 Ml)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)

CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-2)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The UK and AU manufacturers of Litak state that concomitant use of other myelosuppressive medicinal products with cladribine is contraindicated.(1-2) The Israeli manufacturer of Litak states that cladribine should not be used concomitantly with other myelosuppressive medicinal products.(3)

DISCUSSION: The risk of severe myelotoxicity and long-lasting immunosuppression is increased in patients with a disease-related bone marrow infiltration or a previous myelosuppressive treatment.(1-3)

Immunosuppressives; Immunomodulators/Efalizumab; Natalizumab

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Natalizumab,(1-3) efalizumab,(4) immunosuppressives, and immunomodulators all suppress the immune system.

CLINICAL EFFECTS: Concurrent use of natalizumab(1-3) or efalizumab(4) with immunosuppressives or immunomodulators may result in an increased risk of infections, including progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).

PREDISPOSING FACTORS: Previous JCV infection, longer duration of natalizumab treatment - especially if greater than 2 years, and prior or concomitant treatment with immunosuppressant medication are all independent risk factors which increase the risk for PML.(1,5) The FDA has estimated PML incidence stratified by risk factors: If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment less than 25 months, incidence <1/1,000. If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment less than 25 months, incidence 2/1,000 If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 4/1,000 If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 11/1,000.

PATIENT MANAGEMENT: The US manufacturer of natalizumab states patients with Crohn's disease should not receive concurrent immunosuppressants, with the exception of limited overlap of corticosteroids, due to the increased risk for PML. For new natalizumab patients currently receiving chronic oral corticosteroids for Crohn's Disease, begin corticosteroid taper when therapeutic response to natalizumab has occurred. If corticosteroids cannot be discontinued within six months of starting natalizumab, discontinue natalizumab.(3) The US manufacturer of natalizumab states that natalizumab should not ordinarily be used in multiple sclerosis patients receiving immunosuppressants or immunomodulators due to the increased risk for PML. Immunosuppressives include, but are not limited to azathioprine, cyclophosphamide, cyclosporine, mercaptopurine, methotrexate, mitoxantrone, mycophenolate, and corticosteroids.(3,6) The UK manufacturer of natalizumab states that concurrent use with immunosuppressives or antineoplastic agents is contraindicated.(1) The Canadian manufacturer of natalizumab states that natalizumab should not be used with immunosuppressive or immunomodulatory agents.(2) The US manufacturer of certolizumab states that concurrent therapy with natalizumab is not recommended.(7)

DISCUSSION: Progressive multifocal leukoencephalopathy has been reported in patients receiving concurrent natalizumab were recently or concomitantly taking immunomodulators or immunosuppressants.(1-5,8,9) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(10)

Select Immunosuppressants/Ombitasvir-Paritaprevir-Ritonavir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Combination products ombitasvir-paritaprevir-ritonavir or ombitasvir-paritaprevir-ritonavir-dasabuvir including the protease inhibitor ritonavir may inhibit the metabolism of everolimus, sirolimus, tacrolimus, and temsirolimus by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of ombitasvir-paritaprevir-ritonavir or ombitasvir-paritaprevir-ritonavir-dasabuvir may result in increased levels of everolimus, sirolimus, tacrolimus, or temsirolimus.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent administration of everolimus, sirolimus, temsirolimus, or tacrolimus is contraindicated with either ombitasvir-paritaprevir-ritonavir or ombitasvir-paritaprevir-ritonavir-dasabuvir.(1,2)

DISCUSSION: The manufacturer of ombitasvir-paritaprevir-ritonavir and ombitasvir-paritaprevir-ritonavir-dasabuvir state use with everolimus, sirolimus, or tacrolimus is contraindicated due to increased potential for serious and/or life threatening immunosuppressant associated adverse events.(1,2) In an interaction study, ombitasvir-paritaprevir-ritonavir increased the area-under-curve (AUC) of everolimus 0.75 mg 27.21-fold.(1,2) The combination of ombitasvir-paritaprevir-ritonavir-dasabuvir increased the AUC of everolimus 0.75 mg 27.21-fold.(1,2) In an interaction study, ombitasvir-paritaprevir-ritonavir increased the AUC of sirolimus 0.5 mg 37.99-fold.(1,2) The combination of ombitasvir-paritaprevir-ritonavir-dasabuvir increased the AUC of sirolimus 0.5 mg 37.99-fold.(1,2) In an interaction study, ombitasvir-paritaprevir-ritonavir increased the AUC of tacrolimus 0.5 mg 85.81-fold.(1,2) The combination of ombitasvir-paritaprevir-ritonavir-dasabuvir increased the AUC of tacrolimus 2 mg 57.13-fold.(1,2) The selected immunosuppressants linked to this monograph include: everolimus, sirolimus, tacrolimus, and temsirolimus.

Select Immunosuppressives/Ropeginterferon Alfa-2B

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Ropeginterferon alfa-2b and immunosuppressives both suppress the immune system.

CLINICAL EFFECTS: Concurrent use of ropeginterferon alfa-2b with immunosuppressives may result in an increased risk of serious infections.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US and UK manufacturers of ropeginterferon alfa-2b state that concurrent use of ropeginterferon alfa-2b in transplant patients receiving immunosuppressive agents is contraindicated.(1-2)

DISCUSSION: In clinical trials, 20% of patients experienced leukopenia. Interferon alfa products may cause fatal or life-threatening infections.(1-2)

Selected Cyp3a4 Substrates/Mifepristone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Mifepristone is an inhibitor of CYP3A4 and may increase levels and effects of drugs metabolized by this enzyme.(1)

CLINICAL EFFECTS: Lovastatin, simvastatin and CYP3A4 substrates with a narrow therapeutic window such as alprazolam, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, and tacrolimus or CYP3A4 substrates with a high first pass effect such as oral midazolam, sildenafil, and triazolam are particularly susceptible to significant toxicity.(1,2)

PREDISPOSING FACTORS: Due to the need for continuous therapy and mifepristone's long half-life of 85 hours(1) which leads to accumulation, patients with endogenous Cushing's syndrome may be at an increased risk for toxicity. With pimozide, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: The US manufacturer of mifepristone for hypercortisolism due to endogenous Cushing's syndrome states use with lovastatin, simvastatin, CYP3A4 substrates with a narrow therapeutic range, or CYP3A4 substrates with a high first pass effect is contraindicated.(1)

DISCUSSION: Administration of mifepristone 1200 mg daily for 10 days followed by a single dose of simvastatin 80 mg led to an increase of simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC) of 10.4-fold and 15.7-fold, respectively.

Selected Immunosuppressants/Conivaptan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Conivaptan increases plasma levels of cyclosporine, sirolimus, and temsirolimus by inhibition of CYP3A4.(1-4)

CLINICAL EFFECTS: Concurrent conivaptan may result in elevated levels of and toxicity from cyclosporine, sirolimus, and temsirolimus.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of conivaptan states that concomitant use of drugs eliminated primarily by CYP3A-mediated metabolism should be avoided.(1) Cyclosporine, sirolimus, or temsirolimus levels and renal function should be monitored if conivaptan is initiated or discontinued from concurrent therapy. The dosage of cyclosporine, sirolimus, or temsirolimus may need to be adjusted. The US manufacturer of sirolimus states that concurrent therapy with moderate CYP3A4 inhibitors such as conivaptan should be used with caution. The dosage of sirolimus or conivaptan may require adjustment.(3)

DISCUSSION: Erythromycin 800 mg every 8 hours, a moderate CYP3A4 and P-gp inhibitor, given to 24 healthy volunteers increased the maximum concentration (Cmax) and area-under-curve (AUC) of sirolimus 2 mg by 4.4-fold and 4.2-fold, respectively.(3) In a study of 18 healthy volunteers, diltiazem 120 mg, a moderate CYP3A4 inhibitor and P-gp inhibitor, increased the Cmax and AUC of sirolimus 10 mg by 1.4-fold and 1.6-fold, respectively.(3) In 25 healthy volunteers, verapamil 180 mg twice daily, a moderate CYP3A4 inhibitor and P-gp inhibitor, increased the max and AUC of sirolimus 2 mg by 2.3-fold and 2.2-fold, respectively.(3) Concurrent administration of ketoconazole, another inhibitor of CYP3A4, had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is expected to adjust levels to the range observed without inhibitors; however, there are no data available with this dose adjustment.(4)

Selected Immunosuppressants/Nadofaragene Firadenovec

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Nadofaragene firadenovec may contain low levels of replication-competent adenovirus.(1)

CLINICAL EFFECTS: Concurrent use of nadofaragene firadenovec in patients receiving immunosuppressive therapy may cause disseminated adenovirus infection.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Individuals who are immunosuppressed or immune-deficient should not receive nadofaragene firadenovec.(1)

DISCUSSION: Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy but may contain low levels of replication-competent adenovirus. Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection.(1)

Selected Immunosuppressants/Nefazodone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Nefazodone increases plasma levels of sirolimus and temsirolimus by inhibition on CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent nefazodone may result in elevated levels of and toxicity from sirolimus and temsirolimus.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as nefazodone by avoided. Alternative agents with lesser interaction potential with sirolimus should be considered.(1) The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as nefazodone be avoided. If concurrent use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should be considered. If nefazodone is discontinued, a washout period of 1 week should be allowed before adjusting the dosage of temsirolimus to previous levels.(2)

DISCUSSION: Multiple-dose ketoconazole, another inhibitor of CYP3A4, administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of sirolimus oral solution, as reflected by increases in sirolimus concentration maximum (Cmax), time maximum (tmax), and area-under-curve (AUC) of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminal half-life of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations.(1) Concurrent administration of ketoconazole, another inhibitor of CYP3A4, had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is expected to adjust levels to the range observed without inhibitors; however, there are no data available with this dose adjustment.(2)

Selected Immunosuppressants/Talimogene Laherparepvec

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Talimogene laherparepvec is a live, attenuated herpes simplex virus.(1)

CLINICAL EFFECTS: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Talimogene laherparepvec is contraindicated in immunosuppressed patients.(1) The magnitude of immunocompromise and associated risks due to immunosuppressant drugs should be determined by a physician.

DISCUSSION: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)

Selected Immunosuppressants;Temsirolimus/Selected Macrolides

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Macrolide antibiotics may inhibit the metabolism of cyclosporine, sirolimus, and temsirolimus by CYP3A4.

CLINICAL EFFECTS: The concurrent administration of cyclosporine, sirolimus, or temsirolimus with a macrolide that inhibits CYP3A4 may result in elevated levels of cyclosporine, sirolimus, or temsirolimus and possible toxicity. The levels of the macrolide may also be elevated and result in toxicity.

PREDISPOSING FACTORS: Progressively decreasing renal/hepatic function.

PATIENT MANAGEMENT: Cyclosporine, sirolimus, and temsirolimus levels should be carefully monitored in patients receiving concurrent therapy with macrolide antibiotics. The dosage of cyclosporine, sirolimus, or temsirolimus may need to be adjusted during and/or after macrolide therapy or the macrolide may need to be discontinued. The dosage of the macrolide antibiotic may need to be adjusted. Guidelines from the American Society of Transplantation state that clarithromycin and erythromycin are contraindicated with sirolimus (although product labels do not contraindicate these combinations), and that the use of clarithromycin or erythromycin with cyclosporine should be avoided. If the combination must be used, lower the dose of the immunosuppressant by up to 50 % upon initiation of the antibiotic and monitor levels daily with cyclosporine or every 3rd day with sirolimus. The US manufacturer of sirolimus states that concurrent use with erythromycin, clarithromycin, or telithromycin is not recommended and should be avoided. The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as clarithromycin or telithromycin be avoided. If concurrent use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should be considered. If the macrolide is discontinued, a washout period of 1 week should be allowed before adjusting the dosage of temsirolimus to previous levels.

DISCUSSION: Concomitant administration of cyclosporine and erythromycin has been shown to increase cyclosporine trough serum levels and clinical symptoms of drug toxicity. Maximum effect may be seen one week after concurrent administration. These effects reverse when erythromycin is discontinued. The interaction probably occurs with troleandomycin also. Case reports have documented increased cyclosporine and creatinine levels during concurrent administration with clarithromycin. Several studies have shown that spiramycin does not affect cyclosporine pharmacokinetics. Because studies in rats have shown that azithromycin does not affect CYP P-450, it would not be expected to interact with cyclosporine. One case report exists which describes a potential interaction between cyclosporine and azithromycin; however, the time course of the events suggest that other factors, such as the patient's failing renal graft, may have led to the increased cyclosporine levels in this patient. In a cross-over study in 16 healthy subjects, pretreatment with erythromycin (500 mg 3 times daily for 9 days) increased the maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) of a single oral dose of everolimus (2 mg on Day 5) by 2.0-fold, 4.4-fold, and 39%, respectively. There were no effects on erythromycin levels. In a study in 24 healthy subjects, concurrent sirolimus (2 mg daily) and erythromycin ethylsuccinate (800 mg 3 times daily) increased sirolimus Cmax, AUC, and time to Cmax (Tmax) by 4.4-fold, 4.2-fold, and 0.4 hours, respectively. Erythromycin Cmax, AUC, and Tmax were increased by 1.6-fold, 1.7-fold, and 0.3 hours, respectively. There are case reports of toxicity with concurrent sirolimus and erythromycin. Concurrent administration of ketoconazole, another inhibitor of CYP3A4, had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is expected to adjust levels to the range observed without inhibitors; however, there are no data available with this dose adjustment. Azithromycin, a weak CYP3A4 inhibitor, and spiramycin, which does not inhibit the CYP P-450 system, would not be expected to interact with cyclosporine, sirolimus, or temsirolimus.

Selected Immunosuppressive Agents/Live Vaccines; Live Bcg

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: A variety of disease modifying agents suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines or intravesicular BCG. Immune response to vaccines may be decreased during periods of immunocompromise.(1)

CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) After instillation of intravesicular BCG, immunosuppression may interfere with local immune response, or increase the severity of mycobacterial infection following inadvertent systemic exposure.(2)

PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency.

PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) Patients who receive anti-B cell therapies should not receive live vaccines for at least 6 months after such therapies due to a prolonged duration of immunosuppression. An exception is the Zoster vaccine, which can be given at least 1 month after receipt of anti-B cell therapies.(1) The US manufacturer of abatacept states live vaccines should not be given during or for up to 3 months after discontinuation of abatacept.(2) The US manufacturer of live BCG for intravesicular treatment of bladder cancer states use is contraindicated in immunosuppressed patients.(3) The US manufacturer of daclizumab states live vaccines are not recommended during and for up to 4 months after discontinuation of treatment.(4) The US manufacturer of guselkumab states that live vaccines should be avoided during treatment with guselkumab.(5) The US manufacturer of inebilizumab-cdon states that live vaccines are not recommended during treatment and after discontinuation until B-cell repletion. Administer all live vaccinations at least 4 weeks prior to initiation of inebilizumab-cdon.(6) The US manufacturer of ocrelizumab states that live vaccines are not recommended during treatment and until B-cell repletion occurs after discontinuation of therapy. Administer all live vaccines at least 4 weeks prior to initiation of ocrelizumab.(7) The US manufacturer of ozanimod states that live vaccines should be avoided during and for up to 3 months after discontinuation of ozanimod.(8) The US manufacturer of siponimod states that live vaccines are not recommended during treatment and for up to 4 weeks after discontinuation of treatment.(9) The US manufacturer of ustekinumab states BCG vaccines should not be given in the year prior to, during, or the year after ustekinumab therapy.(10) The US manufacturer of satralizumab-mwge states that live vaccines are not recommended during treatment and should be administered at least four weeks prior to initiation of satralizumab-mwge.(11) The US manufacturer of ublituximab-xiiy states that live vaccines are not recommended during treatment and until B-cell recovery. Live vaccines should be administered at least 4 weeks prior to initiation of ublituximab-xiiy.(12) The US manufacturer of etrasimod states that live vaccines should be avoided during and for 5 weeks after treatment. Live vaccines should be administered at least 4 weeks prior to initiation of etrasimod.(13) The US manufacturer of emapalumab-lzsg states that live vaccines should not be administered to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.(14) The US manufacturer of sibeprenlimab-szsi states live vaccines should not be given within 30 days prior to initiation or during treatment with sibeprenlimab-szsi.(15)

DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1)

Selected Nephrotoxic Agents/Bacitracin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3)

CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3)

PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1)

PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3)

DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3)

Selected Nephrotoxic Agents/Cidofovir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Cidofovir is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1-3)

CLINICAL EFFECTS: Concurrent use of cidofovir with nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian,(1) UK,(2) and US(3) manufacturers of cidofovir state that concurrent administration of potentially nephrotoxic agents such as adefovir, intravenous aminoglycosides, amphotericin B, foscarnet, intravenous pentamidine, tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1-3) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin. These agents should be discontinued at least 7 days before the administration of cidofovir.

DISCUSSION: The safety of cidofovir has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of cidofovir.(1-3)

Sirolimus/Posaconazole

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Posaconazole inhibits the metabolism of sirolimus by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of posaconazole may result in elevated levels of and toxicity from sirolimus.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of posaconazole states that concurrent use with sirolimus is contraindicated.(1) The UK manufacturer of posaconazole states that concurrent use with sirolimus is not recommended and should be avoided whenever possible.(2)

DISCUSSION: In a study in 12 healthy subjects, administration of posaconazole (400 mg twice daily for 16 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of sirolimus (2 mg) by 6.7-fold and 8.9-fold (range 3.1-fold to 17.5-fold), respectively.(1-3)

Slt Immunosuppressants;Temsirolimus/Ensitrelvir;Nirmatrelvir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Ensitrelvir and nirmatrelvir-ritonavir may inhibit the metabolism of cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus by CYP3A4.(1-8)

CLINICAL EFFECTS: Concurrent use of ensitrelvir or nirmatrelvir-ritonavir may result in increased levels of and risk of toxicity from cyclosporine, everolimus, sirolimus, tacrolimus, or temsirolimus.(1-8)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The American Society of Transplantation (AST) Statement on Oral Antiviral Therapy for COVID-19 for Organ Transplant Recipients states use of nirmatrelvir-ritonavir will be challenging in transplant patients due to significant drug interactions and difficulty with therapeutic drug monitoring in outpatients with active Covid-19 infections. Alternatives such as early use of either an appropriate monoclonal antibody or outpatient intravenous remdesivir may be preferred as first line therapy in transplant patients to prevent progression.(9) The US manufacturer of nirmatrelvir-ritonavir states concurrent use with immunosuppressants should not be used if close monitoring is not feasible.(6) Specific immunosuppressant recommendations: -Cyclosporine: For therapy with nirmatrelvir-ritonavir in patients on cyclosporine, some experts recommend lowering the cyclosporine dose by 80%. -Tacrolimus: For therapy with nirmatrelvir-ritonavir in patients on tacrolimus, experts recommend holding tacrolimus for the 5-day duration of nirmatrelvir-ritonavir therapy. Tacrolimus level is recommended on day 3 to assess the need for a one-time dose of tacrolimus during nirmatrelvir-ritonavir therapy. -As soon as possible after nirmatrelvir-ritonavir therapy, cyclosporine or tacrolimus levels should be checked, and every 2-4 days thereafter until stable, to determine when to increase cyclosporine doses or resume tacrolimus.(8) -Everolimus: For therapy with nirmatrelvir-ritonavir in patients on everolimus, AST states CYP3A4 inhibitors, such as clarithromycin, ketoconazole, voriconazole, and HIV protease inhibitors, are contraindicated with everolimus. The US manufacturer of everolimus states concurrent use should be avoided with strong CYP3A4 inhibitors. -Sirolimus: The US manufacturer of nirmatrelvir-ritonavir(6) and sirolimus protein-bound injection (Fyarro)(10) state concurrent use should be avoided. -Temsirolimus: The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as nirmatrelvir-ritonavir be avoided. If concurrent use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should be considered. If nirmatrelvir-ritonavir is discontinued, a washout period of 1 week should be allowed before adjusting the dosage of temsirolimus to previous levels.(2) For patients concurrently taking cyclosporine, everolimus, sirolimus, tacrolimus, or temsirolimus with nirmatrelvir, therapeutic concentration monitoring of the immunosuppressant is recommended. Although there are no specific recommendations for concurrent use of ensitrelvir with immunosuppressants, a similar approach would be prudent.

DISCUSSION: A retrospective study evaluated the interaction between cyclosporine or tacrolimus and nirmatrelvir/ritonavir in 25 solid-organ transplant recipients. Upon nirmatrelvir/ritonavir initiation, cyclosporine doses were decreased by 80% and tacrolimus was held for the duration of nirmatrelvir/ritonavir therapy. No patients had acute rejection in the 30 days following nirmatrelvir/ritonavir. In 21 patients on tacrolimus, the median tacrolimus trough concentration before and after nirmatrelvir/ritonavir therapy was 7.4 ng/mL (IQR, 6.6-8.6) and 5.2 ng/mL (IQR, 3.6-8.7), respectively. Four patients had supratherapeutic tacrolimus troughs after restarting tacrolimus. In these patients, tacrolimus was resumed at either reduced dose or at pre-nirmatrelvir/ritonavir dose 2-5 days after completion of nirmatrelvir/ritonavir therapy.(5) Concurrent use of nirmatrelvir/ritonavir with tacrolimus resulted in elevated tacrolimus levels, treatment interruption, and acute kidney injury.(12) In a case series, 12 bilateral lung transplant recipients with COVID-19 were started on nirmatrelvir/ritonavir. All patients were on immediate-release tacrolimus and prednisone, and all except one were also on mycophenolate. Patients stopped tacrolimus 10-14 hours before starting nirmatrelvir-ritonavir and had tacrolimus levels checked between days 3-5 of therapy. One patient required a supplemental 0.5 mg dose of tacrolimus during nirmatrelvir-ritonavir therapy. Six patients had trough levels within goal, and 3 patients had troughs below goal but at adequate immunosuppression level based on the clinicians' judgement. Ten of the patients resumed tacrolimus at 25% of their baseline dose at day 8, and 9 of them resumed full dose tacrolimus by day 10. One patient was hospitalized for worsening COVID-19. No patients experienced tacrolimus side effects or acute rejection.(13) In a case series of 3 renal transplant recipients, tacrolimus was held 1 day before patients started nirmatrelvir-ritonavir therapy. Two patients resumed previous doses of tacrolimus one day after finishing nirmatrelvir/ritonavir; one had stable tacrolimus levels and the other was supratherapeutic. The 3rd patient received a supplemental dose of tacrolimus on day 4 of therapy and resumed his previous dose starting on day 5, and was supratherapeutic on day 6. No patients experienced adverse effects or graft rejection. The authors state that nirmatrelvir/ritonavir is not contraindicated and tacrolimus levels can be closely monitored for patients on tacrolimus.(14) In a case report of a 67-year old patient on chronic tacrolimus therapy, after 4 days of nirmatrelvir-ritonavir she presented to the emergency department with slowed speech, fatigue, weakness, and loss of appetite. The patient's tacrolimus level was 176.4 ng/mL (normal range is 5-20 ng/mL).(15) In a case series of 4 renal transplant recipients, tacrolimus was paused during nirmatrelvir-ritonavir therapy, which resulted in stable therapeutic levels. In one patient, tacrolimus was resumed immediately and resulted in a toxic tacrolimus level. In three patients, tacrolimus was resumed at a reduced dose 24 hours after nirmatrelvir-ritonavir was stopped and resulted in therapeutic to supratherapeutic tacrolimus levels.(16) In a case report of a 39-year-old female, the patient developed a sudden increase in tacrolimus levels after starting nirmatrelvir-ritonavir.(17) In a PKPB model, tacrolimus clearance decreased to 35% and bioavailability increased by 18.7-fold after the coadministration of nirmatrelvir/ritonavir, compared with tacrolimus alone.(18) The selected immunosuppressants linked to this monograph include: cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Cyclosporine;Sirolimus;Temsirolimus/Slt Strong Cyp3a4 Inhib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The metabolism of cyclosporine, sirolimus, and temsirolimus by CYP3A4 may be inhibited by strong CYP3A4 inhibitors.

CLINICAL EFFECTS: Concurrent administration of strong CYP3A4 inhibitors may result in elevated levels of and toxicity from cyclosporine, sirolimus, or temsirolimus.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Cyclosporine, sirolimus, or temsirolimus levels and renal function should be monitored if strong CYP3A4 inhibitors are initiated or discontinued from concurrent therapy. The dosage of cyclosporine, sirolimus, or temsirolimus may need to be adjusted. The manufacturer of ribociclib states that caution is recommended when ribociclib is administered with CYP3A4 substrates with a narrow therapeutic index. The dose of the sensitive CYP3A4 substrate with a narrow therapeutic index may need to be reduced.(5) The manufacturer of sirolimus states that the concurrent use of strong CYP3A4 inhibitors is not recommended and should be avoided.(1) The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as ribociclib be avoided. If concurrent use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should be considered. If ribociclib is discontinued, a washout period of 1 week should be allowed before adjusting the dosage of temsirolimus to previous levels.(2)

DISCUSSION: In a study in healthy subjects, concomitant administration of ribociclib (400 mg once daily for 8 days) with midazolam increased the midazolam maximum concentration (Cmax) and area under the curve (AUC) by 2.1-fold and 3.8-fold, respectively. Administration of ribociclib 600 mg once daily is predicted to increase the midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.(5) Strong CYP3A4 inhibitors linked include: relacorilant and ribociclib.(6,7)

Immunosuppres;Immunomodul/Selected Multiple Sclerosis Agents

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ocrelizumab or ofatumumab in combination with immunosuppressives and immune-modulators all suppress the immune system.(1,2)

CLINICAL EFFECTS: Concurrent use of ocrelizumab or ofatumumab with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1,2)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The ocrelizumab US prescribing information states: - Ocrelizumab and other immune-modulating or immunosuppressive therapies, (including immunosuppressant doses of corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with ocrelizumab. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating ocrelizumab.(1) The ofatumumab US prescribing information states: - Ofatumumab and other immunosuppressive therapies (including systemic corticosteroids) may have the potential for increased immunosuppressive effects and increase the risk of infection. When switching between therapies, the duration and mechanism of action of each therapy should be considered due to the potential for additive immunosuppressive effects. Ofatumumab for MS therapy has not been studied in combination with other MS agents that suppress the immune system.(2)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1,2) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(3)

Immunosuppressives; Immunomodulators/Baricitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of baricitinib with other biologic disease-modifying antirheumatic drugs (DMARDs) or potent immunosuppressants such as azathioprine or cyclosporine may result in additive or synergistic effects on the immune system.

CLINICAL EFFECTS: Concurrent use of baricitinib with other biologic DMARDs or potent immunosuppressants such as azathioprine or cyclosporine may increase the risk of serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of baricitinib states that concurrent use of baricitinib with biologic DMARDs or potent immunosuppressants is not recommended.(1)

DISCUSSION: Most patients who developed serious infections while being treated with baricitinib were on concomitant immunosuppressants like methotrexate and corticosteroids. The combination of baricitinib with other biologic DMARDs has not been studied.(1)

Immunosuppressives; Immunomodulators/Cladribine Oral

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)

CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-2)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US prescribing information states: -Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered. In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of cladribine.(1) The cladribine Canadian prescribing information states: -Use of cladribine in immunocompromised patients is contraindicated because of a risk of additive effects on the immune system. Acute short-term therapy with corticosteroids can be administered during cladribine treatment.(2)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-2)

Immunosuppressives; Immunomodulators/Deuruxolitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Deuruxolitinib, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of deuruxolitinib and potent immunosuppressants may increase the risk of serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of deuruxolitinib states that concurrent use of deuruxolitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1) If concurrent use cannot be avoided, patients should be monitored for signs and symptoms of infection. If a patient develops a serious or opportunistic infection, interrupt deuruxolitinib treatment until the infection is controlled.

DISCUSSION: Serious infections have been reported in patients receiving treatment with deuruxolitinib.(1)

Immunosuppressives; Immunomodulators/Etrasimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Etrasimod causes reversible sequestration of lymphocytes in lymphoid tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte count at 52 weeks.(1) Other immunosuppressives and immune-modulators also suppress the immune system.

CLINICAL EFFECTS: Concurrent use of etrasimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious and fatal infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications increases the risk of adverse effects.

PATIENT MANAGEMENT: The etrasimod US prescribing information states etrasimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Concomitant administration of these therapies with etrasimod should be avoided because of the risk of additive immune effects during therapy and in the weeks following administration. Etrasimod's effect on peripheral lymphocytes may persist for up to 5 weeks after discontinuation.(1) When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with other sphingosine-1 phosphate receptor modulators.(1)

Immunosuppressives; Immunomodulators/Filgotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic disease-modifying antirheumatic drugs (DMARDs), or other Janus kinase (JAK) inhibitors may result in additive or synergistic effects on the immune system.(1)

CLINICAL EFFECTS: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors may increase the risk of serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of filgotinib states that concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors is not recommended.(1)

DISCUSSION: Serious infections have been reported in patients receiving filgotinib. Caution should be used in patients with a higher incidence of serious infection, including elderly patients aged 75 years and older.(1)

Immunosuppressives; Immunomodulators/Fingolimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Fingolimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-3)

CLINICAL EFFECTS: Concurrent use of fingolimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-3)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: Recommendations for fingolimod regarding this interaction differ between regulatory approving agencies. The fingolimod US prescribing information states: - Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with fingolimod. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating fingolimod.(1) The fingolimod Canadian prescribing information states: - Concurrent use with immunosuppressive or immunomodulatory agents is contraindicated due to the risk of additive immune system effects. However, co-administration of a short course of corticosteroids (up to 5 days) did not increase the overall rate of infection in patients participating Phase III clinical trials.(2) The fingolimod UK specific product characteristics states: - Fingolimod is contraindicated in patients currently receiving immunosuppressive therapies or those immunocompromised by prior therapies. When switching patients from another disease modifying therapy to Gilenya, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimizing the risk of disease activation.(3)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-3)

Immunosuppressives; Immunomodulators/Inebilizumab

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inebilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of inebilizumab with immunosuppressive or immunomodulating agents may result in myelosuppression including neutropenia resulting in an increased risk for serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of inebilizumab states that the concurrent use of inebilizumab with immunosuppressive agents, including systemic corticosteroids, may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)

DISCUSSION: Inebilizumab has not been studied in combination with other immunosuppressants. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents. The most common infections reported by inebilizumab treated patients in the randomized and open-label clinical trial periods included urinary tract infections (20%), nasopharyngitis (13%), upper respiratory tract infections (8%), and influenza (7%). Although there been no cases of Hepatitis B virus reactivation or progressive multifocal leukoencephalopathy reported in patients taking inebilizumab, these infections have been observed in patients taking other B-cell-depleting antibodies.(1)

Immunosuppressives; Immunomodulators/Ozanimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ozanimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ozanimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The ozanimod US prescribing information state this information regarding this interaction: -Ozanimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ozanimod after alemtuzumab is not recommended. However, ozanimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)

Immunosuppressives; Immunomodulators/Ponesimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ponesimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ponesimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The ponesimod US prescribing information states ponesimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ponesimod after alemtuzumab is not recommended. However, ponesimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)

Immunosuppressives; Immunomodulators/Ritlecitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ritlecitinib, immunosuppressives, and immunomodulators all suppress the immune system.

CLINICAL EFFECTS: Concurrent use of ritlecitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ritlecitinib states that concurrent use of ritlecitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1)

DISCUSSION: Serious infections have been reported in patients receiving ritlecitinib. Reported infections included appendicitis, COVID-19 infection (including pneumonia), and sepsis. Reports of viral reactivation, including herpes virus reactivation was reported in clinical studies with ritlecitinib.(1)

Immunosuppressives; Immunomodulators/Siponimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Siponimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of siponimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The siponimod US prescribing information state this information regarding this interaction: -Siponimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with siponimod after alemtuzumab is not recommended. However, siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)

DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)

Immunosuppressives; Immunomodulators/Tofacitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of tofacitinib and azathioprine, other biologic disease-modifying antirheumatic drugs (DMARDs), or potent immunosuppressants may result in additive or synergistic effects on the immune system.(1)

CLINICAL EFFECTS: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants use may increase the risk of serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Tofacitinib should not be used concurrently with azathioprine, other biologic DMARDs, or cyclosporine.(1) Patient should be monitored for decreases in lymphocytes and neutrophils. Therapy should be adjusted based on the indication. - For all indications: If absolute neutrophil count (ANC) or lymphocyte count is less than 500 cells/mm3, discontinue tofacitinib. - For rheumatoid arthritis or psoriatic arthritis and absolute neutrophil count (ANC) 500 to 1000 cells/mm3: interrupt dosing. When ANC is greater than 1000 cells/mm3, resume Xeljanz 5 mg twice daily or Xeljanz XR 11 mg once daily. - For ulcerative colitis and ANC 500 to 1000 cells/mm3: -If taking Xeljanz 10 mg twice daily, decrease to 5 mg twice daily. When ANC is greater than 1000 cells/mm3, increase to 10 mg twice daily based on clinical response. -If taking Xeljanz 5 mg twice daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 5 mg twice daily. -If taking Xeljanz XR 22 mg once daily, decrease to 11 mg once daily. When ANC is greater than 1000 cells/mm3, increase to 22 mg once daily based on clinical response. -If taking Xeljanz XR 11 mg once daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 11 mg once daily. - For polyarticular course juvenile idiopathic arthritis (pcJIA) and ANC 500 to 1000 cells/mm3: interrupt dosing until ANC is greater than 1000 cells/mm3.(1)

DISCUSSION: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants may increase the risk of infection.(1) Serious infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. Some patients presented with disseminated disease and were often taking concomitant immunomodulating agents. In the ulcerative colitis population, a greater risk of serious infections was seen with a higher tofacitinib dose. In 7 placebo-controlled rheumatoid arthritis trials (0-3 months exposure), the overall frequency of infections was 20% in the tofacitinib 5 mg twice daily group and 22% in the tofacitinib 10 mg twice daily group compared to 18% in the placebo group. Serious infections were reported in 11 patients (1.7 events per 100 patient-years) with a rate difference between treatment groups of 1.1 (-0.4, 2.5) events per 100 patient-years for both tofacitinib 5 mg twice daily and 10 mg twice daily. During 0-12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient years) in the tofacitinib 5 mg twice daily group and 33 patients (2.7 events per 100 patient years) in the tofacitinib 10 mg twice daily group.(1)

Immunosuppressives; Immunomodulators/Upadacitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Upadacitinib, immunosuppressives, and immunomodulators all suppress the immune system.

CLINICAL EFFECTS: Concurrent use of upadacitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of upadacitinib states that concurrent use of upadacitinib with immunosuppressives or immunomodulators is not recommended.

DISCUSSION: Serious infections have been reported in patients receiving upadacitinib. Reported infections included pneumonia, cellulitis, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, cryptococcosis. Reports of viral reactivation, including herpes virus reactivation and hepatitis B reactivation, were reported in clinical studies with upadacitinib.(1)

Mtor Inhibitors/Ace Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: ACE inhibitors cause reduced bradykinin metabolism, leading to an increase in bradykinin which can cause vasodilation. mTOR inhibitors may also cause a reduction in bradykinin metabolism.

CLINICAL EFFECTS: Concomitant therapy can increase the risk of vasodilation leading to an increase in angioedema risk.

PREDISPOSING FACTORS: History of previous angioedema.

PATIENT MANAGEMENT: Patients may be more susceptible to developing angioedema if concomitantly taking an ACE inhibitor and mTOR inhibitor. Consider switching the patient to an angiotensin receptor blocker. Monitor patients receiving concurrent therapy with ACE inhibitors and mTOR inhibitors closely for signs and symptoms of angioedema (swollen skin, hoarseness, a tight or swollen throat, or trouble breathing). Instruct patients to report angioedema symptoms immediately.

DISCUSSION: A retrospective, single center analysis looked at renal allograft recipients treated with mTOR inhibitors and ACE inhibitors over an 8 year-period. Out of 137 patients on concomitant ACE inhibitor and mTOR inhibitor therapy, 9 patients (6.6%) developed angioedema. Concomitant ACE inhibitor and mTOR inhibitor therapy increased the risk of developing angioedema 3.7-fold. Eight of these patients tolerated therapy with an angiotensin receptor blocker (ARB). 2 patients (1.2%) on concomitant mTOR inhibitor and ARB therapy developed angioedema. Treatment with an ACE inhibitor or mTOR inhibitor alone resulted in a significantly lower incidence of angioedema.(1) In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor.(2) There are case reports of patients on concomitant ACE inhibitor and sirolimus/everolimus that developed angioedema. In the majority of cases, patients had tolerated chronic therapy with an ACE inhibitor before the addition of sirolimus/everolimus.(3-7) The interaction may be dose-dependent.(7)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Selected Cyp3a4 Substrates/Ceritinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ceritinib inhibits CYP3A4, and thus may inhibit the metabolism of agents processed by this isoenzyme.(1)

CLINICAL EFFECTS: Concurrent use of ceritinib with drugs primarily metabolized by CYP3A4 may lead to elevated drug levels and increased side effects of these agents. Drugs with a narrow therapeutic window that are metabolized by this isoenzyme include: cyclosporine, felodipine, hydroquinidine, midazolam, nisoldipine, quinidine, and sirolimus.(1,2)

PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP3A4 inhibition. With pimozide, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: Avoid coadministration of sensitive CYP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoidable, dosage adjustment of the CYP3A4 substrate should be considered when initiating or discontinuing ceritinib.(1) Patients maintained on ceritinib may need lower initial doses of the CYP3A4 substrate. Monitor patients receiving concurrent therapy for adverse effects.

DISCUSSION: In a study, ceritinib (750 mg daily for 3 weeks) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam (a CYP3A4 substrate) by 5.4-fold and 1.8-fold, respectively, compared to midazolam alone.(1) Thus, ceritinib is expected to increase levels of cyclosporine, felodipine, hydroquinidine, midazolam, nisoldipine, quinidine, and sirolimus.

Selected Cyp3a4 Substrates/Lonafarnib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lonafarnib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme. Lonafarnib is also an inhibitor of P-glycoprotein (P-gp) and may increase the absorption of sirolimus.

CLINICAL EFFECTS: Concurrent use of lonafarnib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway or P-gp.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lonafarnib states that coadministration of CYP3A4 substrates should be avoided. If concomitant use is unavoidable, monitor for adverse effects and consider dose reduction of the CYP3A4 substrate according to its prescribing information.(1) The manufacturer of lonafarnib states that the dose of P-gp substrates may need to be reduced with coadministration with lonafarnib.(1)

DISCUSSION: In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam (3 mg) by 639% and 180%, respectively.(1) In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the AUC and Cmax of single-dose fexofenadine (180 mg) by 24% and 21%, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: bromocriptine, cabergoline, cannabidiol-tetrahydrocannabinol, clonazepam, darolutamide, felodipine, mefloquine, nisoldipine, oliceridine, regorafenib, sirolimus, and zanubrutinib.(1-3)

Selected Cyp3a4 Substrates/Mitapivat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Mitapivat is a moderate inducer of CYP3A4 and may increase the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of mitapivat may lead to decreased serum levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: When mitapivat is used for the treatment of hemolytic anemia in patients with pyruvate kinase deficiency, the US manufacturer of mitapivat states that co-administration of CYP3A4 substrates for which minimal concentration decreases may lead to serious therapeutic failure should be monitored for loss of efficacy. If concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in accordance with approved product labeling.(1) When mitapivat is used for the treatment of anemia in patients with alpha- or beta-thalassemia, the US manufacturer of mitapivat states that coadministration of sensitive CYP3A4 substrates with narrow therapeutic indices should be avoided.(2) The Middle Weatern manufacturer of mitapivat states that alternative agents should be considered or the coadministered CYP3A4 substrate should be monitored for loss of efficacy.(3)

DISCUSSION: In a clinical study, coadministration of mitapivat 5 mg twice daily with midazolam, a sensitive CYP3A4 substrate, decreased midazolam area-under-curve (AUC) and maximum concentration (Cmax) by 21% and 19%, respectively. Midazolam AUC and Cmax were decreased by 43% and 39%, respectively with mitapivat 20 mg twice daily by 57% and 32%, respectively with mitapivat 50 mg twice daily, and by 65% and 59%, respectively with mitapivat 100 mg twice daily.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.(4-9)

Selected Cyp3a4 Substrates/Mobocertinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Mobocertinib is a weak inducer of CYP3A4 and may increase the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of mobocertinib may lead to decreased serum levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of mobocertinib states that co-administration of CYP3A4 substrates for which minimal concentration decreases may lead to serious therapeutic failure should be avoided. If concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in accordance with approved product labeling.(1)

DISCUSSION: In a clinical study, coadministration of mobocertinib 160 mg once daily with oral or intravenous midazolam, a sensitive CYP3A4 substrate, decreased midazolam area-under-curve (AUC) by 32% and 16%, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: everolimus and sirolimus.(2-4)

Selected Cyp3a4 Substrates/Pexidartinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Pexidartinib is a moderate inducer of CYP3A4 and may increase the metabolism of drugs metabolized by the CYP3A4 enzyme.

CLINICAL EFFECTS: Concurrent use of pexidartinib may lead to decreased serum levels and effectiveness of drugs metabolized by the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pexidartinib states that co-administration of CYP3A4 substrates for which minimal concentration decreases may lead to serious therapeutic failure should be avoided. If concomitant use is unavoidable, increase the dose of the CYP3A4 substrate in accordance with approved product labeling.(1)

DISCUSSION: Coadministration of pexidartinib 400 mg twice daily with oral midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: everolimus, felodipine, fentanyl, hydroquinidine, midazolam, nisoldipine, quinidine, sirolimus, tacrolimus, ticagrelor, and triazolam.(1-3)

Selected Immunosuppressants/Chloramphenicol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism by which chloramphenicol increases the levels of cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus is unknown. Postulated mechanisms include chloramphenicol inhibition of the CYP3A4 metabolism of the immunosuppressive agents, or chloramphenicol inhibition of efflux transporters (e.g., p-glycoprotein).(1-3)

CLINICAL EFFECTS: Concurrent administration of chloramphenicol may result in elevated levels of and toxicity from cyclosporine, everolimus, sirolimus, tacrolimus, or temsirolimus.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The American Society of Transplantation guidelines recommend lowering the dose of cyclosporine or tacrolimus by 25% and close monitoring of immunosuppressive levels.(1) Although there are no specific recommendations for everolimus or sirolimus, it is expected that a similar interaction would occur and that management would be similar. The US manufacturer of tacrolimus states that coadministration with chloramphenicol may result in a rapid and sharp rise in tacrolimus concentration despite immediate tacrolimus dose reduction. Frequent monitoring of tacrolimus levels should start within 1-3 days of initiation of concurrent therapy and continue as necessary.(2)

DISCUSSION: A retrospective study of 6 kidney transplant patients (3 on cyclosporine and 3 on tacrolimus) who were given chloramphenicol found that cyclosporine troughs increased by a mean of 41.3 %, and tacrolimus troughs increased by a mean of 207 %, compared to levels prior to starting chloramphenicol.(3) Case reports have described highly variable effects of chloramphenicol on drug concentrations of immunosuppressants. One case of an interaction with cyclosporine described an increase in cyclosporine concentrations of 186 %, whereas another case described an increase of 300-850 %, but interpretation of this effect is complicated by the patient's therapy with rifampin just prior to chloramphenicol.(3,4) In other case reports, tacrolimus AUC increased 7.5-fold in one patient,(5) tacrolimus trough increased 5-fold in another patient who received an overdose of chloramphenicol,(6) and tacrolimus trough increased 3-fold in a third patient.(7)

Selected Immunosuppressants/Idelalisib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Idelalisib increases plasma levels of cyclosporine, sirolimus, and temsirolimus by inhibition on CYP3A4.(1-3)

CLINICAL EFFECTS: Concurrent idelalisib may result in elevated levels of and toxicity from cyclosporine, sirolimus, and temsirolimus.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Cyclosporine, sirolimus, or temsirolimus levels and renal function should be monitored if idelalisib is initiated or discontinued from concurrent therapy. The dosage of cyclosporine, sirolimus, or temsirolimus may need to be adjusted. The US manufacturer of sirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as idelalisib by avoided. Alternative agents with lesser interaction potential with sirolimus should be considered.(2) The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as idelalisib be avoided. If concurrent use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should be considered. If idelalisib is discontinued, a washout period of 1 week should be allowed before adjusting the dosage of temsirolimus to previous levels.(3)

DISCUSSION: Multiple-dose ketoconazole, another inhibitor of CYP3A4, administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of sirolimus oral solution, as reflected by increases in sirolimus concentration maximum (Cmax), time maximum (tmax), and area-under-curve (AUC) of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminal half-life of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations.(2) Concurrent administration of ketoconazole, another inhibitor of CYP3A4, had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is expected to adjust levels to the range observed without inhibitors; however, there are no data available with this dose adjustment.(3)

Selected Immunosuppressants/Levoketoconazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The metabolism of cyclosporine, sirolimus, and temsirolimus by CYP3A4 may be inhibited by levoketoconazole.

CLINICAL EFFECTS: Concurrent administration of levoketoconazole may result in elevated levels of and toxicity from cyclosporine, sirolimus, or temsirolimus.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Cyclosporine, sirolimus, or temsirolimus levels and renal function should be monitored if levoketoconazole is initiated or discontinued from concurrent therapy. The dosage of cyclosporine, sirolimus, or temsirolimus may need to be adjusted. The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as levoketoconazole be avoided. If concurrent use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should be considered. If levoketoconazole is discontinued, a washout period of 1 week should be allowed before adjusting the dosage of temsirolimus to previous levels. The US manufacturer of sirolimus protein-bound injection (Fyarro) states concurrent use with strong CYP3A4 inhibitors should be avoided. The US manufacturer of levoketoconazole states concurrent use with sensitive CYP3A4 substrates should be avoided.

DISCUSSION: Ketoconazole has been reported to increase cyclosporine concentrations . Exercise caution when stopping levoketoconazole as cyclosporine concentration may decrease. In a multiple-dose study, concomitant administration of ketoconazole with sirolimus oral solution increased the sirolimus Cmax, time to Cmax (Tmax), and AUC by 4.3-fold, 38%, and 10.9-fold, respectively. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations. In a study in 6 patients, ketoconazole was successfully used to augment sirolimus levels. Patients were able to receive one-eight to one-fourth (0.25 - 0.50 mg daily) of the usual sirolimus dose while taking 100 to 200 mg of ketoconazole daily. Concurrent administration of ketoconazole had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is expected to adjust levels to the range observed without inhibitors; however, there are no data available with this dose adjustment.

Selected Immunosuppressants/Nsaids; Salicylates

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cyclosporine increases the production of prostaglandin E2 and I2. Prostaglandin E2 has been shown to prevent cyclosporine -induced renal toxicity in animals. NSAIDS and salicylates may increase cyclosporine-induced renal toxicity by blocking the formation of prostaglandins. Concurrent use of everolimus, sirolimus or tacrolimus with NSAIDs or salicylates may result in additive nephrotoxicity.

CLINICAL EFFECTS: Concurrent administration of cyclosporine, everolimus, sirolimus, or tacrolimus and a NSAID or salicylate may result in a decrease in renal function, with or without an alteration in immunosuppressant levels.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid the concurrent use of NSAIDs or salicylates in patients maintained on cyclosporine, everolimus, sirolimus, or tacrolimus. If concurrent therapy is warranted, patients should be monitored for a decrease in renal function. The NSAID or salicylate may need to be discontinued.

DISCUSSION: A decrease in renal function has been reported with concurrent cyclosporine and diclofenac, sulindac, mefenamic acid, ketoprofen, piroxicam, and naproxen. Decreasing the cyclosporine dose without discontinuing the NSAID does not appear to improve renal function. The use of agents which decrease renal function concurrently with everolimus, sirolimus or tacrolimus should be approached with caution. An observational study of 63 inpatient encounters for 57 transplant patients evaluated concurrent use between calcineurin inhibitor (CNI) therapy and NSAID use. Patients were matched to 126 transplant patients on CNI therapy without NSAID use. Patients who received at least one dose of NSAID had a 12.2% rate of treatment emergent acute kidney injury (AKI). The relative risk ratio for AKI in patient exposed to NSAID therapy was 2.20 (95% CI 0.74-6.54). An increase in 48 hour post NSAID exposure serum creatinine above baseline was documented in 65.9% of patients compared to 46% in the non NSAID group (p=0.016). Multivariate analysis revealed changes in serum creatinine at 48 hours after admission were independently associated with age (p=0.008) and NSAID use (p=0.026).(12)

Selected Immunosuppressants/Selected Azole Antifungal Agents

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The metabolism of cyclosporine, sirolimus, and temsirolimus by CYP3A4 may be inhibited by clotrimazole, isavuconazonium, itraconazole, and ketoconazole.

CLINICAL EFFECTS: Concurrent administration of an azole antifungal may result in elevated levels of and toxicity from cyclosporine, sirolimus, or temsirolimus.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Cyclosporine, sirolimus, or temsirolimus levels and renal function should be monitored if an azole antifungal is initiated or discontinued from concurrent therapy. The dosage of cyclosporine, sirolimus, or temsirolimus may need to be adjusted. Guidelines from the American Society of Transplantation recommend avoiding concurrent use of cyclosporine with itraconazole or ketoconazole. If the combination must be used, lower the dose of the immunosuppressant by at least 50 % and monitor levels closely.(42) The American Society of Transplantation guidelines state that concurrent use of sirolimus is contraindicated with ketoconazole and is not recommended with itraconazole.(42) The manufacturer of sirolimus states that the concurrent use of itraconazole or ketoconazole is not recommended and should be avoided,(25) while the US manufacturer of itraconazole states that concurrent therapy with sirolimus or temsirolimus (IV) is not recommended during and two weeks after itraconazole treatment.(41) The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as itraconazole or ketoconazole be avoided. If concurrent use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should be considered. If the azole is discontinued, a washout period of 1 week should be allowed before adjusting the dosage of temsirolimus to previous levels.(27) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(44)

DISCUSSION: Clotrimazole, fluconazole, itraconazole and ketoconazole have been reported to increase cyclosporine concentrations although the documentation is most supportive of the interaction with ketoconazole. Exercise caution when stopping the antifungal agent as cyclosporine concentration may decrease. Concurrent isavuconazonium increased the area-under-curve (AUC) of cyclosporine (300 mg) by approximately 1.3-fold. There have been several case reports of increased sirolimus levels with concurrent fluconazole and itraconazole therapy and decreased levels of sirolimus after discontinuation of itraconazole. Concurrent isavuconazonium increased the maximum concentration (Cmax) and AUC of sirolimus (2 mg) by approximately 1.6-fold and 1.8-fold, respectively. In a multiple-dose study, concomitant administration of ketoconazole with sirolimus oral solution increased the sirolimus Cmax, time to Cmax (Tmax), and AUC by 4.3-fold, 38%, and 10.9-fold, respectively. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations. In a study in 6 patients, ketoconazole was successfully used to augment sirolimus levels. Patients were able to receive one-eight to one-fourth (0.25 - 0.50 mg daily) of the usual sirolimus dose while taking 100 to 200 mg of ketoconazole daily. Concurrent administration of ketoconazole had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is expected to adjust levels to the range observed without inhibitors; however, there are no data available with this dose adjustment.

Selected Immunosuppressants/Selected Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of cyclosporine, everolimus, sirolimus and temsirolimus.(1-5)

CLINICAL EFFECTS: Concurrent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of cyclosporine, everolimus, sirolimus and temsirolimus.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: If possible, consider alternatives to strong CYP3A4 inducers in patients maintained on cyclosporine and sirolimus. If concurrent therapy is warranted, monitor cyclosporine and sirolimus serum levels and observe the patient for graft rejection. The dosage of cyclosporine and sirolimus may need to be adjusted following the initiation or discontinuation of these agents. The US manufacturer of everolimus states that concurrent use with strong CYP3A4 inducers should be avoided. If concurrent use is warranted, consider increasing the dose of everolimus. In patients with advanced hormone receptor-positive, HER2-negative breast cancer (HR+BC); advanced pancreatic neuroendocrine tumors (PNET); or advanced renal cell carcinoma; or renal angiomyolipoma with TSC, double the daily dose of everolimus using 5 mg increments or less. If the inducer is discontinued, return the dose to that used prior to inducer therapy once the inducer has been stopped for 5 days. In patients with subependymal giant cell astrocytoma with TSC, double the dose of everolimus using 5 mg increments or less. Subsequent dosing should be individualized based on therapeutic drug monitoring. If the inducer is discontinued, return the dose of everolimus to the dose used prior to the inducer once the inducer has been stopped for 5 days, and assess everolimus trough levels 2 weeks later.(1) The US manufacturer of temsirolimus states that concurrent use of strong inducers of CYP3A4, such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, or rifampin should be avoided. If concurrent therapy is warranted, consider increasing the dosage of temsirolimus from 25 mg/week to 50 mg/week. If the inducer is discontinued, the dosage of temsirolimus should be returned to the previous dose.(2) If possible, consider alternatives to strong CYP3A4 inducers in patients maintained on cyclosporine and sirolimus. If concurrent therapy is warranted, monitor cyclosporine and sirolimus serum levels and observe the patient for graft rejection. The dosage of cyclosporine and sirolimus may need to be adjusted following the initiation or discontinuation of these agents.

DISCUSSION: Encorafenib and ivosidenib are strong CYP3A4 inducers. Other strong CYP3A4 inducers have been documented to decrease exposure to cyclosporine, everolimus, sirolimus, and temsirolimus. In a study in 10 lung transplant patients, significantly higher doses of cyclosporine were required during nafcillin therapy to maintain therapeutic trough levels. Patients also developed higher serum creatinine levels and more renal dysfunction than patients not receiving nafcillin. In a case report, a patient experienced 70% and 85% drops in cyclosporine levels during two separate courses of nafcillin therapy. Trough cyclosporine concentrations have been found to decrease within 48 hours after starting phenytoin even when the dose of cyclosporine is increased. Conversely, cyclosporine concentrations may increase when the hydantoin is discontinued. The effect of the hydantoin on cyclosporine may reverse over a period of one to three weeks after stopping the hydantoin. Concurrent administration of cyclosporine and rifampin has been associated with lowering of cyclosporine to undetectable serum levels. Decreases in cyclosporine levels have been observed within 2 days of concomitant therapy but will probably not be maximal for 1 week. The effects of the interaction may persist for up to 3 weeks after rifampin is stopped. In an open-label study in 11 renal transplant patients, subjects received St. John's wort (600 mg daily) for 14 days in addition to their normal cyclosporine regimen. After 14 days of St. John's wort, dose-corrected cyclosporine area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) decreased by 46%, 42%, and 41%, respectively. Mean cyclosporine dose increased from 2.7 mg/kg/day at 4.2 mg/kg/day at the end of the study. Subjects required their first cyclosporine dosage adjustment at Day 3. There are several case reports of decreased cyclosporine with concurrent carbamazepine, phenobarbital, and St. John's wort. In healthy subjects, concurrent use of rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58%, respectively. Increasing the dosage of everolimus to 20 mg daily in patients taking a strong inducer of CYP3A4 is expected to increase the AUC of everolimus to levels seen without a concurrent inducer; however, there are no clinical data available with this dosage in patients receiving strong CYP3A4 inducers. In an open-label clinical trial, 10 male patients received ridaforolimus (40 mg daily, days 1 and 14) and rifampin (600 mg daily, days 1-21). Administration of rifampin resulted in a reduction in the mean whole-blood concentration of ridaforolimus (AUC-GMR 0.57, Cmax- GMR 0.66). The mean whole-blood concentration of ridaforolimus increased 1.5-fold following ketoconazole administration. In a study in 14 healthy subjects, pretreatment with rifampin (600 mg daily for 14 days) decreased the AUC and Cmax of a single dose of sirolimus (20 mg) by 82% and 71%, respectively. The oral clearance of sirolimus increased by 5.5-fold. There are case report of decreased sirolimus levels with concurrent phenytoin and rifampin. Concurrent rifampin had no significant effects on the AUC or Cmax of temsirolimus; however, sirolimus AUC and Cmax decreased by 56% and 65%, respectively. A dosage adjustment to 50 mg/week of temsirolimus in the presence of strong CYP3A4 inducers is predicted to adjust levels to those seen without inducers; however, there are no clinical data in patients using this dose. There is a case report of decreased temsirolimus effectiveness with concurrent rifampin.

Selected Immunosuppressants/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inducers of CYP3A4 may increase the metabolism of cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.(1)

CLINICAL EFFECTS: Concurrent use of strong inducers of CYP3A4 may result in decreased levels and effectiveness of cyclosporine, everolimus, sirolimus, tacrolimus, and temsirolimus.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The American Society of Transplantation guidelines state that cyclosporine and tacrolimus should be avoided in combination with rifabutin and rifampin. Everolimus should be avoided in combination with rifampin and is contraindicated with rifabutin. Sirolimus is contraindicated with rifabutin and rifampin. If concurrent therapy of cyclosporine, everolimus, sirolimus, or tacrolimus with rifampin is needed, increase the dose of the immunosuppressant by 2-fold when the combination is initiated and monitor immunosuppressant concentrations frequently with rapid subsequent dose increases as needed. The reverse is recommended when rifampin is discontinued.(62) The US manufacturer of everolimus states that concurrent use with strong CYP3A4 inducers should be avoided. If concurrent use is warranted, consider increasing the dose of everolimus. In patients with advanced hormone receptor-positive, HER2-negative breast cancer (HR+BC); advanced pancreatic neuroendocrine tumors (PNET); or advanced renal cell carcinoma; or renal angiomyolipoma with TSC, double the daily dose of everolimus using 5 mg increments or less. If the inducer is discontinued, return the dose to that used prior to inducer therapy once the inducer has been stopped for 5 days. In patients with subependymal giant cell astrocytoma with TSC, double the dose of everolimus using 5 mg increments or less. Subsequent dosing should be individualized based on therapeutic drug monitoring. If the inducer is discontinued, return the dose of everolimus to the dose used prior to the inducer once the inducer has been stopped for 5 days, and assess everolimus trough levels 2 weeks later.(1) St. John's wort may decrease everolimus levels unpredictably and should be avoided entirely.(1) The US manufacturer of temsirolimus states that concurrent use of strong inducers of CYP3A4, such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, or rifampin should be avoided. If concurrent therapy is warranted, consider increasing the dosage of temsirolimus from 25 mg/week to 50 mg/week. If the inducer is discontinued, the dosage of temsirolimus should be returned to the previous dose.(2) If possible, consider alternatives to strong CYP3A4 inducers in patients maintained on cyclosporine, sirolimus, and tacrolimus. If concurrent therapy is warranted, monitor cyclosporine, sirolimus, and tacrolimus serum levels and observe the patient for graft rejection. The dosage of cyclosporine, sirolimus, and tacrolimus may need to be adjusted following the initiation or discontinuation of these agents. Strong CYP3A4 inducers linked to this monograph include: allobarbital, amobarbital, apalutamide, aprobarbital, barbexaclone, barbital, brallobarbital, butabarbital, butalbital, butethal, carbamazepine, cyclobarbital, difebarbamate, ethotoin, febarbamate, fosphenytoin, hexobarbital, lumacaftor, mephenytoin, mephobarbital, metharbital, mitotane, natisedine, pentobarbital, phenobarbital, phenytoin, primidone, probarbital, proxibarbal, rifabutin, rifampin, rifapentine, secobarbital, St. John's wort, talbutal, vinbarbital, and vinylbital.

DISCUSSION: In a study in 10 lung transplant patients, significantly higher doses of cyclosporine were required during nafcillin therapy to maintain therapeutic trough levels. Patients also developed higher serum creatinine levels and more renal dysfunction than patients not receiving nafcillin. In a case report, a patient experienced 70% and 85% drops in cyclosporine levels during two separate courses of nafcillin therapy. Trough cyclosporine concentrations have been found to decrease within 48 hours after starting phenytoin even when the dose of cyclosporine is increased. Conversely, cyclosporine concentrations may increase when the hydantoin is discontinued. The effect of the hydantoin on cyclosporine may reverse over a period of one to three weeks after stopping the hydantoin. Concurrent administration of cyclosporine and rifampin has been associated with lowering of cyclosporine to undetectable serum levels. Decreases in cyclosporine levels have been observed within 2 days of concomitant therapy but will probably not be maximal for 1 week. The effects of the interaction may persist for up to 3 weeks after rifampin is stopped. In an open-label study in 11 renal transplant patients, subjects received St. John's wort (600 mg daily) for 14 days in addition to their normal cyclosporine regimen. After 14 days of St. John's wort, dose-corrected cyclosporine area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) decreased by 46%, 42%, and 41%, respectively. Mean cyclosporine dose increased from 2.7 mg/kg/day at 4.2 mg/kg/day at the end of the study. Subjects required their first cyclosporine dosage adjustment at Day 3. There are several case reports of decreased cyclosporine with concurrent carbamazepine, phenobarbital, and St. John's wort. In healthy subjects, concurrent use of rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58%, respectively. Increasing the dosage of everolimus to 20 mg daily in patients taking a strong inducer of CYP3A4 is expected to increase the AUC of everolimus to levels seen without a concurrent inducer; however, there are no clinical data available with this dosage in patients receiving strong CYP3A4 inducers. In an open-label clinical trial, 10 male patients received ridaforolimus (40 mg daily, days 1 and 14) and rifampin (600 mg daily, days 1-21). Administration of rifampin resulted in a reduction in the mean whole-blood concentration of ridaforolimus (AUC-GMR 0.57, Cmax- GMR 0.66). The mean whole-blood concentration of ridaforolimus increased 1.5-fold following ketoconazole administration. In a study in 14 healthy subjects, pretreatment with rifampin (600 mg daily for 14 days) decreased the AUC and Cmax of a single dose of sirolimus (20 mg) by 82% and 71%, respectively. The oral clearance of sirolimus increased by 5.5-fold. There are case report of decreased sirolimus levels with concurrent phenytoin and rifampin. A study in six healthy subjects examined the effects of rifampin on single doses of oral (0.1 mg/kg) and intravenous (0.025 mg/kg/4 hours) tacrolimus. Rifampin increased tacrolimus clearance by 47% and decreased tacrolimus bioavailability by 51%. In a study in 10 healthy subjects, pretreatment with St. John's wort (300 mg 3 times daily for 18 days) decreased the AUC of a single dose of tacrolimus (0.1 mg/kg) by 35.3%. Tacrolimus apparent oral clearance and volume of distribution increased by 68% and 53%, respectively. In a study in 10 renal transplant patients, concurrent St. John's wort (600 mg daily) for 2 weeks increased tacrolimus dose requirements from a baseline of 4.5 mg/day to 8.0 mg/day. Dose-correct tacrolimus AUC decreased by 57.8%. There have been several case reports of decreased tacrolimus levels with concurrent carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's wort. Phenobarbital and phenytoin have been used successfully to treat tacrolimus overdose. Concurrent rifampin had no significant effects on the AUC or Cmax of temsirolimus; however, sirolimus AUC and Cmax decreased by 56% and 65%, respectively. A dosage adjustment to 50 mg/week of temsirolimus in the presence of strong CYP3A4 inducers is predicted to adjust levels to those seen without inducers; however, there are no clinical data in patients using this dose. There is a case report of decreased temsirolimus effectiveness with concurrent rifampin.

Selected Immunosuppressants; Temsirolimus/Saquinavir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Saquinavir may inhibit the metabolism of cyclosporine, sirolimus, and temsirolimus by CYP3A4.(1-2)

CLINICAL EFFECTS: Concurrent use of saquinavir may result in increased levels of cyclosporine, sirolimus, or temsirolimus.(1-2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients concurrently taking cyclosporine, sirolimus, or temsirolimus and saquinavir, therapeutic concentration monitoring of the immunosuppressant is recommended. Depending upon the agents involved, dose decreases of the immunosuppressant agent may be required.(1-2) The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as saquinavir be avoided. If concurrent use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should be considered. If saquinavir is discontinued, an elimination period of 1 week should be allowed before adjusting the dosage of temsirolimus to previous levels.(2) The selected immunosuppressants linked to this monograph include: cyclosporine, sirolimus, and temsirolimus.

DISCUSSION: Concurrent administration of ketoconazole, another inhibitor of CYP3A4, had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is expected to adjust levels to the range observed without inhibitors; however, there are no data available with this dose adjustment.(2) In a study in 3 HIV+ transplant patients who were receiving lopinavir/ritonavir, another strong inhibitor of CYP3A4, cyclosporine doses were reduced to 5-20% of standard doses to prevent toxicity.(3) One case report describes a 52 year-old male with HIV and hepatitis C who experienced severe tacrolimus toxicity after the addition of an HIV regimen including nelfinavir (750 mg three times daily) following his liver transplantation. The HIV regimen was temporarily stopped until the tacrolimus levels normalized at which time the medications were restarted having replaced nelfinavir with saquinavir (400 mg twice/day) and ritonavir (400 mg twice/day). The patient again experienced neurological symptoms associated with tacrolimus toxicity and was found to have a tacrolimus level over 120 ng/ml. The medications were held allowing for a long recovery. The HIV regimen was rechallenged a third time using the original combination which included nelfinavir. The dose of tacrolimus was dramatically decreased and the schedule changed until the tacrolimus levels finally stabilized.(4)

Selected Myelosuppressive Agents/Clozapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)

CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.

PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.

PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)

DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)

Selected Myelosuppressive Agents/Deferiprone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)

CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.

PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)

PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)

DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)

Selected Myelosuppressive Agents/Dipyrone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)

CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)

DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)

Selected Nephrotoxic Agents/Colistimethate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Colistimethate can cause nephrotoxicity.(1,2) Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1) It is suspected that cephalothin interferes with the excretion of colistimethate resulting in enhanced nephrotoxicity.(2,3)

CLINICAL EFFECTS: Concurrent use of colistimethate with other nephrotoxic agents may result in additive nephrotoxic effects.

PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses of colistimethate, longer treatment duration, hypovolemia, and critical illness.

PATIENT MANAGEMENT: Concurrent use of potentially nephrotoxic agents with colistimethate should be avoided.(1,2) If concurrent use is necessary, it should be undertaken with great caution.(1)

DISCUSSION: In a case control study of 42 patients on intravenous colistimethate sodium, NSAIDs were identified as an independent risk factor for nephrotoxicity (OR 40.105, p=0.044).(4) In 4 case reports, patients developed elevated serum creatinine and blood urea nitrogen following concurrent colistimethate and cephalothin (3 patients) or when colistimethate followed cephalothin therapy (1 patient).(3) A literature review found that individual nephrotoxic agents, including aminoglycosides, vancomycin, amphotericin, IV contrast, diuretics, ACE inhibitors, ARBs, NSAIDs, and calcineurin inhibitors, were not consistently associated with additive nephrotoxicity when used with colistimethate. However, when multiple agents (at least 2 additional potential nephrotoxins) were used concurrently, there was a significant correlation to colistimethate nephrotoxicity.(5)

Selected Nephrotoxic Agents/Foscarnet

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Foscarnet is nephrotoxic. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1) Concurrent intravenous pentamidine may also result in hypocalcemia.(1)

CLINICAL EFFECTS: Concurrent use of foscarnet with nephrotoxic agents such as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, non-steroidal anti-inflammatory agents, intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of foscarnet state that concurrent administration of potentially nephrotoxic agents such as acyclovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, tacrolimus, and intravenous pentamidine should be avoided.(1) Other nephrotoxic agents include adefovir, capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, non-steroidal anti-inflammatory agents, streptozocin, tenofovir, vancomycin and voclosporin. If concurrent therapy is warranted, monitor renal function closely. In patients receiving concurrent foscarnet and pentamidine, also monitor serum calcium levels and instruct patients to report severe muscle spasms, mental/mood changes, and/or seizures.(1)

DISCUSSION: The safety of foscarnet has not been studied in patients receiving other known potentially nephrotoxic agents. Renal impairment is the major toxicity of foscarnet.(1)

Selected Nephrotoxic Agents/Inotersen

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inotersen can cause glomerulonephritis and renal toxicity. Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1)

CLINICAL EFFECTS: Concurrent use of inotersen with nephrotoxic agents such as acyclovir, adefovir, intravenous aminoglycosides, amphotericin B, cyclosporine, methotrexate, non-steroidal anti-inflammatory agents, intravenous pentamidine, tacrolimus, tenofovir, vancomycin and voclosporin may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, and streptozocin.

PREDISPOSING FACTORS: Patients with pre-existing renal impairment.

PATIENT MANAGEMENT: The US manufacturer of inotersen state that caution should be used when administered concurrently with potentially nephrotoxic agents or agents that impair renal function.(1) If concurrent therapy is warranted, monitor renal function closely.(1)

DISCUSSION: The safety of inotersen has not been studied in patients receiving other known potentially nephrotoxic agents. Inotersen is only available through a Tegsedi REMS program because of the risk of glomerulonephritis and severe thrombocytopenia.(1)

Selected P-Glycoprotein (P-Gp) Substrates/Lorlatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lorlatinib is an inducer of the P-glycoprotein (P-gp) system. The absorption of P-gp substrates with a narrow therapeutic index may be decreased.(1)

CLINICAL EFFECTS: Concurrent use of lorlatinib with narrow therapeutic index P-gp substrates may result in decreased levels and effectiveness of the substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of lorlatinib states that the concurrent use of narrow therapeutic index P-gp substrates should be avoided. If concurrent therapy cannot be avoided, the dosage of the narrow therapeutic index P-gp substrate should be increased according to the substrate prescribing information.(1)

DISCUSSION: In a study, lorlatinib 100 mg daily for 15 days decreased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose fexofenadine 60 mg (a P-gp substrate) by 67% and 63%, respectively.(1) Selected narrow therapeutic index P-gp substrates include: digoxin, everolimus, pazopanib, sirolimus, and topotecan.(1,2)

Selected P-Glycoprotein (P-Gp) Substrates/Venetoclax

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Venetoclax is an inhibitor of the P-glycoprotein (P-gp) system and may increase the absorption of P-gp substrates.(1)

CLINICAL EFFECTS: Concurrent use of venetoclax with P-gp substrates may result in elevated levels and toxicities of the substrate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of venetoclax states that the concurrent use of P-gp substrates should be avoided. If concurrent therapy cannot be avoided, the P-gp substrate should be taken at least 6 hours before venetoclax.(1) If concurrent therapy with afatinib is unavoidable and not tolerated, the US manufacturer of afatinib states that the afatinib dose should be reduced by 10 mg. Resume the previous dose of afatinib if venetoclax is discontinued.(2) The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant when coadministered with P-gp inhibitors. The initial dose of ubrogepant should not exceed 50 mg. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(8)

DISCUSSION: In vitro data suggests venetoclax is a P-gp inhibitor at therapeutic doses in the gut.(1) Administration of a single venetoclax 100 mg dose with digoxin increased the maximum concentration (Cmax) and area-under-the-curve of digoxin by 35% and 9%, respectively.(1) Selected P-gp substrates linked to this monograph include: afatinib, aliskiren, betrixaban, bilastine, cyclosporine, dabigatran, digoxin, edoxaban, everolimus, loperamide, sirolimus, talazoparib, topotecan, and ubrogepant.(1-9)

Selected Sensitive Cyp3a4 Substrates/Tucatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tucatinib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme. Tucatinib is also an inhibitor of P-glycoprotein (P-gp) and may increase the absorption of sirolimus.

CLINICAL EFFECTS: Concurrent use of tucatinib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway or P-gp.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of tucatinib states that coadministration of CYP3A4 substrates should be avoided. If concomitant use is unavoidable, consider dose reduction of the CYP3A4 substrate.(1) The manufacturer of tucatinib states that the dose of P-gp substrates may need to be reduced with coadministration with tucatinib.(1)

DISCUSSION: In a study, tucatinib increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam (2 mg) by 5.7-fold and 3-fold, respectively.(1) In a study, tucatinib increased the AUC and Cmax of digoxin (0.5 mg single dose) by 1.5-fold and 2.4-fold, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: cyclosporine, midazolam, nisoldipine, and sirolimus.(1-3)

Sensitive Cyp3a4; Cyp2c9; Cyp2c19 Substrates/Enzalutamide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Enzalutamide may induce the metabolism of agents metabolized by CYP3A4, CYP2C9, and CYP2C19.(1)

CLINICAL EFFECTS: Concurrent use of enzalutamide with agents metabolized by CYP3A4, CYP2C9, and CYP2C19 may result in decreased levels and effectiveness of these agents.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent use of agents metabolized by CYP3A4, CYP2C9, or CYP2C19 that have a narrow therapeutic index with enzalutamide. If concurrent use is required, consider increased monitoring of the affected agent.(1) Dosage adjustments may be required.

DISCUSSION: In a clinical trial in healthy subjects, enzalutamide was shown to reduce the area-under-curve (AUC) of midazolam (a sensitive CYP3A4 substrate), warfarin (a sensitive CYP2C9 substrate), and omeprazole (a sensitive CYP2C19 substrate.(1) A case report in a 77-year-old Caucasian male was initiated on 160 mg of enzalutamide after being stable on warfarin with an INR of 3.5. The INR dropped to 1.4 after approximately 20 days on enzalutamide therapy. Due to the drop in INR, the warfarin dose was increased by 50% which lead to a therapeutic INR. When enzalutamide was discontinued, the warfarin dose was decreased by 33% to remain at a therapeutic level. Upon reinitiation, the warfarin dose was increased once by 50% to achieve a therapeutic INR.(2) Sensitive CYP3A4 substrates with narrow therapeutic indexes include: astemizole, cisapride, clarithromycin, cyclosporine, dihydroergotamine, ergonovine, ergotamine, pimozide, sirolimus, tacrolimus, temsirolimus, and terfenadine.(1,3,4) Sensitive CYP2C9 substrates with narrow therapeutic indexes include: warfarin.(1,3) Sensitive CYP2C19 substrates with narrow therapeutic indexes include: S-mephenytoin.(1,3)

Sirolimus/Selected Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: CYP3A4 inhibitors may inhibit the metabolism of sirolimus.(1,2)

CLINICAL EFFECTS: Concurrent use of CYP3A4 inhibitors may result in elevated levels of and toxicity from sirolimus.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Closely monitor for an increase in sirolimus levels and for renal dysfunction during concurrent therapy with CYP3A4 inhibitors, especially at initiation and discontinuation of therapy. Dose adjustment of sirolimus may be necessary.(1,2) The manufacturers of gepotidacin and sevabertinib state that concurrent use of drugs that are extensively metabolized by CYP3A4 and have a narrow therapeutic window like sirolimus should be avoided.(3,4)

DISCUSSION: In a clinical study, coadministration of single-dose midazolam 2 mg (a sensitive CYP3A4 substrate) with gepotidacin (3,000 mg every 12 hours for 2 doses) increased the area-under-curve (AUC) of midazolam by 1.9-fold.(3) Selected CYP3A4 inhibitors linked to this monograph include: camizestrant, gepotidacin, and sevabertinib.

Sirolimus/Selected P-Glycoprotein (P-Gp) Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of sirolimus.(1,2)

CLINICAL EFFECTS: Concurrent administration of a P-gp inhibitor may result in elevated levels and toxicities of sirolimus.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of sirolimus with P-gp inhibitors. If concomitant use cannot be avoided, sirolimus blood levels and the patient's condition should be closely monitored. Sirolimus dosage adjustment may be required.(1,2) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(3)

DISCUSSION: Sirolimus is a known substrate of P-gp. Inhibitors of P-gp may increase toxicity of sirolimus.(1) In a study of 24 healthy volunteers, cyclosporine 300 mg (a CYP3A4 and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose sirolimus 10 mg given simultaneously by 148% and 512%, respectively, compared to sirolimus alone. When sirolimus was given 4 hours after cyclosporine, sirolimus AUC and Cmax both increased by only 33%.(1) In a cross-over study with 33 healthy volunteers, cyclosporine 300 mg increased the AUC and Cmax of sirolimus 5 mg given 2 hours after cyclosporine by 141% and 126%, respectively, compared to sirolimus alone. When sirolimus was given 2 hours before cyclosporine, there was no effect on AUC and Cmax.(1) Inhibitors of P-gp linked to this monograph include: aumolertinib, belumosudil, daraxonrasib, dronedarone, flibanserin, glecaprevir/pibrentasvir, lapatinib, propafenone, quinidine, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, vemurafenib, vepdegestrant, verapamil and vimseltinib.(4,5)

Sirolimus/Sotorasib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sotorasib is a moderate inducer of CYP3A4 and may increase the metabolism of sirolimus.(1,2) Sotorasib is also an inhibitor of the P-glycoprotein (P-gp) system. P-gp substrates with a narrow therapeutic index such as sirolimus may be increased.(1,2)

CLINICAL EFFECTS: Concurrent use of sotorasib may lead to increased or decreased serum levels and effectiveness of sirolimus.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent use with sotorasib and sirolimus.(1) If concurrent use cannot be avoided, use caution and monitor sirolimus serum concentrations. The dose of sirolimus may need to be adjusted.(2)

DISCUSSION: Coadministration of sotorasib with midazolam, a sensitive CYP3A4 substrate, decreased midazolam area-under-curve (AUC) by 53% and maximum concentration (Cmax) by 48%.(1) In a study, sotorasib increased the AUC of digoxin, a P-gp substrate, by 21% and Cmax by 91%.(1)

Sirolimus/Voriconazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Voriconazole may inhibit the metabolism of sirolimus by CYP3A4.(1,2)

CLINICAL EFFECTS: The concurrent administration of sirolimus and voriconazole may result in elevated levels of sirolimus and toxicity.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of voriconazole states that concurrent use of sirolimus is contraindicated.(1) The manufacturer of sirolimus states that concurrent use of voriconazole is not recommended and should be avoided.(2) If concurrent therapy is warranted, sirolimus levels should be closely monitored.(3)

DISCUSSION: In healthy subjects, voriconazole (400 mg every 12 hours Day 1, 200 mg every 12 hours on Days 2-9) increased the maximum concentration (Cmax) and area-under-curve (AUC) of sirolimus (2 mg single dose) by 7-fold and 11-fold, respectively.(1) One set of authors reports 2 case of concurrent sirolimus and voriconazole. Concurrent voriconazole required dosage reductions of 75% to 87.5% in sirolimus dosage.(3) Another set of authors reports 3 cases of concurrent sirolimus and voriconazole. In the first, concurrent voriconazole increased sirolimus AUC by 4.5-fold. In the second, concurrent voriconazole increased sirolimus trough concentrations (Cmin) by 1.5-fold, despite a 75% reduction in sirolimus dose. In the third report, voriconazole increased sirolimus Cmin by 45% and the dose of sirolimus was decreased by two-thirds. Following the discontinuation of voriconazole, sirolimus levels were undetectable.(4) A study in 67 allogenic hematopoetic stem-cell transplant patients were coadministered voriconazole prophylaxis in combination with sirolimus. Concurrent voriconazole prompted an empiric dose reduction of sirolimus of 90% and all patients received concurrent therapy. Median sirolimus trough levels before and at steady state of coadministration with voriconazole were 5.8 ng/mL and 6.1 ng/mL, respectively (p=0.45).(5)

Sirolimus; Temsirolimus/Tacrolimus

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Temsirolimus is a pro-drug of sirolimus.(1)

CLINICAL EFFECTS: Concurrent use of sirolimus may result in decreased tacrolimus levels,(2,3) as well as an increased risk of wound healing complications, renal function impairment, and insulin dependent post transplant diabetes.(2) Sirolimus may increase the risk of calcineurin-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy.(4) Concurrent use of sirolimus and tacrolimus in liver transplant patients may result in hepatic artery thrombosis (HAT), graft loss, and death.(4,5) Most cases of HAT occurred within 30 days of transplantation and most lead to graft loss or death.(4) Concurrent use of sirolimus and tacrolimus in lung transplant patients may result in fatal bronchial anastomotic dehiscence.(4)

PREDISPOSING FACTORS: Adverse hepatic effects were noted in liver transplant patients. Adverse renal effects were noted in renal transplant patients and heart transplant patients.

PATIENT MANAGEMENT: The US manufacturer of tacrolimus states that concurrent use with sirolimus is not recommended.(2) It may be prudent to avoid concurrent use of sirolimus and tacrolimus in liver and lung transplant patients. If concurrent use is warranted, monitor patients and tacrolimus levels closely. The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(6) Since temsirolimus is converted to sirolimus,(1) it would be prudent to follow this advice with concurrent temsirolimus and tacrolimus.

DISCUSSION: Two transplant centers have reported cases of bronchial anastomotic dehiscence, including fatal cases, in lung transplant patients treated with a combination of sirolimus and tacrolimus. In one center, four out of 15 patients developed bronchia anastomotic dehiscence, three of these four patients died. The second center reported two cases of bronchial anastomotic dehiscence, one of these patients died.(4) In two studies of liver transplant patients, concurrent sirolimus and tacrolimus was associated with an increase in hepatic artery thrombosis, graft loss, and excess mortality.(4,5) In a study in de novo liver transplant patients, concurrent use of sirolimus and tacrolimus resulted in excess mortality and graft loss (22% with combination therapy versus 9% with tacrolimus alone). Many of these patients had evidence of infection at or near death. In this study and another study, concurrent sirolimus and tacrolimus was associated with an increase in HAT (7% with combination therapy versus 2% in the control arm).(4) In renal transplant patients, coadministration of tacrolimus and sirolimus (2 or 5 mg daily) resulted in decreases in tacrolimus area-under-curve (AUC) and trough concentration (Cmin) by 30%. Tacrolimus AUC and Cmin decreased 3% and 11%, respectively, following concurrent sirolimus at 1 mg daily.(2) In a study in eight pediatric renal transplant patients, the addition of sirolimus increased tacrolimus dosage requirements by 71.2%.(3) Concurrent use in heart transplant patients was associated with renal function impairment, wound healing complications, and insulin depended post transplant diabetes.(2) Temsirolimus is a pro-drug of sirolimus.(1)

Slt Immunosuppressants;Temsirolimus/Protease Inh;Cobicistat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: HIV and HCV protease inhibitors as well as cobicistat may inhibit the metabolism of cyclosporine, sirolimus, and temsirolimus by CYP3A4.(1-15)

CLINICAL EFFECTS: Concurrent use of HIV or HCV protease inhibitors as well as cobicistat may result in increased levels of cyclosporine, sirolimus, or temsirolimus.(1-15)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients concurrently taking cyclosporine, sirolimus, or temsirolimus and either a HIV or HCV protease inhibitor or cobicistat, therapeutic concentration monitoring of the immunosuppressant is recommended. Depending upon the agents involved, dose decreases of the immunosuppressant agent may be required.(1-15) Guidelines from the American Society of Transplantation recommend avoiding the use of ritonavir- or cobicistat-based HIV or HCV antiviral regimens with cyclosporine or sirolimus due to an increased risk of graft loss and death, as well as the availability of HIV integrase inhibitors that avoid interactions with immunosuppressants. If the combination must be used, lower the dose of cyclosporine to 25-50 mg daily or sirolimus to 1 mg once or twice weekly. Monitor drug concentrations closely.(1) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(16) The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors such as protease inhibitors be avoided. If concurrent use is warranted, a dosage reduction to 12.5 mg/week of temsirolimus should be considered. If the protease inhibitor is discontinued, a washout period of 1 week should be allowed before adjusting the dosage of temsirolimus to previous levels.(2) The selected immunosuppressants linked to this monograph include: cyclosporine, sirolimus, and temsirolimus. The protease inhibitors linked to this monograph include: amprenavir, atazanavir, boceprevir, cobicistat, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, telaprevir, and tipranavir.

DISCUSSION: A retrospective study of 42 HIV+ kidney transplant recipients examined rejection rates in patients on ritonavir-boosted protease inhibitor (PI) antiretroviral regimens compared to patients on other antiretroviral regimens. Immunosuppression therapy consisted of cyclosporine in 7 patients (17%) and tacrolimus in 32 patients (76%). The remaining 3 patients were transitioning between drugs. Over 3 years, 65% of patients on PI-based antiretroviral therapy experienced rejection, compared with 36% of patients on other antiretroviral therapies (p<0.001). There was no difference in patient or graft survival at 3 years.(17) Cyclosporine: Boceprevir (800 mg TID for 7 days) increased the Cmax and AUC of cyclosporine (100 mg single dose) by 2-fold and 2.68-fold, respectively. Boceprevir AUC increased 16%.(4) In a case report, cyclosporine dosage requirements decreased 12-fold following the addition of amprenavir/ritonavir. In another patient, cyclosporine dosage requirements decreased 3.5-fold following the addition of fosamprenavir.(18) In a study in 3 HIV+ transplant patients who were receiving lopinavir/ ritonavir, cyclosporine doses were reduced to 5-20% of standard doses to prevent toxicity.(19) In a clinical study, 7 HIV+ patients concurrently taking cyclosporine and nelfinavir experienced a 19% increase in time to Cmax (Tmax) and a 2-fold increase in AUC of cyclosporine when nelfinavir was added.(20) In a case report, cyclosporine levels tripled and signs of toxicity developed 3 days after the addition of saquinavir (1200 mg 3 times daily) to cyclosporine (150 mg twice daily). Cyclosporine and saquinavir dosages were decreased to 75 mg twice daily and 600 mg 3 times daily, respectively. Cyclosporine Cmin levels were 90% of those seen with 150 mg twice daily. Saquinavir AUC was 4.3-fold higher than in patients taking saquinavir 600 mg twice daily without cyclosporine and 11.1-fold higher than literature values.(21) In a study in 9 subjects, the concurrent administration of telaprevir (750 mg TID) decreased the Cmax and AUC of a single dose of cyclosporine (10 mg) by 87% and 54%, respectively, when compared to levels achieved with a single 100 mg dose of cyclosporine. Extrapolated to level expected with the 100 mg dose, cyclosporine Cmax and AUC would have increased by 32% and 4.64-fold, respectively.(5) Sirolimus: Boceprevir (800 mg TID for 9 days) increased the Cmax and AUC of sirolimus (2 mg single dose) by 4.84-fold and 8.121-fold, respectively. Boceprevir Cmin increased 21%.(4) In a case report, the pharmacokinetics of a liver transplant patient concurrently taking nelfinavir (250 mg) and sirolimus (2 mg) were compared to the pharmacokinetics in 3 other liver transplant patients that were also taking sirolimus, but not nelfinavir. The maximum concentration (Cmax) was 3.2 times higher, the area-under-curve (AUC) was 1.6 times higher, the half life was prolonged by 60%, and the 0-hr and 24-hour trough levels (Cmin) of sirolimus were 9-fold and 5-fold higher, respectively, in patients concurrently taking nelfinavir and sirolimus.(22) Temsirolimus: Concurrent administration of ketoconazole, another inhibitor of CYP3A4, had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is expected to adjust levels to the range observed without inhibitors; however, there are no data available with this dose adjustment.(3)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Cyclosporine; Sirolimus/Metoclopramide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown but is possibly due to a metoclopramide-induced increase in gastric emptying time leading to an increase in cyclosporine absorption.(1)

CLINICAL EFFECTS: The pharmacological and toxic effects of cyclosporine and sirolimus may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum cyclosporine or sirolimus concentrations and adjust dose as necessary.

DISCUSSION: In a study involving 14 renal transplant patients, a single oral dose of metoclopramide 20 mg produced nearly a 30% increase in cyclosporine bioavailability.(2,3) Similar results were reported in a patient receiving cyclosporine and metoclopramide concurrently.(4) Additional studies with varying dosage schedules of metoclopramide administration are needed to determine the extent of this interaction.

Immunosuppressives; Immunomodulators/Cladribine Oncology Inj

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-4)

CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-4)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US, UK, and Australian prescribing information state: -Caution should be exercised if cladribine injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression.(1-3) The cladribine Canadian prescribing information states: -Proceed carefully in patients with severe bone marrow impairment of any etiology since further suppression of bone marrow function should be anticipated.(4)

DISCUSSION: Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with cladribine injection, especially at high doses.(1-4)

Immunosuppressives; Immunomodulators/Covid-19 Vaccines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Immunosuppressants and immunomodulators may prevent the immune system from properly responding to the COVID-19 vaccine.(1-3)

CLINICAL EFFECTS: Administration of a COVID-19 vaccine with immunosuppressants or immunomodulators may interfere with vaccine-induced immune response and impair the efficacy of the vaccine. However, patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Centers for Disease Control and Prevention (CDC),(1) Infectious Diseases Society of America (IDSA),(2) and the American College of Rheumatology (ACR)(3) have published guidances for COVID-19 vaccination in patients on immunosuppressants. The CDC states that all immunocompromised patients over 6 months of age should receive at least 1 dose of COVID-19 vaccine if eligible. See the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for specific recommendations based on age, vaccination history, and vaccine manufacturer.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(1) IDSA recommends timing COVID-19 vaccination at least 2 weeks before starting or at least 3 months after completing immunosuppressive therapy.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose.(3) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted, though the immune response will likely be blunted. COVID-19 vaccines should not be delayed in patients taking immunosuppressive therapies.(1-2) See below for specific recommendations for certain agents. B-cell depleting agents, including rituximab: The CDC states that the utility of B-cell quantification to guide clinical care is not known and is not recommended. Patients who receive B-cell depleting therapy on a continuing basis should receive COVID-19 vaccines about 4 weeks before the next scheduled dose. For patients who received 1 or more doses of COVID-19 vaccine during treatment with B-cell-depleting therapies that were administered over a limited period (e.g., as part of a treatment regimen for certain malignancies), revaccination may be considered according to the current CDC recommendations for unvaccinated patients. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(1) IDSA recommends waiting for at least 3-6 months after the last infusion of B-cell depleting therapy before administering COVID-19 vaccines.(2) The ACR recommends consulting with the rheumatologist to determine optimal timing of COVID-19 vaccination. Measuring CD19 B cells may be considered to determine need for a booster vaccine dose. If B cell levels are not measured, a supplemental vaccine dose 2-4 weeks before the next scheduled dose of rituximab is recommended.(3) Recipients of hematopoietic cell transplant or CAR-T-cell therapy who received one or more doses of COVID-19 vaccine prior to or during treatment should undergo revaccination following the current CDC recommendations for unvaccinated patients. Revaccination should start at least 3 months (12 weeks) after transplant or CAR-T-cell therapy.(1,2) The CDC includes abatacept, cyclophosphamide, and TNF-alpha and cytokine inhibitors in their general recommendation to hold therapy for at least 2 weeks following vaccination (1) while the ACR provides different recommendations:(3) *Abatacept: - Subcutaneous abatacept should be withheld for 1-2 weeks after each vaccine dose, as disease activity allows. - For intravenous abatacept, time administration so that vaccination will occur 1 week before the next abatacept infusion. *Cyclophosphamide: When feasible, administer cyclophosphamide 1 week after each COVID-19 vaccine dose. *TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to reach consensus on whether to modify dosing or timing of these agents with COVID-19 vaccination.

DISCUSSION: IDSA recommendations are based on cohort and case control studies in immunocompromised patients that found low to modest vaccine effectiveness (37-61%) but lower risks of COVID-19 association hospitalization, COVID-19 related mortality, and critical illness.(2) The ACR convened a COVID-19 Vaccine Guidance Task Force to provide guidance on optimal use of COVID-19 vaccines in rheumatology patients. These recommendations are based on limited clinical evidence of COVID-19 vaccines in patients without rheumatic and musculoskeletal disorders and evidence of other vaccines in this patient population.(3) The ACR recommendation for rituximab is based on studies of humoral immunity following receipt of other vaccines. These studies have uncertain generalizability to vaccination against COVID-19, as it is unknown if efficacy is attributable to induction of host T cells versus B cell (antibody-based) immunity.(3) The ACR recommendation for mycophenolate is based on preexisting data of mycophenolate on non-COVID-19 vaccine immunogenicity. Emerging data suggests that mycophenolate may impair SARS-CoV-2 vaccine response in rheumatic and musculoskeletal disease and transplant patients.(3) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(3) The ACR recommendation for JAK inhibitors is based on concerns related to the effects of JAK inhibitors on interferon signaling that may result in a diminished vaccine response.(3) The ACR recommendation for subcutaneous abatacept is based on several studies suggesting a negative effect of abatacept on vaccine immunogenicity. The first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct. CTLA-4 should not inhibit boosts of already primed T cells at the time of the second vaccine dose.(3)

Immunosuppressives; Immunomodulators/Sarilumab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Sarilumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sarilumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sarilumab recommends caution because the concurrent use of sarilumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)

DISCUSSION: Sarilumab was studied as monotherapy and in combination with methotrexate or conventional disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis studies. Sarilumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by sarilumab treated patients in the clinical trial periods included pneumonia and cellulitis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving sarilumab. Cases of tuberculosis, candidiasis, and pneumocystis with sarilumab have been reported.(1)

Immunosuppressives; Immunomodulators/Tocilizumab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tocilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of tocilizumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of tocilizumab recommends caution because the concurrent use of tocilizumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)

DISCUSSION: Tocilizumab was studied as monotherapy and in combination with methotrexate, non-biologic DMARDs or corticosteroids, depending on the indication. Tocilizumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by tocilizumab treated patients in the clinical trial periods included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving tocilizumab. Cases of tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis have been reported.(1)

Immunosuppressives; Immunomodulators/Ublituximab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ublituximab, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ublituximab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)

PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.

PATIENT MANAGEMENT: The US manufacturer of ublituximab recommends caution because the concurrent use of ublituximab with immunomodulating or immunosuppressive agents, including immunosuppressant doses of corticosteroids, may increase the risk of infection.(1) If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents. When switching from agents with immune effects, the half-life and mechanism of action of these drugs must be taken into consideration in order to prevent additive immunosuppressive effects.(1)

DISCUSSION: The most common infections reported by ublituximab-treated patients in the clinical trial periods included upper respiratory tract infections and urinary tract infections. Serious, including life-threatening or fatal, bacterial and viral infections were observed in patients receiving ublituximab.(1) Serious and/or fatal bacterial, fungal, and new or reactivated viral infections have been associated with other anti-CD20 B-cell depleting therapies. There were no cases of progressive multifocal leukoencephalopathy (PML) reported during the clinical trials; however, there have been reports of PML during or following completion of other anti-CD20 B-cell depleting therapies.(1)

Immunosuppressives; Immunomodulators/Ustekinumab

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ustekinumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of ustekinumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ustekinumab recommends caution because the concurrent use of ustekinumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)

DISCUSSION: Ustekinumab has not been studied in combination with other immunosuppressants in psoriasis studies. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by ustekinumab treated patients in the clinical trial periods included nasopharyngitis(8%) and upper respiratory tract infection(5%). Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab. Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia resulting in respiratory failure or prolonged hospitalization have been reported in patients receiving ustekinumab.(1)

Selected Immunosuppressants/Maribavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The metabolism of cyclosporine, everolimus, sirolimus, tacrolimus and temsirolimus by CYP3A4 may be inhibited by maribavir.

CLINICAL EFFECTS: Concurrent administration of maribavir may result in elevated levels of and toxicity from cyclosporine, everolimus, sirolimus, tacrolimus or temsirolimus.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Cyclosporine, everolimus, sirolimus, tacrolimus or temsirolimus levels and renal function should be monitored frequently during therapy with maribavir. Monitor immunosuppressant levels closely during initiation and after discontinuation of maribavir. The dosage of cyclosporine, everolimus, sirolimus, tacrolimus or temsirolimus may need to be adjusted.

DISCUSSION: In a study in 20 patients, maribavir increased the area-under-curve (AUC), concentration maximum (Cmax), and Ctau of tacrolimus by 51%, 38%, and 57%, respectively. In a multiple-dose study, concomitant administration of ketoconazole with sirolimus oral solution increased the sirolimus Cmax, time to Cmax (Tmax), and AUC by 4.3-fold, 38%, and 10.9-fold, respectively. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations. In a study in 6 patients, ketoconazole was successfully used to augment sirolimus levels. Patients were able to receive one-eight to one-fourth (0.25 - 0.50 mg daily) of the usual sirolimus dose while taking 100 to 200 mg of ketoconazole daily. Concurrent administration of ketoconazole had no effects on temsirolimus AUC or Cmax; however, sirolimus AUC and Cmax increased 3.1-fold and 2.2-fold, respectively. Dosage adjustment of temsirolimus to 12.5 mg/week in the presence of strong CYP3A4 inhibitors is expected to adjust levels to the range observed without inhibitors; however, there are no data available with this dose adjustment.

Selected Immunosuppressants;Temsirolimus/Letermovir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Letermovir may inhibit the metabolism of sirolimus and temsirolimus by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent administration of sirolimus or temsirolimus with letermovir may result in elevated levels of sirolimus or temsirolimus and possible toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Sirolimus and temsirolimus levels should be carefully monitored in patients receiving concurrent therapy with letermovir. The dosage of sirolimus and temsirolimus may need to be adjusted during and/or after letermovir therapy.(1) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(2)

DISCUSSION: In a study of healthy subjects, concurrent administration of letermovir (480 mg once daily) increased sirolimus' (2 mg single dose) area-under-the-curve (AUC), maximum concentration (Cmax), and C24hr by 3.4-fold, 2.76-fold, and 3.15-fold.(1,3)

Selected Immunosuppressive Cyp3a4 Substrates/Cannabidiol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction is not fully understood, but may involve inhibition of CYP3A4 and of the P-glycoprotein transporter by cannabidiol (CBD).(1) Everolimus and sirolimus are substrates of both CYP3A4 and P-gp.(1)

CLINICAL EFFECTS: Concurrent use of CBD may result in increased levels and effects of everolimus and sirolimus.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian manufacturer of the combination of the CBD-THC buccal spray advises caution when it is used concurrently with CYP3A4 substrates.(2) For patients concurrently taking everolimus or sirolimus, therapeutic concentration monitoring of the immunosuppressant is recommended. Depending upon the agents involved, dose decreases of the immunosuppressant agent may be required.(3,4) In patients with advanced hormone receptor-positive, HER-2 negative breast cancer (HR+BC); advanced pancreatic neuroendocrine tumors (PNET); advanced renal cell carcinoma; or renal angiomyolipoma with TSC, decrease the dose of everolimus to 5 mg once daily with concurrent use of cannabidiol oral solution. An increase to 7.5 mg daily may be considered based on patient tolerance. If cannabidiol oral solution is discontinued, allow an elimination period of 3 days before increasing the dose to that used prior to the inhibitor.(7) In patients with subependymal giant astrocytoma with TSC and TSC-associated partial-onset seizures, reduce the dosage of everolimus by 50% to maintain trough concentrations of 5 ng/ml to 15 ng/ml with concurrent use of cannabidiol oral solution. If the patient is already receiving the lowest daily dose, change to every other day dosing. Assess everolimus levels 2 weeks after the addition of the inhibitor. Resume the everolimus dose used prior to initiation of the inhibitor after the inhibitor has been discontinued for 3 days, and assess everolimus trough levels 2 weeks later.(7)

DISCUSSION: Elevation of everolimus levels by cannabinoids has been reported in a retrospective study and a case report. In the retrospective study, everolimus levels in 18 patients with tuberous sclerosis complex (TSC) were examined before and after initiation of CBD for epilepsy. Everolimus levels increased by a median of 9.8 ng/mL. No patients experienced serious adverse events.(3) In the case report, a 6.5-year-old girl who was stable for 3 years on everolimus 0.3 mg/kg/day for TSC was started on CBD for refractory epilepsy. Everolimus levels became unstable, ranging between 1.7 up to 16 mcg/L.(4) In a study with healthy volunteers, cannabidiol (12.5 mg/kg twice daily) increased everolimus AUC and Cmax by 2.5-fold.(5,6) In a retrospective study, sirolimus levels in 7 patients with tuberous sclerosis complex were examined before and after initiation of CBD for epilepsy. Sirolimus levels increased by a median of 5.1 ng/mL. No patients experienced serious adverse events.(3)

Selected Nephrotoxic Agents/Adefovir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Recommended doses of adefovir have been associated with delayed nephrotoxicity.(1-4) Concurrent administration of other nephrotoxic agents may result in additive or synergistic effects on renal function.(1)

CLINICAL EFFECTS: Concurrent use of adefovir with nephrotoxic agents such as intravenous aminoglycosides, amphotericin B, cyclosporine, tacrolimus,tenofovir, vancomycin, voclosporin and non-steroidal anti-inflammatory agents may result in renal toxicity.(1) Other nephrotoxic agents include capreomycin, cisplatin, gallium nitrate, high-dose methotrexate, intravenous pentamidine, and streptozocin.

PREDISPOSING FACTORS: Patients with pre-existing renal impairment(1,2) or receiving multiple nephrotoxic agents appear to be at greater risk for nephrotoxicity.

PATIENT MANAGEMENT: Evaluate renal function prior to initiation of concurrent therapy and continue renal function monitoring during therapy. Dose adjustments may be required for impaired renal function. Weigh the risks and benefits of concurrent therapy in patients with treatment-emergent nephrotoxicity.

DISCUSSION: Because of the known risks for adefovir nephrotoxicity, particularly at higher than recommended doses, the safety of adefovir has not been studied in patients receiving other known potentially nephrotoxic agents.

Selected Nephrotoxic Agents/Cisplatin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The nephrotoxic effects of aminoglycosides or non-steroidal anti-inflammatory drugs (NSAIDs) may be additive to those of cisplatin.

CLINICAL EFFECTS: The concurrent administration of amikacin, gentamicin, tobramycin, or NSAIDs with cisplatin may result in additive nephrotoxic effects.(1,2,5,6)

PREDISPOSING FACTORS: Pre-existing renal insufficiency, advanced age, dehydration may increase the risk of nephrotoxicity.(1,5,6)

PATIENT MANAGEMENT: The US labeling for aminoglycosides and cisplatin states that the concurrent use of aminoglycosides and cisplatin should be avoided.(1,3,4,6) Inform patients that concurrent cisplatin and aminoglycosides or NSAIDs can cause nephrotoxicity and that renal function and electrolyte monitoring during treatment is necessary.(2)

DISCUSSION: The US manufacturers of amikacin, gentamicin and tobramycin state that since the nephrotoxic effects of these medications may be additive, avoid concurrent or sequential use of other neurotoxic and/or nephrotoxic agents including cisplatin.(1,3,6)

Selected Nephrotoxic Agents/Tenofovir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tenofovir and other nephrotoxic agents may result in additive or synergistic effects on renal function and increase nephrotoxicity risk.(1)

CLINICAL EFFECTS: Concurrent use of tenofovir and other nephrotoxic agents may result in renal toxicity and acute renal failure.(1) Reports of acute renal failure and Fanconi syndrome have been reported with tenofovir use.(2,3) However, this has been reported in 3 case reports and the renal failure may have been complicated by other pre-existing conditions.(2)

PREDISPOSING FACTORS: Pre-existing renal dysfunction, long duration of use, low body weight, concomitant use of drugs that may increase tenofovir levels may increase the risk of nephrotoxicity.(1)

PATIENT MANAGEMENT: The US prescribing information for tenofovir recommends avoiding concurrent or recent use of a nephrotoxic agent.(3) Evaluate renal function prior to initiation of concurrent therapy and continue renal function monitoring during therapy. Dose adjustments may be required for impaired renal function. Tenofovir should be avoided with high-dose or multiple NSAIDs. Alternatives to NSAIDs should be considered in patients at risk for renal dysfunction.(3) Patients receiving concurrent NSAIDs with tenofovir should be monitored for possible renal toxicity.(1,2) The dosing interval should be adjusted in patients with a baseline creatinine clearance of less than 50 ml/min.(1-3)

DISCUSSION: From March 18, 2003 to December 1, 2005, Health Canada received 10 reports of nephrotoxic reactions with tenofovir. Three of these occurred following the addition of a NSAID to tenofovir therapy. In the first report, a patient maintained on tenofovir for 29 months developed acute renal failure and acute tubular necrosis requiring dialysis 5 days after beginning indomethacin (100 mg rectally twice daily). In the second report, a patient maintained on tenofovir for 7 months developed acute renal failure and acute tubular necrosis after taking 90 tablets of naproxen (375 mg) over 2 months. The patient died. In the third report, a patient maintained on tenofovir for over a year developed acute renal failure and nephrotic syndrome after 2 months of valdecoxib (20 mg daily) therapy. Symptoms subsided following discontinuation of valdecoxib.(1)

Selected Sensitive Cyp3a4 Substrates/Schisandra

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Schisandra is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)

CLINICAL EFFECTS: Concurrent use of Schisandra may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(3-7)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)

PATIENT MANAGEMENT: If Schisandra must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate and adjust its dose as appropriate.(3-7) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(8)

DISCUSSION: A study in 12 healthy volunteers found that Schisandra led to an increase in midazolam area-under-curve (AUC) and maximum concentration (Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam administered alone.(3) In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by 2.07-fold and 1.96-fold, respectively when given with Schisandra compared to sirolimus administered alone.(4) The effect of Schisandra on tacrolimus has been examined in several small pharmacokinetic studies in healthy volunteers as well as liver and kidney transplant patients. Compared to tacrolimus given alone, tacrolimus AUC when administered with Schisandra was consistently increased by 2.1-fold, while the increase in Cmax varied between 1.83- and 2.11-fold in the transplant studies(5-6) and 3-fold in the study on healthy subjects.(7) In the study with kidney transplant patients, a decrease in tacrolimus dose of 40.9 % was required to bring tacrolimus levels into the therapeutic range.(5)

Sirolimus/Amiodarone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Amiodarone may inhibit the metabolism of sirolimus by CYP3A4.

CLINICAL EFFECTS: Concurrent use of amiodarone may result in elevated levels of and toxicity from sirolimus.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor sirolimus levels and renal function in patients receiving concurrent therapy, especially at the initiation of amiodarone. The dosage of sirolimus may need adjusting. If concurrent amiodarone is discontinued, the dosage of sirolimus may need adjusting. The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(3)

DISCUSSION: There are case reports of sirolimus toxicity with both amiodarone(1) and dronedarone(2).

Sirolimus/Selected P-Glycoprotein (P-Gp) Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of sirolimus.(1)

CLINICAL EFFECTS: Concurrent administration of a P-gp inhibitor may result in elevated levels and toxicities of sirolimus.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use caution during coadministration of P-gp inhibitors with sirolimus. Sirolimus blood levels and the patient's condition should be closely monitored. Sirolimus dosage adjustment may be required.(1)

DISCUSSION: Sirolimus is a known substrate of P-gp. Inhibitors of P-gp may increase toxicity of sirolimus.(1) In a study of 24 healthy volunteers, cyclosporine 300 mg (a CYP3A4 and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose sirolimus 10 mg given simultaneously by 148% and 512%, respectively, compared to sirolimus alone. When sirolimus was given 4 hours after cyclosporine, sirolimus AUC and Cmax both increased by only 33%.(1) In a cross-over study with 33 healthy volunteers, cyclosporine 300 mg increased the AUC and Cmax of sirolimus 5 mg given 2 hours after cyclosporine by 141% and 126%, respectively, compared to sirolimus alone. When sirolimus was given 2 hours before cyclosporine, there was no effect on AUC and Cmax.(1) Inhibitors of P-gp linked to this monograph include: abrocitinib, capmatinib, imlunestrant, and selpercatinib.(2-3)

Sirolimus; Temsirolimus/Cyclosporine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown. Temsirolimus is a pro-drug of sirolimus.(1)

CLINICAL EFFECTS: The concurrent administration of sirolimus and cyclosporine may result in elevated levels of sirolimus and cyclosporine. Elevated levels of sirolimus may be seen as soon as after one concurrent dose. Elevated levels of cyclosporine may take several weeks to develop.(2) Sirolimus may increase the risk of calcineurin-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy.(2) In liver transplant patients, concurrent sirolimus and cyclosporine has been associated with an increase in hepatic artery thrombosis (HAT). Most cases occurred within 30 days post-transplantation and most led to graft loss or death.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of sirolimus recommends that sirolimus be administered four hours after cyclosporine oral solution (MODIFIED) and cyclosporine capsules (MODIFIED).(2) Blood levels of sirolimus and cyclosporine and renal function should be carefully monitored in patients receiving concurrent therapy with these agents. The dosages of one or both both agents may need to be adjusted. The manufacturer of sirolimus recommends that sirolimus not be used in liver transplant patients.(2) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(3) Since temsirolimus is a pro-drug of sirolimus, it would be prudent to monitor cyclosporine levels during concurrent therapy.

DISCUSSION: In a single dose study in 24 healthy subjects, simultaneous administration of sirolimus oral solution (10 mg) and cyclosporine capsules (300 mg, MODIFIED) resulted in increases in the sirolimus maximum concentration (Cmax) and area-under-curve (AUC) by 116% and 230%, respectively. Sirolimus four hours after the administration of cyclosporine capsules (MODIFIED) resulted in increases in sirolimus Cmax and AUC by 37% and 80%, respectively. Cyclosporine Cmax and AUC were initially not significantly affected; however, after multiple doses, the clearance of cyclosporine was decreased and lower doses of cyclosporine were required.(2) In a single dose study in 24 healthy subjects, simultaneous administration of sirolimus tablets (10 mg) and cyclosporine capsules (300 mg) resulted in increases of sirolimus Cmax and AUC by 512% and 148%, respectively. Sirolimus four hours after the administration of cyclosporine capsules resulted in increases of only 33%. (2) In a single dose cross-over study in 33 healthy subjects, sirolimus (5 mg) was administered alone, 2 hours before cyclosporine capsules (300 mg, MODIFIED), and 2 hours after cyclosporine capsules (300 mg, MODIFIED). There was no significant difference in sirolimus Cmax and AUC when administered 2 hours before cyclosporine; however, sirolimus Cmax and AUC increased by 126% and 141%, respectively, when given 2 hours after cyclosporine.(2) The concurrent administration of sirolimus and cyclosporine oral solution resulted in increases in sirolimus trough concentrations by 67%-86%. There was no significant effect on cyclosporine concentrations.(2)

Slt Immunosuppressants/Quinpristin-Dalfoprist; Pristinamycin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The metabolism of immunosuppressants by CYP3A4 may be inhibited by quinupristin-dalfopristin and pristinamycin.

CLINICAL EFFECTS: Concurrent administration of quinupristin-dalfopristin or pristinamycin may result in elevated levels of and toxicity from immunosuppressants.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Immunosuppressant levels and renal function should be monitored if quinupristin-dalfopristin or pristinamycin is initiated or discontinued from concurrent therapy. The dosage of the immunosuppressant may need to be adjusted. The US manufacturer of quinupristin-dalfopristin recommends caution and monitoring with immunosuppressants.(1) The Australian manufacturer of pristinamycin recommends monitoring of immunosuppressants levels, renal function, and adjustment of dose during concomitant use and after discontinuation of the inhibitor.(2) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently moderate or weak CYP3A4 inhibitors.(3)

DISCUSSION: In a study in 24 subjects, concurrent administration of quinupristin-dalfopristin (7.5 mg/kg every 8 hours for 2 days) and cyclosporine (300 mg on Day 3, CYP3A4 substrate) resulted in an increase in cyclosporine's area-under-the-curve (AUC) and maximum concentration (Cmax) of 63% and 30%, respectively. Cyclosporine half-life increased 77% while clearance decreased 34%.(1) Concurrent administration of quinupristin-dalfopristin with nifedipine (repeat oral doses) in healthy volunteers increased the Cmax and AUC by 18% and 44%. Concurrent midazolam (intravenous bolus dose) in healthy volunteers increased the Cmax and AUC by 14% and 33%.(1) In a case report, concurrent administration of cyclosporine and quinupristin-dalfopristin resulted in a 3-fold increase in cyclosporine trough level which was managed by a 33% dose reduction in the cyclosporine dose.(4) There are several other case reports of toxicity and increased cyclosporine trough levels.(7,8) In a case report, concurrent administration of everolimus and pristinamycin resulted in a significant increase in everolimus levels (increased to 33.5 mcg/L on Day 3 of pristinamycin) which was managed by a 25% reduction in the everolimus dose.(5) In a case report, concurrent administration of tacrolimus and pristinamycin resulted in a 5-fold increase in tacrolimus trough level.(6) Immunosuppressants linked to this monograph include sirolimus, everolimus, temsirolimus, and tacrolimus.

*Known hypersensitivity to sirolimus or its derivatives or any ingredient in the sirolimus formulation.

• Bronchial anastomotic dehiscence in lung transplant
• Hepatic artery thrombosis in liver transplant
• Lactation
• Malignancy
• Malignant lymphoma
• Progressive multifocal leukoencephalopathy

• BK polyomavirus reactivation nephropathy
• Disease of liver
• Interstitial lung disease
• Liver transplantation
• Lung transplantation
• Pregnancy

• Ascites
• Cytomegalovirus disease
• Edema
• Hypercholesterolemia
• Hyperlipidemia
• Hypertension
• Hypertriglyceridemia
• Impaired wound healing
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Lymphedema
• Male infertility
• Malignant neoplasm of skin
• Pericardial effusion
• Peripheral edema
• Pleural effusions
• Pneumocystis jirovecii pneumonia
• Proteinuria

Adverse reactions occurring in >=30% of patients receiving sirolimus in clinical trials for prevention of rejection of renal allografts include peripheral edema, hypercholesterolemia, hypertriglyceridemia, hypertension, increased serum creatinine concentrations, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia.

Adverse reactions occurring in >=20% of patients receiving sirolimus in clinical trials for treatment of lymphangioleiomyomatosis include stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia.

More Frequent

• Anemia
• Hypertension
• Hypokalemia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Thrombocytopenic disorder

Less Frequent

• Hemolytic uremic syndrome
• Leukopenia
• Lymphocele
• Pyelonephritis
• Surgical wound dehiscence
• Thrombotic thrombocytopenic purpura

Rare or Very Rare

• Abdominal herniation
• Anaphylaxis
• Angioedema
• Ascites
• BK polyomavirus reactivation nephropathy
• Bronchial anastomotic dehiscence in lung transplant
• Bronchiolitis obliterans
• Chest pain
• Clostridioides difficile infection
• Cytomegalovirus disease
• Deep venous thrombosis
• Diabetes mellitus
• Dyspnea
• Exfoliative dermatitis
• Focal segmental glomerulosclerosis
• Hepatic artery thrombosis in liver transplant
• Hepatic necrosis
• Hepatitis
• Herpes simplex infection
• Herpes zoster
• Hyperkalemia
• Hypersensitivity angiitis
• Hypersensitivity drug reaction
• Hypophosphatemia
• Impaired wound healing
• Increased alanine transaminase
• Increased aspartate transaminase
• Infection
• Infectious mononucleosis
• Interstitial lung disease
• Interstitial pneumonitis
• Malignant lymphoma
• Malignant melanoma
• Mycobacteriosis
• Nephrotic syndrome
• Neutropenic disorder
• Pancreatitis
• Pancytopenia
• Pericardial effusion
• Pleural effusions
• Pneumocystis jirovecii pneumonia
• Pneumonia
• Post-transplant lymphoproliferative disease
• Posterior reversible encephalopathy syndrome
• Progressive multifocal leukoencephalopathy
• Pulmonary fibrosis
• Pulmonary hemorrhage
• Pulmonary hypertension
• Pulmonary thromboembolism
• Sepsis
• Squamous cell carcinoma
• Thromboembolic disorder
• Viral infection

More Frequent

• Acne vulgaris
• Acute abdominal pain
• Arthralgia
• Constipation
• Diarrhea
• Dizziness
• Edema
• Fever
• Headache disorder
• Hypercholesterolemia
• Hypertriglyceridemia
• Myalgia
• Nausea
• Pain
• Peripheral edema
• Skin rash
• Upper respiratory infection
• Urinary tract infection

Less Frequent

• Avascular necrosis of bone
• Epistaxis
• Menstrual disorder
• Ovarian cyst
• Stomatitis

Rare or Very Rare

• Azoospermia
• Basal cell carcinoma of skin
• Lymphedema
• Merkel cell carcinoma
• Oligospermia
• Proteinuria
• Tachycardia

No enhanced messaging available.

Safety and efficacy of sirolimus have not been established in pediatric patients <13 years of age for prophylaxis of organ rejection in renal transplantation.

Safety and efficacy of sirolimus have been established in pediatric and adolescent renal transplant patients >=13 years of age judged to be at low to moderate immunologic risk. Use of sirolimus in this subpopulation of pediatric patients is supported by evidence from adequate and well-controlled trials of sirolimus in adults with additional pharmacokinetic data in pediatric renal transplant patients.

Safety and efficacy data from a controlled, multicenter clinical trial of 36 months' duration in pediatric and adolescent renal transplant patients <18 years of age judged to be at high immunologic risk (i.e., history of one or more acute rejection episodes and/or presence of chronic allograft nephropathy) did not support the chronic use of sirolimus in combination with calcineurin inhibitors and corticosteroids because of the higher incidence of lipid abnormalities and deterioration of renal function and the lack of a demonstrated therapeutic benefit compared with a calcineurin inhibitor-based regimen.

Safety and efficacy of sirolimus in pediatric patients <18 years of age have not been established for the treatment of lymphangioleiomyomatosis.

Sirolimus can cause fetal harm when administered to a pregnant woman based on animal studies and the drug's mechanism of action. There are limited data on the use of sirolimus during pregnancy to inform a drug-associated risk of adverse developmental outcomes. Animal studies showed that the drug was embryotoxic and fetotoxic at subtherapeutic doses. Advise pregnant females of the potential risk to a fetus.

The National Transplantation Pregnancy Registry (NTPR) is a pregnancy registry for pregnant women receiving immunosuppressants following any solid organ transplantation; the NTPR encourages reporting of all immunosuppressant exposures during pregnancy in transplant patients by telephone at 877-955-6877 or via their website: https://www.transplantpregnancyregistry.org/.

Sirolimus is distributed into milk in trace amounts in rats; it is not known whether the drug is distributed into milk in humans. It is not known whether sirolimus has any effects on the breastfed infant or on milk production. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for sirolimus and any potential adverse effects on the breastfed infant from the drug.

The manufacturer states that routine dosage adjustment in geriatric patients receiving sirolimus is not necessary; however, dosage selection in geriatric patients should be cautious, usually starting at the lower end of the dosage range, reflecting the greater frequency of decreased hepatic or cardiac function and of concomitant diseases or other drug therapy in this population.

Clinical studies of sirolimus did not include a sufficient number of patients >=65 years of age to determine whether they respond differently than younger patients. Differences in responses between geriatric patients and younger patients have not been identified. Following administration of sirolimus oral solution or tablets, sirolimus trough concentrations in renal transplant patients >65 years of age were similar to those observed in adults 18-65 years of age. These data suggest that dosage adjustments based solely on age are not necessary in geriatric renal transplant patients. The manufacturer states that dosage selection in geriatric patients should generally be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic or cardiac function and of concomitant disease or other drug therapy.