Temsirolimus (temsirolimus)
Antineoplastic - mTOR Kinase Inhibitors Intravenous Vial (ML)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) kinase, is an antineoplastic agent.
Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) kinase, is an antineoplastic agent. Receptor tyrosine kinases (RTKs) are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (e.g., angiogenesis, metastasis), inhibition of apoptosis. Temsirolimus binds with high affinity to the intracellular protein FK506 binding protein-12 in vitro, forming a drug-protein complex that inhibits the activation of mTOR, which regulates cell division.
This disruption of mTOR signaling suppresses proteins that regulate cell-cycle progression, thereby blocking cells in the G1 phase of the cell cycle. Inhibition of mTOR by temsirolimus also has been associated with reduced expression of hypoxia inducible factor 1alpha and 2alpha (HIF-1alpha and HIF-2alpha) in vitro, resulting in reduced expression of vascular endothelial growth factor (VEGF) and a potential antiangiogenic effect.
Temsirolimus inhibited T lymphocyte activity in mice, but the effects were reversible and T lymphocyte activity returned to normal within 24 hours of discontinuance. No consistent effect on lymphocyte population or activation was demonstrated in humans. However, infections may result from immunosuppression.
Temsirolimus is metabolized by hydrolysis to sirolimus, the principal active metabolite. Both temsirolimus and sirolimus also are metabolized by cytochrome P-450 (CYP) isoenzyme 3A4. Although temsirolimus is metabolized to sirolimus, temsirolimus itself exhibits antitumor activity and is not considered a prodrug.
The mean half-lives of temsirolimus and sirolimus were 17.3 hours and 54.6 hours, respectively. Following IV administration of a single radiolabeled dose of temsirolimus, approximately 78% of the total radioactivity is recovered in feces and 4.6% in urine within 14 days.
USES: This medication is used to treat kidney cancer. It works by slowing or stopping the growth of cancer cells.
Generic name: temsirolimus
Pronunciation: (tem-sir-oh-LEE-muss)
Drug class: Antineoplastic - mTOR Kinase Inhibitors
Therapeutic class: Antineoplastics
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Temsirolimus
Indications
The following indications are listed for Temsirolimus:
- Renal Cell Carcinoma
Also known as: Carcinoma Of Kidney, Grawitz Tumor, Hypernephroid Carcinoma, Hypernephroma, Kidney Adenocarcinoma, Nephroid Carcinoma, Renal Adenocarcinoma, Renal Carcinoma, Renal Cell Adenocarcinoma.
Dosing
Concomitant use of temsirolimus with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice) should be avoided. If patients must be administered a strong CYP3A4 inhibitor, consider a dosage reduction of temsirolimus to 12.5 mg weekly. If the strong CYP3A4 inhibitor is discontinued, allow a washout period of approximately 1 week before temsirolimus is adjusted back to the dosage used prior to initiation of the CYP3A4 inhibitor.
Concomitant use with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital) should be avoided. If patients must be administered a strong CYP3A4 inducer, consider a dosage increase of temsirolimus from 25 mg weekly to 50 mg weekly. If the strong inducer is discontinued, adjust temsirolimus dosage back to the dosage used prior to initiation of the strong CYP3A4 inducer.
Therapy should be temporarily interrupted if hematologic toxicities (e.g., absolute neutrophil count less than 1000/mm3, platelet count less than 75,000/mm3) or National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or greater toxicity occurs.
Following resolution of toxicity to grade 2 or less, temsirolimus may be restarted at a reduced weekly dosage that is 5 mg less than the previous dosage, but not less than 15 mg weekly.
No dosing information is available for this tab.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Temsirolimus 25 Mg Vial | Maintenance | Infuse 25 mg over 30-60 minute(s) by intravenous route once weekly. |
| Drug label | Dosing type | Instructions |
|---|---|---|
| Temsirolimus 25 Mg Vial | Maintenance | Infuse 25 mg over 30-60 minute(s) by intravenous route once weekly. |
Drug interactions
Patients should avoid concomitant use of temsirolimus with strong inhibitors or inducers of cytochrome P-450 (CYP) isoenzyme 3A; if alternative treatment cannot be given, adjustment of temsirolimus dosage is recommended.
Concomitant use of temsirolimus and sunitinib has resulted in dose-limiting toxicity.
Both temsirolimus and its principal active metabolite, sirolimus, are metabolized by cytochrome P-450 (CYP) isoenzyme 3A4. In vitro studies using human liver microsomes indicate that temsirolimus inhibits CYP isoenzymes 2D6 and 3A4.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
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.
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)
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/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 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/Leflunomide; Teriflunomide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of leflunomide or teriflunomide and potent immunosuppressants may result in additive or synergistic effects on the immune system.(1,2) Leflunomide is a prodrug and is converted to its active metabolite teriflunomide.(1)
CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide with immunosuppressants may result in an increased risk of serious infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: If leflunomide or teriflunomide is used concurrently with immunosuppressive agents, chronic CBC monitoring should be performed more frequently, every month instead of every 6 to 8 weeks. If bone marrow suppression or a serious infection occurs, leflunomide or teriflunomide should be stopped and rapid drug elimination procedure should be performed.(1,2)
DISCUSSION: Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving leflunomide or teriflunomide alone, but most frequently in patients taking concurrent immunosuppressants.(1,2) Severe and potentially fatal infections, including sepsis, have been reported in patients receiving leflunomide or teriflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Tuberculosis has also been reported.(1,2)
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/Posaconazole
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The metabolism of cyclosporine and temsirolimus by CYP3A4 may be inhibited by posaconazole.(1-3)
CLINICAL EFFECTS: Concurrent administration of posaconazole may result in elevated levels of and toxicity from cyclosporine or temsirolimus.(1-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Cyclosporine or temsirolimus levels and renal function should be monitored if posaconazole is initiated or discontinued from concurrent therapy.(1-3) The US manufacturer of posaconazole recommends that the dose of cyclosporine be reduced by approximately 75% of the original dosage when posaconazole is initiated. Cyclosporine levels should be closely monitored during concurrent azole therapy. The dosage of cyclosporine may need adjusting when azole therapy has been completed.(1-2) The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors 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.(3) Posaconazole tablets have improved bioavailability and higher concentrations per dose than posaconazole suspension. A greater dose reduction of the immunosuppressant may be necessary when posaconazole tablets are used.(4-6)
DISCUSSION: Concurrent use of posaconazole in heart transplant patients resulted in increased cyclosporine levels requiring dosage adjustments. In clinical trials, increased cyclosporine levels resulting in serious adverse events including nephrotoxicity, leukoencephalopathy, and death were reported. One study looked at the effects of posaconazole on the metabolism of cyclosporine when administered concurrently in heart transplant recipients. The study found when both medications were used concomitantly that cyclosporine exposure increased. The increased exposure required dosage adjustments of 14-29% in three out of four patients.(7)
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/Voriconazole
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The metabolism of cyclosporine and temsirolimus by CYP3A4 may be inhibited by voriconazole.(1-2)
CLINICAL EFFECTS: Concurrent administration of voriconazole may result in elevated levels of and toxicity from cyclosporine or temsirolimus.(1-2)
PREDISPOSING FACTORS: Concurrent use of voriconazole in patients who are poor or intermediate CYP2C19 metabolizers may necessitate larger immunosuppressant dose adjustments than in patients who are extensive CYP2C19 metabolizers.(3)
PATIENT MANAGEMENT: Cyclosporine or temsirolimus levels and renal function should be monitored if voriconazole is initiated or discontinued from concurrent therapy.(1-2) The manufacturer of voriconazole recommends that the dose of cyclosporine be reduced by 50% when used with voriconazole.(1) Cyclosporine levels should be closely monitored during concurrent azole therapy. The dosage of cyclosporine may need adjusting when azole therapy has been completed.(1) The US manufacturer of temsirolimus recommends that concurrent therapy with strong CYP3A4 inhibitors 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.(2)
DISCUSSION: In renal transplant recipients, voriconazole (200 mg orally every 12 hours for 8 days) increased the maximum concentration (Cmax), area-under-curve (AUC), and trough concentration (Cmin) of cyclosporine by 1.1-fold, 1.7-fold, and 2.48-fold, respectively.(4)
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)
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; 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 Immunosuppress; Immunomodulator/Ropeginterferon Alfa-2B
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
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: Avoid concurrent use of myelosuppressive agents.(1-2) If concurrent use cannot be avoided, monitor for effects of excessive immunosuppression.
DISCUSSION: In clinical trials, 20% of patients experienced leukopenia. Interferon alfa products may cause fatal or life-threatening infections.(1-2)
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)
Temsirolimus/Dexamethasone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Dexamethasone may induce the metabolism of temsirolimus by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent dexamethasone may result in decreased levels and effectiveness of temsirolimus.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of temsirolimus states that concurrent use of strong inducers of CYP3A4, such as dexamethasone, 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.(1)
DISCUSSION: Concurrent rifampin, a potent inducer of CYP3A4 and CYP3A5, had no significant effects on the area-under-curve (AUC) or maximum concentration (Cmax) of temsirolimus; however, sirolimus AUC and Cmax decreased by 56% and 65%, respectively.(1) 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.(1)
Temsirolimus/Sunitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Possible additive or synergistic effects on the immune system.(1)
CLINICAL EFFECTS: Concurrent use of temsirolimus and sunitinib may increase the risk of dose-limiting toxicity without providing any clinical benefit.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concurrent therapy with temsirolimus and sunitinib.(1) Patients receiving concurrent therapy should be closely monitored for signs and symptoms of toxicity. Dose reduction or discontinuation of therapy may be required.
DISCUSSION: In a phase I study with temsirolimus and sunitinib utilizing a 3+3 dose escalation design, six patients required dose reduction due to grade 3 stomatitis or grade 3 thrombocytopenia and four patients required removal from the trial because of unacceptable toxicity. A total of 21 grade 3 or 4 adverse events occurred. At 50% of the FDA-approved doses of sunitinib (25 mg) and temsirolimus (12.5 mg), significant mucositis requiring dose reduction occurred.(2) In the first cohort of a phase I study with temsirolimus (15 mg intravenously once weekly) and sunitinib (25 mg by mouth daily on days 1 through 28, followed by a 2-week rest), dose-limiting toxicities (grade 3 rash, grade 3 thrombocytopenia/cellulitis/gout) were observed in 2 of 3 patients. The study was terminated because of the dose-limiting toxicity observed at low starting doses of both agents.(3)
Moderate Interaction: Assess the risk to the patient and take action as needed.
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 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)
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.
Temsirolimus/Selected Calcium Channel Blockers
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Some calcium channel blockers may inhibit the metabolism of sirolimus by CYP3A4.(1) Sirolimus is the active metabolite of temsirolimus.(2) Therefore, temsirolimus is expected to be affected in the same manner as sirolimus.
CLINICAL EFFECTS: Concurrent use of calcium channel blockers may result in elevated levels of and side effects from temsirolimus.(2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of temsirolimus states that if an agent inhibiting CYP3A4 is prescribed and alternative treatment cannot be used, a dose adjustment of temsirolimus should be considered.(2)
DISCUSSION: The pharmacokinetics of temsirolimus was not affected by ketoconazole, a strong CYP3A4 inhibitor. However, sirolimus area-under-curve (AUC) increased 3.1-fold and maximum concentration (Cmax) increased 2.2-fold compared to temsirolimus alone.(2) In an open, randomized, cross-over trial in 18 healthy subjects, concurrent single doses of diltiazem (120 mg) and sirolimus (10 mg) increased sirolimus area-under-curve (AUC) and maximum concentration (Cmax) by 60% and by 43%, respectively. Sirolimus apparent oral clearance and volume of distribution decreased by 38% and 45%, respectively. There were no effects on diltiazem pharmacokinetics or pharmacodynamics.(1,3) Nicardipine may increase sirolimus levels.(1) In a study in 26 healthy subjects, concurrent sirolimus (2 mg daily) with verapamil (180 mg twice daily) increased sirolimus AUC and Cmax by 2.2-fold and 2.3-fold, respectively. The AUC and Cmax of the active S-enantiomer of verapamil each increased by 1.5-fold. Verapamil time to Cmax (Tmax) was increased by 1.2 hours.(1) In a study in 25 healthy subjects, concurrent sirolimus with verapamil increased sirolimus Cmax and AUC 130% and 120%, respectively.(4)
Contraindications
*Patients with bilirubin >1.5 times upper limit of normal (ULN).
- Hyperbilirubinemia
- Lactation
- Cerebrovascular accident
- Disease of liver
- Gastrointestinal perforation
- Interstitial pneumonitis
- Kidney disease with reduction in glomerular filtration rate (GFr)
- Pregnancy
- Severe infection
- Cerebral metastases
- Diabetes mellitus
- Hyperlipidemia
- Impaired wound healing
- Invasive surgical procedure
- Malignant brain neoplasm
- Perioperative care
Adverse reactions
The most common adverse reactions (>=30%) reported with temsirolimus are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common laboratory abnormalities (>=30%) are anemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia.
More Frequent
- Abnormal hepatic function tests
- Anaphylaxis
- Anemia
- Chest pain
- Dyspnea
- Edema
- Fever
- Hyperglycemia
- Hyperlipidemia
- Hypertension
- Hypertriglyceridemia
- Hypokalemia
- Hypophosphatemia
- Immunosuppression
- Infection
- Leukopenia
- Lymphopenia
- Neutropenic disorder
- Stomatitis
- Thrombocytopenic disorder
- Upper respiratory infection
- Urinary tract infection
Less Frequent
- Depression
- Diabetes mellitus
- Gastrointestinal hemorrhage
- Interstitial lung disease
- Pleural effusions
- Pneumonia
- Thrombophlebitis
- Venous thrombosis
Rare or Very Rare
- Acute renal failure
- Angioedema
- Apnea
- Biliary calculus
- Cholecystitis
- Hypersensitivity drug reaction
- Hypotension
- Intestinal perforation
- Nephrotic syndrome
- Pancreatitis
- Pericardial effusion
- Pneumocystis jirovecii pneumonia
- Rectal bleeding
- Rhabdomyolysis
- Seizure disorder
- Sepsis
- Stevens-johnson syndrome
More Frequent
- Abdominal pain with cramps
- Acne vulgaris
- Anorexia
- Arthralgia
- Back pain
- Chills
- Constipation
- Cough
- Diarrhea
- Dry skin
- Dysgeusia
- Flushing
- General weakness
- Headache disorder
- Insomnia
- Nausea
- Pain
- Pharyngitis
- Pruritus of skin
- Rhinitis
- Skin rash
- Vomiting
- Weight loss
Less Frequent
- Conjunctivitis
- Epistaxis
- Impaired wound healing
- Myalgia
- Nail disorders
Rare or Very Rare
- Extravasation injury
- Injection site sequelae
- Proteinuria
Precautions
No enhanced messaging available.
There is limited information on the use of temsirolimus in pediatric patients. Effectiveness of the drug in pediatric patients with advanced recurrent/refractory solid tumors has not been established. In a clinical study that included 59 pediatric patients ages 1-17 years of age, temsirolimus 10 mg/m2 to 150 mg/m2 was given in 3 week cycles for treatment of advanced recurrent/refractory solid tumors to explore safety and pharmacodynamics. In a later study, 52 pediatric patients with recurrent/relapsed neruoblastoma, rhabdomyosarcoma, or high grade glioma received temsirolimus 75 mg/m2 weekly. One patient with neuroblastoma had a partial response; no objective responses were observed with the other indications for use.
Adverse reactions associated with temsirolimus in the pediatric population were similar to adults. The most common reactions (>=20%) in pediatric patients receiving the temsirolimus 75 mg/m2 weekly dosage included thrombocytopenia, infections, asthenia/fatigue, fever, pain, leukopenia, rash, anemia, hyperlipidemia, increased cough, stomatitis, anorexia, increased plasma levels of alanine aminotransferase and aspartate aminotransferase, hypercholesterolemia, hyperglycemia, abdominal pain, headache, arthralgia, upper respiratory infection, nausea and vomiting, neutropenia, hypokalemia, and hypophosphatemia.
Temsirolimus may cause fetal harm. Animal studies indicate adverse effects on embryofetal development. Advise pregnant women and females of reproductive potential of the potential risk to the fetus.
Not known whether temsirolimus is distributed into milk or the effects on the breastfed child or milk production. Advise lactating females not to breastfeed during treatment with temsirolimus and for 3 weeks after the final dose.
The manufacturer makes no specific geriatric dosage recommendations at this time.
Older adults are more likely to experience certain adverse reactions with temsirolimus (e.g., diarrhea, edema, pneumonia).
There is insufficient experience in patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults. Elderly patients may be more likely to experience adverse reactions of temsirolimus such as diarrhea, edema, and pneumonia.
ICD codes
| Code | Type | Description |
|---|---|---|
| Renal cell carcinoma | ||
| C64 | ICD10CM | Malignant neoplasm of kidney, except renal pelvis |
| C64.1 | ICD10CM | Malignant neoplasm of right kidney, except renal pelvis |
| C64.2 | ICD10CM | Malignant neoplasm of left kidney, except renal pelvis |
| C64.9 | ICD10CM | Malignant neoplasm of unspecified kidney, except renal pelvis |
ICD code information from First Databank (FDB).
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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