Imbruvica (ibrutinib)

Withhold ibrutinib therapy for adverse reactions listed in Table 2. Upon improvement to grade 1 or baseline (recovery), follow the recommended dosage modifications described in Table 2.

Table 2. Dosage Modification for Toxicity

Adverse Reaction Occurrence Dosage Dosage Modification for Modification for CLL/SLL, WM, and Patients 1 to Patients12 Years Less than12 Years of Age and of Agewith Greaterwith Chronic GVHD Chronic GVHD after Recovery after Recovery Starting Dose Starting Dose = =240 mg/m2 420 mg Grade 2 cardiac First Restart at 280 mg Restart at 160 failure daily mg/m2 daily Grade 2 cardiac Second Restart at 140 mg Restart at 80 failure daily mg/m2 daily Grade 2 cardiac Third Discontinue Discontinue failure ibrutinib ibrutinib Grade 3 cardiac First Restart at 280 mg Restart at 160 arrhythmias daily mg/m2 daily Grade 3 cardiac Second Discontinue Discontinue arrhythmias ibrutinib ibrutinib Grade 3 or 4 First Discontinue Discontinue cardiac failure, ibrutinib ibrutinib OR Grade 4 cardiac arrhythmias Other grade 3 or First Restart at 280 mg Restart at 160 4 daily mg/m2 daily nonhematological toxicities, OR Grade 3 or 4 neutropenia with infection or fever, OR Grade 4 hematological toxicities Other grade 3 or Second Restart at 140 mg Restart at 80 4 daily mg/m2 daily nonhematological toxicities, OR Grade 3 or 4 neutropenia with infection or fever, OR Grade 4 hematological toxicities Other grade 3 or Third Discontinue Discontinue 4 ibrutinib ibrutinib nonhematological toxicities, OR Grade 3 or 4 neutropenia with infection or fever, OR Grade 4 hematological toxicities

See Table 3 for dosage modifications based on BSA.

Assess the benefit-risk before resuming treatment.

For grade 4 non-hematologic toxicities, assess the benefit-risk before resuming treatment.

Table 3. Recommended Dosage Modifications Based on BSA Using Either ibrutinib Capsules/Tablets or Oral Suspension

BSA (m2) range Dose (mg) of Volume (mL) of Dose (mg) of Volume (mL) of capsules or ibrutinib oral capsules or ibrutinib oral tablets to suspension to tablets to suspension to administer to administer to administer to administer to achieve 160 achieve 160 achieve 80 achieve 80 mg/m2 mg/m2 mg/m2 mg/m2 >0.3-0.4 0.8 mL 0.4 mL >0.4-0.5 1 mL 0.5 mL >0.5-0.6 1.3 mL 0.6 mL >0.6-0.7 1.5 mL 0.7 mL >0.7-0.8 140 mg 1.7 mL 70 mg 0.9 mL >0.8-0.9 140 mg 1.9 mL 70 mg 1 mL >0.9-1 140 mg 2.2 mL 70 mg 1.1 mL >1-1.1 140 mg 2.4 mL 70 mg 1.2 mL >1.1-1.2 210 mg 2.6 mL 1.3 mL >1.2-1.3 210 mg 2.9 mL 1.4 mL >1.3-1.4 210 mg 3.1 mL 1.5 mL >1.4-1.5 210 mg 3.3 mL 140 mg 1.7 mL >1.5-1.6 280 mg 3.5 mL 140 mg 1.8 mL >1.6 280 mg 4 mL 140 mg 2 mL

Refer to Table 4 for recommended dosage modifications for use of ibrutinib with cytochrome P-450 (CYP) 3A inhibitors. After discontinuation of a CYP3A inhibitor, resume previous dosage of ibrutinib.

Table 4. Recommended Dosage Modifications for Use with CYP3A Inhibitors

Patient Population Coadministered Drug Recommended Ibrutinib Dosage B-cell malignancies Moderate CYP3A inhibitor 280 mg once daily Modify (CLL/SLL or WM) dosage as recommended for adverse reactions B-cell malignancies Voriconazole 200 mg 140 mg once daily Modify (CLL/SLL or WM) twice daily Posaconazole dosage as recommended suspension 100 mg once for adverse reactions daily, 100 mg twice daily, or 200 mg twice daily B-cell malignancies Posaconazole suspension 70 mg once daily (CLL/SLL or WM) 200 mg three times daily Interrupt dosage as or 400 mg twice daily recommended for adverse Posaconazole IV 300 mg reactions once daily Posaconazole delayed-release tablets 300 mg once daily B-cell malignancies Other strong CYP3A Avoid concomitant use If (CLL/SLL or WM) inhibitors these inhibitors will be used short-term (e.g., anti-infectives for7 days or less), interrupt ibrutinib Patients12 years of age Moderate CYP3A inhibitor 420 mg once daily Modify and greaterwith chronic dosage as recommended GVHD for adverse reactions Patients12 years of age Voriconazole 200 mg 280 mg once daily Modify and greaterwith chronic twice daily Posaconazole dosage as recommended GVHD suspension 100 mg once for adverse reactions daily, 100 mg twice daily, or 200 mg twice daily Patients12 years of age Posaconazole suspension 140 mg once daily and greaterwith chronic 200 mg three times daily Interrupt dosage as GVHD or 400 mg twice daily recommended for adverse Posaconazole IV 300 mg reactions once daily Posaconazole delayed-release tablets 300 mg once daily Patients12 years of age Other strong CYP3A Avoid concomitant use If and greaterwith chronic inhibitors these inhibitors will be GVHD used short-term (e.g., anti-infectives for7 days or less), interrupt ibrutinib Patients 1 to less Moderate CYP3A inhibitor 240 mg/m2 once daily than12 years of age with Modify dosage as chronic GVHD recommended for adverse reactions Patients 1 to less Voriconazole for 160 mg/m2 than12 years of age with suspension 9 mg/kg chronic GVHD (maximum dose: 350 mg) twice daily Patients 1 to less Posaconazole at any 80 mg/m2 than12 years of age with dosage chronic GVHD Patients 1 to less Other strong CYP3A Avoid concomitant use If than12 years of age with inhibitors these inhibitors will be chronic GVHD used short-term (e.g., anti-infectives for7 days or less), interrupt ibrutinib

Ibrutinib is available as immediate-release capsules containing 70 mg or 140 mg; immediate-release tablets containing 140 mg, 280 mg, or 420 mg; and as an immediate-release oral suspension containing 70 mg of ibrutinib per mL. The oral suspension bottle is provided in a carton with two 3 mL reusable oral dosing syringes.

Administer ibrutinib orally once daily at approximately the same time each day. Swallow tablets or capsules whole with a glass of water; do not open, break, or chew capsules, and do not cut, crush, or chew tablets. For administration of ibrutinib oral suspension, refer to the full instructions for use in the prescribing information for details.

Store ibrutinib capsules and tablets in the original packaging at 20-25degreesC; brief exposures to 15-30degreesC are permitted.

Store ibrutinib oral suspension at 2-25degreesC; do not freeze. Dispense in original sealed container, and do not use if the carton seal is missing or broken. Discard any unused oral suspension remaining 60 days after first opening the bottle.

If a dose is missed, administer the missed dose on the same day as soon as it is remembered and resume the normal schedule the following day; do not take extra doses to make up for a missed dose.

No dosing information is available for this tab.

Metabolism of ibrutinib to several metabolites is mediated principally by cytochrome P-450 (CYP) isoenzyme 3A and, to a lesser extent, by CYP2D6.

In vitro studies indicate that ibrutinib and PCI-45227 (active metabolite)are not expected to inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A or induce CYP isoenzymes 1A2, 2B6, or 3A at clinically relevant concentrations.

In vitro studies indicate that ibrutinib may inhibit P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transport at clinically relevant concentrations. In vitro studies suggest that ibrutinib is not a substrate of P-gp or BCRP.

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

Antineoplastic Systemic Enzyme Inhibitors/Apalutamide

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: Apalutamide(1) may induce the metabolism of antineoplastic systemic enzyme inhibitors, including bosutinib,(2) cabozantinib,(3) erlotinib,(4) gefitinib,(5) ibrutinib,(6) idelalisib,(7) and imatinib.(8)

CLINICAL EFFECTS: Concurrent use of apalutamide may decrease the levels and effectiveness of antineoplastic systemic enzyme inhibitors, including bosutinib,(2) cabozantinib,(3) erlotinib,(4) gefitinib,(5) ibrutinib,(6) idelalisib,(7) and imatinib.(8)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of apalutamide in patients receiving therapy with antineoplastic enzyme inhibitors. Consider the use of alternative agents with less enzyme induction potential.(1-8) If concurrent use of apalutamide cannot be avoided with antineoplastic enzyme inhibitors: Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer.(9) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(3) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued.(4) Consider a dose increase to 500 mg daily of gefitinib in the absence of severe adverse drug reaction. Clinical response and adverse events should be closely monitored.(5) The dose of imatinib should be increased by at least 50% and clinical response should be carefully monitored. Dosages up to 1200 mg/day (600 mg twice daily) have been used in patients receiving concurrent therapy with strong CYP3A4 inducers.(8)

DISCUSSION: In a study in 24 healthy subjects, rifampin (a strong CYP3A4 inducer) decreased bosutinib area-under-curve (AUC) and maximum concentration (Cmax) by 94% and 86%. Bosutinib clearance increased by 13-fold.(2,11) In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(3) Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(4) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(4) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(10) In a study in healthy male volunteers, rifampicin decreased AUC of gefitinib by 85%.(5) The coadministration of rifampin decreased the Cmax and AUC of ibrutinib by more than 13-fold and 10-fold.(6) In a study in healthy subjects, rifampin (600 mg daily for 8 days) decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and 75%, respectively.(7) Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10 days) increased the clearance of a single dose of imatinib (400 mg) by 3.8-fold. The area-under-curve (AUC) and maximum concentration (Cmax) decreased by 74% and 54%, respectively.(8,12) The Cmax of the CGP74588 metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(12)

Antineoplastic Systemic Enzyme Inhibitors/Carbamazepine

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: Agents that induce the CYP3A4 isoenzyme, such as carbamazepine, may induce the metabolism of antineoplastic systemic enzyme inhibitors, including bosutinib,(1) cabozantinib,(2,3) dasatinib,(4) erlotinib,(5) gefitinib,(6) ibrutinib,(7) lapatinib,(8) pazopanib,(9) sorafenib,(10) sunitinib,(11) and vandetanib.(12)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may decrease the levels and effectiveness of antineoplastic systemic enzyme inhibitors, including bosutinib,(1) cabozantinib,(2,3) dasatinib,(4) erlotinib,(5) gefitinib,(6) ibrutinib,(7) lapatinib,(8) pazopanib,(9) sorafenib,(10) sunitinib,(11) and vandetanib.(12)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with antineoplastic enzyme inhibitors. Consider the use of alternative agents with less enzyme induction potential.(1-12) Pazopanib should not be administered to patients who cannot avoid chronic use of strong CYP3A4 inducers.(8) If concurrent use of a CYP3A4 inducer cannot be avoided with other antineoplastic enzyme inhibitors: Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer.(2) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(3) Consider increasing the dose of dasatinib.(4) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued. If the inducer is dexamethasone, monitor the patient for sign of gastrointestinal perforation. Discontinue erlotinib in patients who develop gastrointestinal perforation.(5) Consider a dose increase to 500 mg daily of gefitinib in the absence of severe adverse drug reaction. Clinical response and adverse events should be closely monitored.(6) The dose of lapatinib should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive breast cancer indication) based on patient tolerability. If the inducer is discontinued, the dose of lapatinib should be adjusted to the normal dose.(8) A dosage increase of sunitinib to a maximum of 87.5 mg daily in patients with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma (RCC) or to a maximum of 62.5 mg in patients with pancreatic neuroendocrine tumors (pNET) should be considered.(11)

DISCUSSION: In a study in 24 healthy subjects, rifampin (a strong CYP3A4 inducer) decreased bosutinib area-under-curve (AUC) and maximum concentration (Cmax) by 94% and 86%. Bosutinib clearance increased by 13-fold.(1,14) In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(2) In a study in healthy subjects, concurrent rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of dasatinib by 81% and 82%, respectively.(4) Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(5) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(5) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(14) In a study in healthy male volunteers, rifampicin decreased AUC of gefitinib by 85%.(6) The coadministration of rifampin decreased the Cmax and AUC of ibrutinib by more than 13-fold and 10-fold.(7) In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of lapatinib by 72%. The dose adjustment recommendations are based on pharmacokinetic studies and are predicted to adjust lapatinib AUC to the range observed without concurrent CYP3A4 inducers; however, there are no clinical data with these doses in patients receiving strong CYP3A4 inducers.(8) Pazopanib is primarily metabolized by CYP3A4.(9) Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a single dose of sorafenib (400 mg) by 37%.(10) In a study with healthy subjects, concurrent rifampin decreased the combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and 46%, respectively, of a single dose of sunitinib.(11) Strong CYP3A4 inducers are expected to alter vandetanib concentrations. The patient developed nystagmus, a sign of phenytoin toxicity.(12)

Ibrutinib/Strong Cyp3a4 Inducers

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: Strong inducers of CYP3A4 may induce the metabolism of ibrutinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of ibrutinib.(1)

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

PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers in patients receiving therapy with ibrutinib. Consider the use of alternative agents with less enzyme induction potential.(1)

DISCUSSION: The coadministration of rifampin decreased the maximum concentration (Cmax) and area-under-curve (AUC) of ibrutinib by more than 13-fold and 10-fold.(1) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(2,3)

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)

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/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 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)

Slt Antineoplastic Systemic Enzyme Inh/Lumacaftor-Ivacaftor

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: Lumacaftor-ivacaftor(1) may induce the metabolism of antineoplastic systemic enzyme inhibitors, including bosutinib,(2) cabozantinib,(3) crizotinib,(4) dasatinib,(5) erlotinib,(6) gefitinib,(7) ibrutinib,(8) imatinib,(9) lapatinib,(10) nilotinib,(11) pazopanib,(12) sorafenib,(13) sunitinib,(14) and vandetanib.(15)

CLINICAL EFFECTS: Concurrent use of lumacaftor-ivacaftor may decrease the levels and effectiveness of antineoplastic systemic enzyme inhibitors, including bosutinib,(2) cabozantinib,(3) crizotinib,(4) dasatinib,(5) erlotinib,(6) gefitinib,(7) ibrutinib,(8) imatinib,(9) lapatinib,(10) nilotinib,(11) pazopanib,(12) sorafenib,(13) sunitinib,(14) and vandetanib.(15)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of lumacaftor-ivacaftor in patients receiving therapy with antineoplastic enzyme inhibitors. Consider the use of alternative agents with less enzyme induction potential.(2-15) Because of the nonlinear pharmacokinetic profile of nilotinib, increasing its dose is unlikely to compensate for enzyme induction.(11) Pazopanib should not be administered to patients who cannot avoid chronic use of strong CYP3A4 inducers.(12) If concurrent use of a CYP3A4 inducer cannot be avoided with other antineoplastic enzyme inhibitors: Increase the daily dose of cabozantinib TABlets by 20 mg (e.g. from 60 mg to 80 mg daily) as tolerated. The daily dose should not exceed 80 mg. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer.(16) Increase the daily dose of cabozantinib CAPsules by 40 mg (from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of cabozantinib should not exceed 180 mg. If the CYP3A4 inducer is discontinued, reduce the dosage of cabozantinib to the dose used prior to initiation of the inducer 2 to 3 days after discontinuation of the strong inducer.(2) Consider increasing the dose of dasatinib.(5) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued. If the inducer is dexamethasone, monitor the patient for sign of gastrointestinal perforation. Discontinue erlotinib in patients who develop gastrointestinal perforation.(6) Consider a dose increase to 500 mg daily of gefitinib in the absence of severe adverse drug reaction. Clinical response and adverse events should be closely monitored.(7) The dose of imatinib should be increased by at least 50% and clinical response should be carefully monitored. Dosages up to 1200 mg/day (600 mg twice daily) have been used in patients receiving concurrent therapy with strong CYP3A4 inducers.(9) The dose of lapatinib should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive breast cancer indication) based on patient tolerability. If the inducer is discontinued, the dose of lapatinib should be adjusted to the normal dose.(10) A dosage increase of sunitinib to a maximum of 87.5 mg daily in patients with gastrointestinal stromal tumors (GIST) or advanced renal cell carcinoma (RCC) or to a maximum of 62.5 mg in patients with pancreatic neuroendocrine tumors (pNET) should be considered.(14)

DISCUSSION: In a study, 24 healthy subjects received a single dose of bosutinib 500 mg (days 1 and 14) and rifampin 600 mg (days 8-17). Bosutinib Cmax and AUC decreased by 86% and 92%, respectively. Bosutinib clearance increased by 13-fold.(2,17) In a study in healthy subjects, rifampin (600 mg daily for 31 days) decreased the AUC of a single dose of cabozantinib by 77%.(3) Rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of crizotinib (250 mg) by 69% and 82%, respectively.(4) In a study in healthy subjects, concurrent rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of dasatinib by 81% and 82%, respectively.(5) Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(6) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(6) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(18) In a study in healthy male volunteers, rifampicin decreased AUC of gefitinib by 85%.(7) The coadministration of rifampin decreased the Cmax and AUC of ibrutinib by more than 13-fold and 10-fold.(8) Pretreatment of 14 healthy subjects with rifampin (600 mg daily for 10 days) increased the clearance of a single dose of imatinib (400 mg) by 3.8-fold. The area-under-curve (AUC) and maximum concentration (Cmax) decreased by 74% and 54%, respectively.(9,19) The Cmax of the CGP74588 metabolite increased by 88.6%, but the AUC of CGP74588 decreased by 11%.(19) In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of lapatinib by 72%. The dose adjustment recommendations are based on pharmacokinetic studies and are predicted to adjust lapatinib AUC to the range observed without concurrent CYP3A4 inducers; however, there are no clinical data with these doses in patients receiving strong CYP3A4 inducers.(10) In a study in healthy subjects, concurrent rifampin (600 mg daily for 12 days) decreased nilotinib AUC by 80%.(11) Pazopanib is primarily metabolized by CYP3A4.(12) Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a single dose of sorafenib (400 mg) by 37%.(13) In a study with healthy subjects, concurrent rifampin decreased the combined (sunitinib plus primary active metabolite) Cmax and AUC by 23% and 46%, respectively, of a single dose of sunitinib.(14) Strong CYP3A4 inducers are expected to alter vandetanib concentrations. The patient developed nystagmus, a sign of phenytoin toxicity.(15)

Slt Antineoplastic Systemic Enzyme Inhib/St. John's Wort

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: St. John's wort may induce the metabolism of antineoplastic systemic enzyme inhibitors, including bortezomib,(1) bosutinib,(2) ceritinib,(3) crizotinib,(4) dasatinib,(5) erlotinib,(6) gefitinib,(7) ibrutinib,(15) idelalisib,(8) imatinib,(9) lapatinib,(10) pazopanib,(11) sorafenib,(12) and vandetanib(13) by CYP3A4.

CLINICAL EFFECTS: Concurrent use of St. John's wort may result in decreased levels and effectiveness of antineoplastic systemic enzyme inhibitors, including bortezomib,(1) bosutinib,(2) ceritinib,(3) crizotinib,(4) dasatinib,(5) erlotinib,(6) gefitinib,(7) ibrutinib,(15) idelalisib,(8) imatinib,(9) lapatinib,(10) pazopanib,(11) sorafenib,(12) and vandetanib.(13)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the concurrent use of strong CYP3A4 inducers such as St. John's wort in patients receiving therapy with antineoplastic enzyme inhibitors. Consider the use of alternative agents with less enzyme induction potential.(1-13,15) If concurrent use of dasatinib is warranted, consider increasing the dose of dasatinib.(5) If concurrent therapy with erlotinib cannot be avoided, consider increasing the dosage of erlotinib as tolerated at two week intervals while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when St. John's wort is discontinued.(6) In patients receiving a potent CYP3A4 inducer, a dose increase to 500 mg daily of gefitinib should be considered in the absence of severe adverse drug reaction. Clinical response and adverse events should be closely monitored.(7) If concurrent therapy with imatinib is warranted, the dose of imatinib should be increased by at least 50% and clinical response should be carefully monitored. Dosages up to 1200 mg/day (600 mg twice daily) have been used in patients receiving concurrent therapy with strong CYP3A4 inducers.(9) If concurrent therapy with lapatinib is warranted, the dose of lapatinib should be gradually titrated from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer indication) or from 1,500 mg/day up to 5,500 mg/day (hormone receptor positive, HER2 positive breast cancer indication) based on patient tolerability. If St. John's wort is discontinued, the dose of lapatinib should be adjusted to the normal dose.(10) Pazopanib should not be administered to patients who cannot avoid chronic use of strong CYP3A4 inducers.(11)

DISCUSSION: Rifampin (600 mg daily), a strong CYP3A4 inducer, decreased bortezomib area-under-curve (AUC) by 45%.(1) In a study in 24 healthy subjects, rifampin decreased bosutinib AUC and maximum concentration (Cmax) by 94% and 86%.(2) In a study in 19 healthy subjects, rifampin (600 mg daily for 14 days) decreased the Cmax and AUC of a single dose of ceritinib by 44% and 70%, respectively.(3) Rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of crizotinib (250 mg) by 69% and 82%, respectively.(4) In a study in healthy subjects, concurrent rifampin (600 mg daily) decreased the Cmax and AUC of a single dose of dasatinib by 81% and 82%, respectively.(5) Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(6) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(6) In a study in healthy male volunteers, rifampicin decreased the AUC of gefitinib by 85%.(7) In a study in healthy subjects, rifampin (600 mg daily for 8 days) decreased the Cmax and AUC of idelalisib (150 mg single dose) by 58% and 75%, respectively.(8) Concurrent St. John's wort decreased the AUC of imatinib by 30%.(9) In healthy subjects, carbamazepine (100 mg twice daily for 3 days and 200 mg twice daily for 17 days), another CYP3A4 inducer, decreased the AUC of lapatinib by 72%. The dose adjustment recommendations are based on pharmacokinetic studies and are predicted to adjust lapatinib AUC to the range observed without concurrent CYP3A4 inducers; however, there are no clinical data with these doses in patients receiving strong CYP3A4 inducers.(10) Pazopanib is primarily metabolized by CYP3A4.(11) Concurrent rifampin (600 mg daily for 5 days) decreased the AUC of a single dose of sorafenib (400 mg) by 37%.(12) Strong CYP3A4 inducers are expected to alter vandetanib concentrations.(13) Rifampin, a strong CYP3A4 inducer, decreased ibrutinib's Cmax and AUC by more than 13-fold and 10-fold.(15)

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

Ibrutinib/Diltiazem

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

MECHANISM OF ACTION: Agents that are strong or moderate inhibitors of the CYP3A4 isoenzyme may inhibit the metabolism of ibrutinib.(1) Diltiazem is a moderate to strong CYP3A4 inhibitor.(2-4)

CLINICAL EFFECTS: Concurrent use of diltiazem may increase levels of and effects from ibrutinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of ibrutinib recommends avoiding concurrent use with strong and moderate CYP3A4 inhibitors. If concurrent use is warranted with moderate CYP3A4 inhibitor, consider dose modifications.(1) If a moderate CYP3A4 inhibitor is required for B-cell malignancies treatment, reduce the dose of ibrutinib to 280 mg daily.(1) If a moderate CYP3A4 inhibitor is required for chronic graft versus host disease treatment, reduce the dose of ibrutinib in patients 12 years and older to 420 mg once daily, and in patients 1 year to 12 years old to 240 mg/m2 once daily.(1) After discontinuation of a CYP3A4 inhibitor, resume previous dose of ibrutinib.(1) Diltiazem is a moderate to strong CYP3A4 inhibitor.(2-4)

DISCUSSION: A pharmacokinetic model simulating human pharmacokinetics and drug interactions in healthy men predicted that diltiazem would increase ibrutinib Cmax and AUC by 5-fold and 5.5-fold, respectively.(2) In a study in 18 healthy subjects, ketoconazole (400 mg daily for 7 days) increased the Cmax and AUC of ibrutinib (single 40 mg dose) by 24-fold and 29-fold, respectively.(1) The coadministration of multiple doses of voriconazole increased ibrutinib's Cmax and AUC by 6.7-fold and 5.7-fold.(1) Simulations under fed conditions suggest that posaconazole may increase ibrutinib's AUC by 7-fold to 10-fold.(1)

Ibrutinib/Moderate Cyp3a4 Inducers

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

MECHANISM OF ACTION: Agents that induce the CYP3A4 isoenzyme may induce the metabolism of ibrutinib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inducers may decrease the levels and effectiveness of ibrutinib.(1)

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

PATIENT MANAGEMENT: Avoid the concurrent use of moderate CYP3A4 inducers in patients receiving therapy with ibrutinib.(1) Consider the use of alternative agents with less enzyme induction potential.(1)

DISCUSSION: The coadministration of rifampin decreased the maximum concentration (Cmax) and area-under-curve (AUC) of ibrutinib by more than 13-fold and 10-fold.(1) In a pharmacokinetic model, efavirenz (600 mg daily), a moderate CYP3A4 inducer, was predicted to decrease the Cmax and AUC of ibrutinib (560 mg) by 2.4-fold and 2.5-fold, respectively.(2) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(4)

Ibrutinib/Posaconazole; Voriconazole

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

MECHANISM OF ACTION: Posaconazole and voriconazole inhibit the CYP3A4 isoenzyme and may inhibit the metabolism of ibrutinib.(1)

CLINICAL EFFECTS: Concurrent use of posaconazole and voriconazole, strong CYP3A4 inhibitors, may increase levels of and effects from ibrutinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients with B-cell malignancies, reduce the ibrutinib dose to 140 mg once daily during coadministration with posaconazole at doses of posaconazole suspension 100 mg daily, 100 mg twice daily or 200 mg twice daily. Reduce the ibrutinib dose to 70 mg once daily with posaconazole suspension 200 mg three times daily or 400 mg twice daily; posaconazole IV 300 mg daily; or posaconazole delayed-release tablets 300 mg once daily. Interrupt ibrutinib dose as recommended for adverse reactions.(1) For patients with B-cell malignancies, reduce the ibrutinib dose to 140 mg once daily during coadministration with any dose of voriconazole. Interrupt ibrutinib dose as recommended for adverse reactions.(1) For patients 12 years and older with chronic graft versus host disease (cGVHD), reduce the ibrutinib dose to 280 mg once daily for patients coadministered ibrutinib with posaconazole suspension 100 mg daily, 100 mg twice daily, or 200 mg twice daily; or any dose of voriconazole. Reduce the ibrutinib dose to 140 mg once daily with posaconazole suspension 200 mg three times daily or 400 mg twice daily; posaconazole IV 300 mg once daily; or posaconazole delayed-release tablets 300 mg once daily. For patients 1 year to 12 years old with cGVHD, reduce the ibrutinib dose to 160 mg/m2 once daily with voriconazole suspension and reduce the ibrutinib dose to 80 mg/m2 once daily with any dose of posaconazole. Interrupt ibrutinib dose as recommended for adverse reactions. Avoid concomitant administration of ibrutinib with posaconazole at higher doses.(1) After discontinuation of posaconazole or voriconazole, resume previous dose of ibrutinib.(1)

DISCUSSION: The coadministration of multiple doses of voriconazole increased ibrutinib's steady state maximum concentration (Cmax) and area-under-the-curve (AUC) by 6.7-fold and 5.7-fold, respectively.(1) Simulations under fed conditions suggest that posaconazole may increase the AUC of ibrutinib by 7-fold to 10-fold.(1) A randomized, placebo-controlled, three-phase crossover study in 11 healthy participants found that concomitant use of repeated doses of posaconazole (300 mg in morning) with a single dose of ibrutinib (30, 70, or 140 mg administered 1 hour after preceding posaconazole dose) increased the ibrutinib AUC and Cmax by 9.5-fold and 8.5-fold. Administration of posaconazole in the evening with a single dose of ibrutinib (30, 70, or 140 mg 12 hours after preceding posaconazole dose) increased the ibrutinib AUC and Cmax by 10.3-fold and 8.2-fold.(3)

Ibrutinib/Strong Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of ibrutinib.(1)

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may increase levels of and effects from ibrutinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of strong CYP3A4 inhibitors in patients undergoing therapy with ibrutinib.(1) The concurrent chronic use of strong CYP3A4 inhibitors with ibrutinib is not recommended. For short-term use of strong CYP3A4 inhibitors, such as 7 days or less of antibiotics/antifungals, consider interruption of ibrutinib therapy.(1) The Australian and UK manufacturers of ibrutinib state that use of strong CYP3A4 inhibitors should be avoided. If the benefit outweighs the risk and a strong CYP3A4 inhibitor must be used, reduce the ibrutinib dose to 140 mg for the duration of the inhibitor use or withhold ibrutinib temporarily (for 7 days or less). Monitor patient closely for toxicity and follow dose modification guidance as needed.(2,3)

DISCUSSION: In a study in 18 healthy subjects, ketoconazole (400 mg daily for 7 days) increased the Cmax and AUC of ibrutinib (single 40 mg dose) by 24-fold and 29-fold, respectively.(1) The coadministration of multiple doses of voriconazole increased ibrutinib's Cmax and AUC by 6.7-fold and 5.7-fold.(1) Simulations under fed conditions suggest that posaconazole may increase ibrutinib's AUC by 7-fold to 10-fold.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir/ritonavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, troleandomycin and tucatinib.(4,5)

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)

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 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 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)

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)

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

Ibrutinib/Moderate Cyp3a4 Inhibitors

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

MECHANISM OF ACTION: Agents that inhibit the CYP3A4 isoenzyme may inhibit the metabolism of ibrutinib.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may increase levels of and effects from ibrutinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of moderate CYP3A4 inhibitors in patients undergoing therapy with ibrutinib requires a dose adjustment.(1) If a moderate CYP3A4 inhibitor is required for B-cell malignancies treatment, reduce the dose of ibrutinib to 280 mg daily.(1) If a moderate CYP3A4 inhibitor is required for chronic graft versus host disease treatment, reduce the dose of ibrutinib in patients 12 years and older to 420 mg once daily, and in patients 1 year to 12 years old to 240 mg/m2 once daily.(1) After discontinuation of a CYP3A4 inhibitor, resume previous dose of ibrutinib.(1)

DISCUSSION: The coadministration of multiple doses of erythromycin (moderate CYP3A inhibitor) increased ibrutinib's concentration maximum (Cmax) and area-under-curve (AUC) by 3.4-fold and 3-fold.(1) In a case report, concomitant administration of ibrutinib and verapamil/trandolapril resulted in ibrutinib toxicity consisting of nausea, dizziness, malaise, and severe diarrhea.(2) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, casopitant, clofazimine, clotrimazole, conivaptan, crizotinib, darunavir, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, grapefruit juice, imatinib, isavuconazonium, ledipasvir, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(1,3,4)

Ibrutinib/Selected Anticoagulants; Antiplatelets

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

MECHANISM OF ACTION: Ibrutinib administration lowers platelet count in the majority of patients.(1,2) In addition, ibrutinib has been shown to inhibit collagen-mediated platelet aggregation.(3-4) Bleeding has been reported with the use of ibrutinib,(1-4) anticoagulants, or antiplatelets alone.

CLINICAL EFFECTS: Concurrent use of ibrutinib with either anticoagulants or antiplatelets may increase the risk of hemorrhage.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: The Canadian product monograph for ibrutinib recommends concurrent use with anticoagulants or antiplatelets should be approached with caution. If therapeutic anticoagulation is required, consider temporarily withholding ibrutinib therapy until stable anticoagulation in achieved.(2) The US prescribing information for ibrutinib states patients receiving concurrent therapy with ibrutinib and anticoagulants and/or antiplatelets should be closely monitored for changes in platelet count or in International Normalized Ratio (INR). Carefully weigh the risks vs. benefits of concurrent therapy in patients with significant thrombocytopenia. If a bleeding event occurs, follow manufacturer instructions for ibrutinib dose adjustment.(1) If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory tests (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Bleeding has been reported with ibrutinib alone.(1-3) Across 27 clinical trials, grade 3 or higher bleeding events, e.g. subdural hematoma, gastrointestinal bleeding or hematuria, have occurred in up to 4% of patients, with 0.4% fatality. Grade 3 or 4 thrombocytopenia occurred in 5-19% of patients. Bleeding events of any grade occurred in 39% of patients treated with ibrutinib.(1) Concurrent use of anticoagulants or antiplatelets has been reported to increase the risk for major bleeding. In clinical trials, major bleeding occurred in 3.1% of patients taking ibrutinib without concurrent anticoagulants or antiplatelets, 4.4% of patients on concurrent antiplatelets with or without anticoagulants, and 6.1% of patients on concurrent anticoagulants with or without antiplatelets.(1) In an open-label, phase 2 trial of patients with relapsed/refractory mantle cell lymphoma on ibrutinib, 61 patients (55%) on concurrent anticoagulants or antiplatelets had a higher rate of bleeding (69% any grade, 8% grade 3-4) than patients not on anticoagulants or antiplatelets (28% any grade, 4% grade 3-4).(5) A retrospective trial found a hazard ratio of 20 (95% CI, 2.1-200) for patients on ibrutinib with concurrent anticoagulants and antiplatelets. There was a trend towards an increased bleeding risk in patients on either anticoagulants or antiplatelets, but this was not statistically significant on multivariate analysis.(6) A case report of 2 patients with chronic lymphocytic leukemia (CLL) on ibrutinib and dabigatran demonstrated no stroke nor bleeding events during the mean 11.5 month follow-up.(7) A case report of 4 patients with lymphoproliferative disease on concurrent dabigatran and ibrutinib demonstrated no stroke nor major bleeding events. 1 patient experienced grade 2 conjunctival hemorrhage whilst on both ibrutinib and dabigatran. The anticoagulant was withheld and successfully re-initiated at a lower dose with no further bleeding events.(8)

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)

*None.

• Child-pugh class C hepatic impairment
• Lactation
• Progressive multifocal leukoencephalopathy

• Anemia
• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Chronic heart failure
• Disease of liver
• Hemorrhage
• Increased risk of bleeding
• Infection
• Interstitial lung disease
• Neutropenic disorder
• Pregnancy
• Thrombocytopenic disorder
• Ventricular tachycardia

• Atrial fibrillation
• Atrial flutter
• Cerebrovascular accident
• Hypertension
• Invasive surgical procedure

Adverse effects reported in >=30% of patients with B-cell malignancies include thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.

Adverse effects reported in >=20% of adult or pediatricpatients with chronic graft versus host disease include fatigue, anemia,bruising, diarrhea, thrombocytopenia, musculoskeletal pain, pyrexia,muscle spasms, stomatitis, nausea, hemorrhage, abdominal pain,headache, and pneumonia.

More Frequent

• Anemia
• Hemorrhage
• Infection
• Neutropenic disorder
• Pneumonia
• Thrombocytopenic disorder

Less Frequent

• Atrial fibrillation
• Atrial flutter
• Cardiac arrhythmia
• Gastrointestinal hemorrhage
• Hypertension

Rare or Very Rare

• Abnormal hepatic function tests
• Anaphylaxis
• Angioedema
• Cerebrovascular accident
• Cutaneous vasculitis
• Drug-induced hepatitis
• Heart failure
• Hepatic cirrhosis
• Hepatic failure
• Hyperbilirubinemia
• Interstitial lung disease
• Intracranial bleeding
• Ocular hemorrhage
• Panniculitis
• Pneumocystis jirovecii pneumonia
• Progressive multifocal leukoencephalopathy
• Reactivation of hepatitis B
• Renal failure
• Sepsis
• Squamous cell carcinoma of skin
• Stevens-johnson syndrome
• Subdural intracranial hemorrhage
• Sweet's syndrome
• Tumor lysis syndrome
• Uveitis
• Ventricular tachycardia

More Frequent

• Acute abdominal pain
• Anorexia
• Bruising
• Constipation
• Diarrhea
• Dyspnea
• Fatigue
• Fever
• Musculoskeletal pain
• Nausea
• Peripheral edema
• Skin rash
• Upper respiratory infection
• Vomiting

Less Frequent

• Arthralgia
• Blurred vision
• Cough
• Dehydration
• Dizziness
• Dyspepsia
• Ecchymosis
• Epistaxis
• General weakness
• Headache disorder
• Hematuria
• Insomnia
• Muscle spasm
• Petechiae
• Reduced visual acuity
• Sinusitis
• Skin and skin structure infection
• Stomatitis
• Symptoms of anxiety
• Urinary tract infection

Rare or Very Rare

• Basal cell carcinoma of skin
• Onycholysis
• Peripheral neuropathy
• Urticaria

No enhanced messaging available.

Safety and efficacy of ibrutinib have been established for treatment of chronic graft-versus-host-disease (GVHD) after failure of >=1 lines of systemic therapy in pediatric patients >=1 year of age. For this indication, the recommended dosage of ibrutinib in children >=12 years of age is the same as that in adults, and the recommended dosage in children 1 to <12 years of age is based on body surface area. Safety and efficacy of ibrutinib have not been established for treatment of chronic GVHD in pediatric patients <1 year of age.

Safety and efficacy of ibrutinib have not been established in pediatric patients withchronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL),CLL/SLL with 17p deletion, or Waldenstrom's macroglobulinemia.

Although there are no available data in pregnant females, ibrutinib may cause fetal harm based on animal findings. Verify pregnancy status prior to initiating ibrutinib therapy in females of reproductive potential. If ibrutinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, apprise the patient of the potential fetal hazard.

It is not known whether ibrutinib or its metabolites are distributed into human milk or if the drug has any effect on milk production or the nursing infant. Advisefemales not to breast-feed during treatment with ibrutinib and for 1 week after discontinuing the drug due to the potential for serious adverse reactions in the breast-fed child.

The manufacturer makes no specific dosage recommendations for geriatric patients. Certain ibrutinib toxicities may be more frequent in geriatric patients.

In clinical trials ofibrutinib for B-cell malignancies or chronic GVHD, 62% of patients were >=65 years of age and 22% were >=75 years of age. No overall differences in efficacy were observed between geriatric and younger patients, but some adverse effects (e.g., anemia, grade 3 or higher pneumonia, thrombocytopenia, hypertension, atrial fibrillation) occurred more frequently in geriatric patients.