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Drug overview for IRINOTECAN HCL (irinotecan hcl):
Generic name: IRINOTECAN HCL (eye-ree-no-TEE-kan)
Drug class: Antineoplastic - Topoisomerase I Inhibitors
Therapeutic class: Antineoplastics
Irinotecan, a type I DNA topoisomerase inhibitor, is an antineoplastic agent.
Irinotecan is commercially available in 2 types of formulations: conventional (nonencapsulated) and liposomal irinotecan hydrochloride. The efficacy and safety of irinotecan for each indication is based on research and clinical experience using a specific formulation.
Generic name: IRINOTECAN HCL (eye-ree-no-TEE-kan)
Drug class: Antineoplastic - Topoisomerase I Inhibitors
Therapeutic class: Antineoplastics
Irinotecan, a type I DNA topoisomerase inhibitor, is an antineoplastic agent.
Irinotecan is commercially available in 2 types of formulations: conventional (nonencapsulated) and liposomal irinotecan hydrochloride. The efficacy and safety of irinotecan for each indication is based on research and clinical experience using a specific formulation.
DRUG IMAGES
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The following indications for IRINOTECAN HCL (irinotecan hcl) have been approved by the FDA:
Indications:
Metastatic colorectal cancer
Professional Synonyms:
None.
Indications:
Metastatic colorectal cancer
Professional Synonyms:
None.
The following dosing information is available for IRINOTECAN HCL (irinotecan hcl):
Irinotecan is commercially available in 2 types of formulations: conventional (nonencapsulated) and liposomal irinotecan hydrochloride. The properties of irinotecan may differ according to formulation, and the dosage and reconstitution instructions for irinotecan are specific to formulation. Liposomal irinotecan hydrochloride may not be substituted for other formulations of irinotecan hydrochloride.
Dosage of liposomal irinotecan hydrochloride is expressed in terms of anhydrous irinotecan, whereas dosage of conventional irinotecan hydrochloride is expressed in terms of the hydrated salt.
In addition to GI and hematologic toxicity, other severe adverse effects have occurred in patients receiving conventional or liposomal irinotecan. Hypersensitivity reactions, including severe anaphylactic or anaphylactoid reactions, have been reported. Renal impairment and acute renal failure have occurred, usually in patients who became volume-depleted from severe vomiting and/or diarrhea.
Cardiovascular and thromboembolic events also have been reported in patients receiving conventional irinotecan. (See Cardiovascular Toxicity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)
The manufacturer of conventional irinotecan recommends close monitoring in patients older than 65 years of age because of increased risk of treatment-related toxicity, such as early and late diarrhea, during therapy with conventional irinotecan. Patients receiving conventional irinotecan/fluorouracil/leucovorin therapy should be monitored closely (e.g., weekly assessment), particularly during the first cycle of treatment, since most of the treatment-related toxicities leading to early death occurred within the first 3-4 weeks. Changes in serum electrolytes and/or acid-base balance, including hyponatremia or hypernatremia, hypokalemia, and/or metabolic acidosis, may be an early indication of treatment-related toxicity; patients with abnormalities in serum sodium, potassium, and/or bicarbonate concentrations, with or without concomitant elevations in BUN or serum creatinine concentrations, should be evaluated carefully for dehydration and receive aggressive medical management, including fluid and electrolyte replacement.
Liposomal irinotecan hydrochloride can only be obtained through select specialty distributors. Clinicians may consult the Onivyde(R) website for specific availability information (https://www.onivyde.com).
Because irinotecan often causes neutropenia, leukopenia, and anemia, which can be severe, the drug should not be used in patients with severe bone marrow failure. In addition, concurrent radiation therapy has not been adequately studied and is not recommended. Because conventional irinotecan hydrochloride for injection concentrate contains sorbitol, the drug should not be given to patients with hereditary fructose intolerance.
Treatment with conventional or liposomal irinotecan should not be initiated until resolution of bowel obstruction.
Irinotecan is considered an antineoplastic agent of moderate emetic risk (i.e., incidence of emesis without antiemetics exceeds 30% but does not exceed 90%). Because nausea and/or vomiting occur frequently in patients receiving irinotecan therapy and may be severe, effective antiemetic therapy (e.g., dexamethasone 8 mg and a 5-HT3 serotonin receptor antagonist such as palonosetron) should be administered orally or IV at least 30 minutes prior to irinotecan therapy. Additional oral antiemetic therapy also should be considered for subsequent home use by the patient as needed.
Unless clinically contraindicated, clinicians should consider prophylactic or therapeutic administration of antimuscarinic therapy (e.g., 0.25-1 mg of atropine sulfate by IV or subcutaneous injection) for patients experiencing rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, bradycardia, abdominal cramping, or early diarrhea (i.e., diarrhea with an onset during or shortly after (within 24 hours of) administration of irinotecan); such symptoms are expected to occur more frequently in patients receiving higher doses of irinotecan.
Dosage adjustment may be required according to the patient's status for activity of UGT1A1, a uridine diphosphate-glucuronosyltransferase (UGT) enzyme involved in the metabolism of SN-38, an active metabolite of irinotecan. In patients who are homozygous for the UGT1A1*28 allele, UGT1A1 activity is reduced, and the risk of irinotecan-induced neutropenia is increased; reduction in the initial dosage of conventional irinotecan by at least one dose level should be considered in such patients. The optimal dosage reduction for conventional irinotecan has not been established, and subsequent dosage adjustment may be necessary according to patient tolerance.
The recommended initial dose of liposomal irinotecan in patients with metastatic adenocarcinoma of the pancreas who are homozygous for the UGT1A1*28 allele is 50 mg/m2; the dose may be increased to 70 mg/m2 as tolerated during subsequent cycles. In patients who are heterozygous for the UGT1A1*28 allele, UGT1A1 activity is intermediate, and the risk of irinotecan-induced neutropenia may be increased. Clinical results have been variable with conventional irinotecan.
Inadvertent overdosage of conventional irinotecan has occurred in several patients, including at least one fatal case, because the manufacturer's label on the vial was misread. Therefore, particular care should be taken to ensure that the correct dose of the drug is administered, including careful attention to the concentration of conventional irinotecan for injection concentrate present in the vial and the appropriate volume needed to provide the prescribed dose.
Patients should be instructed to contact their clinician if any of the following occur during irinotecan therapy: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration, such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth because of nausea or vomiting; inability to control diarrhea within 24 hours; new-onset cough or dyspnea; manifestations of severe hypersensitivity reactions; or fever or evidence of infection. Patients should be warned about the potential for dizziness or visual disturbances that may occur within 24 hours following the administration of conventional irinotecan and be advised not to drive or operate machinery if these symptoms occur. Patients also should be alerted to the possibility of alopecia during conventional or liposomal irinotecan therapy.
Dosage of conventional or liposomal irinotecan should be modified as necessary based on individual patient tolerance; the patient should be monitored carefully to obtain optimum therapeutic response with minimum adverse effects. Among those receiving conventional or liposomal irinotecan-based combination therapy, doses of fluorouracil also should be modified as necessary based on individual patient tolerance.
The manufacturer states that a new cycle of conventional irinotecan therapy should not be undertaken until the granulocyte count has recovered to at least 1500/mm3, the platelet count has recovered to at least 100,000/mm3, and treatment-related diarrhea has fully resolved. If the patient experiences multiple toxicities, adjustment of conventional irinotecan hydrochloride dose within a cycle of therapy and prior to starting a new cycle of therapy should be based on the preceding toxicity requiring the largest dose reduction. Treatment should be delayed for 1-2 weeks to allow for recovery from treatment-related toxicities.
If the patient experiences an irinotecan-induced toxicity that does not resolve after delaying drug administration for 2 weeks, discontinuance of the drug should be considered.
Among patients receiving conventional irinotecan as a single agent, initial doses of conventional irinotecan hydrochloride are based on body surface area alone, but subsequent doses within a cycle of therapy or for a new cycle of therapy in patients receiving the drug on a weekly dosage schedule should be adjusted in increments of 25-50 mg/m2 to a dose within the range of 50-150 mg/m2 based on the worst toxicity encountered with the previous dose of conventional irinotecan; subsequent doses for a new cycle of therapy in patients receiving the drug once every 3 weeks should be decreased in increments of 50 mg/m2 to a dose as low as 200 mg/m2 based on the worst toxicity encountered with the previous dose of conventional irinotecan. If the patient experiences no toxicity within a cycle of therapy using the once-every-3-weeks dosage schedule, the current conventional irinotecan hydrochloride dose should be maintained for the subsequent cycle of therapy. If the patient experiences no toxicity during an entire 6-week cycle of therapy using the weekly dosage schedule, the dose of conventional irinotecan hydrochloride may be increased by 25 mg/m2 at the start of the next cycle; however, the dose should not exceed 150 mg/m2.
The Recommended Dosage Modifications tables (Tables 2-4) describe recommended modifications in conventional irinotecan hydrochloride dose based on commonly observed toxicities of the drug for patients receiving combination or single-agent therapy with the drug. The dose-limiting toxicities of conventional irinotecan are diarrhea and neutropenia.
Recommended dosage modifications for liposomal irinotecan based on observed toxicities of the drug are described in the following sections on specific types and severities of toxicity.
For a more complete discussion of dosage modifications, cautions, and precautions associated with conventional or liposomal irinotecan therapy, the respective manufacturer's labeling should be consulted.
Dosage of liposomal irinotecan hydrochloride is expressed in terms of anhydrous irinotecan, whereas dosage of conventional irinotecan hydrochloride is expressed in terms of the hydrated salt.
In addition to GI and hematologic toxicity, other severe adverse effects have occurred in patients receiving conventional or liposomal irinotecan. Hypersensitivity reactions, including severe anaphylactic or anaphylactoid reactions, have been reported. Renal impairment and acute renal failure have occurred, usually in patients who became volume-depleted from severe vomiting and/or diarrhea.
Cardiovascular and thromboembolic events also have been reported in patients receiving conventional irinotecan. (See Cardiovascular Toxicity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)
The manufacturer of conventional irinotecan recommends close monitoring in patients older than 65 years of age because of increased risk of treatment-related toxicity, such as early and late diarrhea, during therapy with conventional irinotecan. Patients receiving conventional irinotecan/fluorouracil/leucovorin therapy should be monitored closely (e.g., weekly assessment), particularly during the first cycle of treatment, since most of the treatment-related toxicities leading to early death occurred within the first 3-4 weeks. Changes in serum electrolytes and/or acid-base balance, including hyponatremia or hypernatremia, hypokalemia, and/or metabolic acidosis, may be an early indication of treatment-related toxicity; patients with abnormalities in serum sodium, potassium, and/or bicarbonate concentrations, with or without concomitant elevations in BUN or serum creatinine concentrations, should be evaluated carefully for dehydration and receive aggressive medical management, including fluid and electrolyte replacement.
Liposomal irinotecan hydrochloride can only be obtained through select specialty distributors. Clinicians may consult the Onivyde(R) website for specific availability information (https://www.onivyde.com).
Because irinotecan often causes neutropenia, leukopenia, and anemia, which can be severe, the drug should not be used in patients with severe bone marrow failure. In addition, concurrent radiation therapy has not been adequately studied and is not recommended. Because conventional irinotecan hydrochloride for injection concentrate contains sorbitol, the drug should not be given to patients with hereditary fructose intolerance.
Treatment with conventional or liposomal irinotecan should not be initiated until resolution of bowel obstruction.
Irinotecan is considered an antineoplastic agent of moderate emetic risk (i.e., incidence of emesis without antiemetics exceeds 30% but does not exceed 90%). Because nausea and/or vomiting occur frequently in patients receiving irinotecan therapy and may be severe, effective antiemetic therapy (e.g., dexamethasone 8 mg and a 5-HT3 serotonin receptor antagonist such as palonosetron) should be administered orally or IV at least 30 minutes prior to irinotecan therapy. Additional oral antiemetic therapy also should be considered for subsequent home use by the patient as needed.
Unless clinically contraindicated, clinicians should consider prophylactic or therapeutic administration of antimuscarinic therapy (e.g., 0.25-1 mg of atropine sulfate by IV or subcutaneous injection) for patients experiencing rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, bradycardia, abdominal cramping, or early diarrhea (i.e., diarrhea with an onset during or shortly after (within 24 hours of) administration of irinotecan); such symptoms are expected to occur more frequently in patients receiving higher doses of irinotecan.
Dosage adjustment may be required according to the patient's status for activity of UGT1A1, a uridine diphosphate-glucuronosyltransferase (UGT) enzyme involved in the metabolism of SN-38, an active metabolite of irinotecan. In patients who are homozygous for the UGT1A1*28 allele, UGT1A1 activity is reduced, and the risk of irinotecan-induced neutropenia is increased; reduction in the initial dosage of conventional irinotecan by at least one dose level should be considered in such patients. The optimal dosage reduction for conventional irinotecan has not been established, and subsequent dosage adjustment may be necessary according to patient tolerance.
The recommended initial dose of liposomal irinotecan in patients with metastatic adenocarcinoma of the pancreas who are homozygous for the UGT1A1*28 allele is 50 mg/m2; the dose may be increased to 70 mg/m2 as tolerated during subsequent cycles. In patients who are heterozygous for the UGT1A1*28 allele, UGT1A1 activity is intermediate, and the risk of irinotecan-induced neutropenia may be increased. Clinical results have been variable with conventional irinotecan.
Inadvertent overdosage of conventional irinotecan has occurred in several patients, including at least one fatal case, because the manufacturer's label on the vial was misread. Therefore, particular care should be taken to ensure that the correct dose of the drug is administered, including careful attention to the concentration of conventional irinotecan for injection concentrate present in the vial and the appropriate volume needed to provide the prescribed dose.
Patients should be instructed to contact their clinician if any of the following occur during irinotecan therapy: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration, such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth because of nausea or vomiting; inability to control diarrhea within 24 hours; new-onset cough or dyspnea; manifestations of severe hypersensitivity reactions; or fever or evidence of infection. Patients should be warned about the potential for dizziness or visual disturbances that may occur within 24 hours following the administration of conventional irinotecan and be advised not to drive or operate machinery if these symptoms occur. Patients also should be alerted to the possibility of alopecia during conventional or liposomal irinotecan therapy.
Dosage of conventional or liposomal irinotecan should be modified as necessary based on individual patient tolerance; the patient should be monitored carefully to obtain optimum therapeutic response with minimum adverse effects. Among those receiving conventional or liposomal irinotecan-based combination therapy, doses of fluorouracil also should be modified as necessary based on individual patient tolerance.
The manufacturer states that a new cycle of conventional irinotecan therapy should not be undertaken until the granulocyte count has recovered to at least 1500/mm3, the platelet count has recovered to at least 100,000/mm3, and treatment-related diarrhea has fully resolved. If the patient experiences multiple toxicities, adjustment of conventional irinotecan hydrochloride dose within a cycle of therapy and prior to starting a new cycle of therapy should be based on the preceding toxicity requiring the largest dose reduction. Treatment should be delayed for 1-2 weeks to allow for recovery from treatment-related toxicities.
If the patient experiences an irinotecan-induced toxicity that does not resolve after delaying drug administration for 2 weeks, discontinuance of the drug should be considered.
Among patients receiving conventional irinotecan as a single agent, initial doses of conventional irinotecan hydrochloride are based on body surface area alone, but subsequent doses within a cycle of therapy or for a new cycle of therapy in patients receiving the drug on a weekly dosage schedule should be adjusted in increments of 25-50 mg/m2 to a dose within the range of 50-150 mg/m2 based on the worst toxicity encountered with the previous dose of conventional irinotecan; subsequent doses for a new cycle of therapy in patients receiving the drug once every 3 weeks should be decreased in increments of 50 mg/m2 to a dose as low as 200 mg/m2 based on the worst toxicity encountered with the previous dose of conventional irinotecan. If the patient experiences no toxicity within a cycle of therapy using the once-every-3-weeks dosage schedule, the current conventional irinotecan hydrochloride dose should be maintained for the subsequent cycle of therapy. If the patient experiences no toxicity during an entire 6-week cycle of therapy using the weekly dosage schedule, the dose of conventional irinotecan hydrochloride may be increased by 25 mg/m2 at the start of the next cycle; however, the dose should not exceed 150 mg/m2.
The Recommended Dosage Modifications tables (Tables 2-4) describe recommended modifications in conventional irinotecan hydrochloride dose based on commonly observed toxicities of the drug for patients receiving combination or single-agent therapy with the drug. The dose-limiting toxicities of conventional irinotecan are diarrhea and neutropenia.
Recommended dosage modifications for liposomal irinotecan based on observed toxicities of the drug are described in the following sections on specific types and severities of toxicity.
For a more complete discussion of dosage modifications, cautions, and precautions associated with conventional or liposomal irinotecan therapy, the respective manufacturer's labeling should be consulted.
Conventional or liposomal irinotecan hydrochloride is administered by IV infusion. Care should be taken to avoid extravasation of conventional irinotecan, and the infusion site should be monitored for signs of inflammation. Should manifestations of extravasation appear, the infusion should immediately be stopped and restarted in another vein.
The manufacturer of conventional irinotecan recommends that extravasation of the drug be treated by flushing the infusion site promptly with sterile water and applying an ice pack. Procedures for proper handling and disposal of antineoplastic drugs (e.g., use of protective clothing and gloves) should be used to avoid exposure to conventional or liposomal irinotecan during preparation of IV solutions. If conventional irinotecan hydrochloride for injection concentrate or a solution of the drug comes in contact with the skin or mucous membranes, the skin should be washed immediately and thoroughly with soap and water or the mucosa should be flushed with copious amounts of water.
The manufacturer of conventional irinotecan recommends that extravasation of the drug be treated by flushing the infusion site promptly with sterile water and applying an ice pack. Procedures for proper handling and disposal of antineoplastic drugs (e.g., use of protective clothing and gloves) should be used to avoid exposure to conventional or liposomal irinotecan during preparation of IV solutions. If conventional irinotecan hydrochloride for injection concentrate or a solution of the drug comes in contact with the skin or mucous membranes, the skin should be washed immediately and thoroughly with soap and water or the mucosa should be flushed with copious amounts of water.
No dosing information available.
No generic dosing information available.
The following drug interaction information is available for IRINOTECAN HCL (irinotecan hcl):
There are 6 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Irinotecan/Strong CYP3A4 Inhibitors; Darunavir 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: Inhibitors of CYP3A4 may inhibit the metabolism of SN-38, the active metabolite of irinotecan. Strong CYP3A4 inhibitors and darunavir may prevent the breakdown of SN-38 to its inactive metabolites APC, NPC, M2, M3, and M4.(1,2) CLINICAL EFFECTS: Coadministration of irinotecan with a strong CYP3A4 inhibitor may result in increased irinotecan plasma concentration, and therefore increased exposure to its active metabolite SN-38. Increased SN-38 exposure may lead to serious toxicity, including severe neutropenia, interstitial pulmonary disease, and even death.(3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of irinotecan and strong CYP3A4 inhibitors or darunavir is contraindicated.(2-4) Strong CYP3A4 inhibitors should be discontinued at least 1 week prior to starting irinotecan.(4) The US manufacturer of itraconazole states that concomitant administration with irinotecan is contra-indicated during and two weeks after itraconazole treatment.(5) If concurrent therapy is warranted, consider a four-fold reduction in irinotecan dose.(3) Patients receiving concurrent therapy should be closely monitored for toxicity. DISCUSSION: A randomized cross-over study involving seven patients was performed in which each was given irinotecan 350 mg/m2 IV alone for 90 minutes and followed 3 weeks later by irinotecan 100 mg/m2 given with ketoconazole 200 mg orally 1 hour before or 23 hours after the infusion of irinotecan, or both cycles were given vice versa. With ketoconazole coadministration, the conversion of irinotecan to its inactive metabolite was reduced by 87%, whereas the relative exposure to the active prodrug was increased by 109%. Both hematologic (degree of myelosuppression; percent decrease in neutrophil count) and nonhematologic (nausea, vomiting, and diarrhea) parameters were similar between the courses, despite a 3.5 fold reduced irinotecan dose when given in combination with ketoconazole. The authors concluded that the coadministration of various CYP3A4 inhibitors could potentiate a fatal outcome.(3) A prospective, open-label, randomized study was conducted to determine the pharmacokinetics of lopinavir (LPV)/ritonavir (RTV) administration with irinotecan (CPT11). Eight HIV-infected, Caucasian male patients with Kaposi's sarcoma, stage IV (according to New York University classification) were administered highly active antiretroviral therapy (HAART). HAART consisted of 400 mg lopinavir/ 100 mg ritonavir (Kaletra) twice daily (b.i.d) in association with NRTIs b.i.d. for at least 1 month before the start of anticancer chemotherapy. Patients were then treated with irinotecan as a single agent (150 mg/m2) over a 90 min infusion at days 1 and 10, every 3 weeks. Concomitant LPV/RTV treatment reduced the irinotecan clearance from 21.3 +/- 6.3 to 11.3 +/- 3.5 l/h/m2 (P=0.0008) causing an 89% increase of CPT11 AUC (P=0.001) and a 20% increase in the Cmax of CPT11 (p=0.02). The LPV/RTV treatment increased the AUC of SN38 by 204% (p=0.0001) and AUC of SN38G by 94% (P=0.002). Conversely, LPV/RTV treatment caused an 81% reduction in AUC of APC (p=0.02). Overall, the authors concluded that CYP3A4 inhibitors like LPV/RTV decrease CPT11 clearance and increase SN-38 exposure, potentially leading to CPT11 toxicity if not monitored closely.(7) Strong CYP3A4 Inhibitors include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir/ritonavir, paritaprevir, posaconazole, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(8) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
APTIVUS, CLARITHROMYCIN, CLARITHROMYCIN ER, DARUNAVIR, EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KISQALI, KORLYM, KRAZATI, LANSOPRAZOL-AMOXICIL-CLARITHRO, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NEFAZODONE HCL, NOXAFIL, OMECLAMOX-PAK, PAXLOVID, POSACONAZOLE, PREZCOBIX, PREZISTA, RECORLEV, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST, VFEND, VFEND IV, VIRACEPT, VOQUEZNA TRIPLE PAK, VORICONAZOLE, ZOKINVY, ZYDELIG, ZYKADIA |
| Irinotecan/UGT1A1 Inhibitors 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: Inhibitors of UGT1A1 may inhibit the metabolism of SN-38, the active metabolite of irinotecan.(1) Atazanavir may inhibit the metabolism of irinotecan by UGT1A1.(1,2) This increases the system exposure to SN-38, the active metabolite of irinotecan.(3) CLINICAL EFFECTS: Concurrent use of UGT1A1 inhibitors may result in increased exposure to and toxicity from irinotecan.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of irinotecan states do not administer UGT1A1 inhibitors with irinotecan unless there are no therapeutic alternatives. The increased exposure to the active metabolite should be taken into consideration when co-administering these agents.(1) The US manufacturer of atazanavir states that concurrent use of irinotecan is contraindicated.(2) The Australian manufacturer of atazanavir states that irinotecan should not be administered with atazanavir.(3) DISCUSSION: Because atazanavir inhibits UGT1A1 at therapeutic concentrations, it is expected to interfere with the metabolism of irinotecan. Therefore, the manufacturer of atazanavir states that irinotecan should not be administered with atazanavir.(1,2) UGT1A1 inhibitors linked to this monograph include: atazanavir, capivasertib, belumosudil, erlotinib, gemfibrozil, lapatinib, nilotinib, pazopanib, probenecid, regorafenib, and sorafenib. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
ATAZANAVIR SULFATE, DANZITEN, ERLOTINIB HCL, EVOTAZ, GEMFIBROZIL, LAPATINIB, LOPID, NEXAVAR, NILOTINIB HCL, NILOTINIB TARTRATE, PAZOPANIB HCL, PROBENECID, PROBENECID-COLCHICINE, REYATAZ, REZUROCK, SORAFENIB, STIVARGA, TASIGNA, TRUQAP, TYKERB, VOTRIENT |
| Efalizumab; Natalizumab/Immunosuppressives; Immunomodulators 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) |
TYSABRI |
| Live Vaccines; Live BCG/Selected Immunosuppressive Agents 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) 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) |
ACAM2000 (NATIONAL STOCKPILE), ADENOVIRUS TYPE 4, ADENOVIRUS TYPE 4 AND TYPE 7, ADENOVIRUS TYPE 7, BCG (TICE STRAIN), BCG VACCINE (TICE STRAIN), DENGVAXIA, ERVEBO (NATIONAL STOCKPILE), FLUMIST 2025-2026, FLUMIST HOME 2025-2026, IXCHIQ, M-M-R II VACCINE, PRIORIX, PROQUAD, ROTARIX, ROTATEQ, STAMARIL, VARIVAX VACCINE, VAXCHORA ACTIVE COMPONENT, VAXCHORA VACCINE, VIVOTIF, YF-VAX |
| Talimogene laherparepvec/Selected Immunosuppressants 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) |
IMLYGIC |
| Nadofaragene Firadenovec/Selected Immunosuppressants 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) |
ADSTILADRIN |
There are 23 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Irinotecan/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers including barbiturates, carbamazepine, fosphenytoin, phenytoin, phenobarbital, and primidone may induce the metabolism of irinotecan by CYP3A4.(1-4) CLINICAL EFFECTS: Concurrent use of barbiturates, carbamazepine, fosphenytoin, phenytoin, phenobarbital, or primidone with irinotecan may result in decreased levels of irinotecan, as well as its active metabolites, and decreased clinical effectiveness. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer states do not administer strong CYP3A4 inducers with irinotecan unless there are no therapeutic alternatives. Consideration should be given to substituting non-enzyme inducing anticonvulsants at least 2 weeks prior to irinotecan therapy.(1) Levels of irinotecan and the active metabolites should be monitored in patients receiving concurrent carbamazepine, fosphenytoin, phenytoin, phenobarbital, or primidone. If these agents are added to or discontinued from concurrent irinotecan the dosage of irinotecan may need to be adjusted to ensure therapeutic effects or prevent toxicity. DISCUSSION: In a clinical trial, irinotecan clearance values were 65.4% higher in patients receiving phenytoin when compared to patients who were not taking enzyme-inducing anticonvulsants.(2) In another clinical trial, irinotecan clearance was 117% higher in patients receiving anticonvulsants that included phenytoin.(5) Data from another clinical trial also suggested that phenytoin increases irinotecan clearance.(6) Case reports have also noted increased irinotecan clearance by 4-fold(3) and by 62.7%(4) in patients receiving concurrent phenytoin. Levels of irinotecan and its active metabolite, SN-38 were both decreased. |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPITOL, EQUETRO, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, MYSOLINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIMIDONE, SEZABY, TEGRETOL, TEGRETOL XR, TENCON |
| Irinotecan/Selected Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of irinotecan by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inducers may result in decreased levels of irinotecan, as well as its active metabolites, and decreased clinical effectiveness. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer states do not administer strong CYP3A4 inducers with irinotecan unless there are no therapeutic alternatives. Consideration should be given to substituting non-enzyme inducing therapies at least 2 weeks prior to irinotecan therapy.(1) Levels of irinotecan and the active metabolites should be monitored in patients receiving concurrent use of strong CYP3A4 inducers. If strong CYP3A4 inducers are added to or discontinued from concurrent irinotecan, the dosage of irinotecan may need to be adjusted to ensure therapeutic effects or prevent toxicity. DISCUSSION: The manufactures states that irinotecan may interact with strong CYP3A4 inducers which may result in increased irinotecan metabolism.(1) In a clinical trial, irinotecan clearance values were 65.4% higher in patients receiving phenytoin when compared to patients who were not taking enzyme-inducing anticonvulsants.(2) In another clinical trial, irinotecan clearance was 117% higher in patients receiving anticonvulsants that included phenytoin.(5) Data from another clinical trial also suggested that phenytoin increases irinotecan clearance.(6) Case reports have also noted increased irinotecan clearance by 4-fold(3) and by 62.7%(4) in patients receiving concurrent phenytoin. Levels of irinotecan and its active metabolite, SN-38 were both decreased. Selected strong CYP3A4 inducers linked include: apalutamide, encorafenib, enzalutamide, ivosidenib, lumacaftor, mitotane, rifabutin, rifampin, and rifapentine. |
BRAFTOVI, ERLEADA, LYSODREN, MITOTANE, ORKAMBI, PRIFTIN, RIFABUTIN, RIFADIN, RIFAMPIN, TALICIA, TIBSOVO, XTANDI |
| Deferiprone/Selected Myelosuppressive Agents 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) |
DEFERIPRONE, DEFERIPRONE (3 TIMES A DAY), FERRIPROX, FERRIPROX (2 TIMES A DAY), FERRIPROX (3 TIMES A DAY) |
| Tofacitinib/Immunosuppressives; Immunomodulators 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) |
TOFACITINIB CITRATE, XELJANZ, XELJANZ XR |
| Clozapine/Selected Myelosuppressive Agents 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 ANC monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. Clozapine is only available through a restricted distribution system which requires documentation of the absolute neutrophil count (ANC) prior to dispensing.(1-2) 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: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing.(1) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26) |
CLOZAPINE, CLOZAPINE ODT, CLOZARIL, VERSACLOZ |
| Selected Multiple Sclerosis Agents/Immunosuppressants; Immunomodulators 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) |
KESIMPTA PEN, OCREVUS, OCREVUS ZUNOVO |
| Selected BCRP Substrates/Darolutamide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Darolutamide inhibits BCRP, which may result in increased absorption of BCRP substrates.(1) CLINICAL EFFECTS: Administration of darolutamide with BCRP substrates may result in elevated levels of and toxicity from these agents.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer recommends avoiding concurrent use of darolutamide with BCRP substrates when possible. DISCUSSION: Concurrent administration of darolutamide with rosuvastatin increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 5-fold.(1) BCRP substrates linked to this monograph include: ciprofloxacin, diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, and topotecan.(1-3) |
NUBEQA |
| Upadacitinib/Immunosuppressives; Immunomodulators 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) |
RINVOQ, RINVOQ LQ |
| Selected BCRP Substrates/Capmatinib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Capmatinib inhibits BCRP, which may result in increased absorption of BCRP substrates.(1) CLINICAL EFFECTS: Administration of capmatinib with BCRP substrates may result in elevated levels of and toxicity from these agents.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of capmatinib states that the concurrent use of narrow therapeutic index BCRP substrates should be avoided. If concurrent therapy cannot be avoided, the dosage of the narrow therapeutic index BCRP substrate should be decreased according to the substrate prescribing information.(1) DISCUSSION: In a study, capmatinib increased rosuvastatin (a BCRP substrate) area-under-curve (AUC) by 108% and maximum concentration (Cmax) by 204%.(1) BCRP substrates linked to this monograph include: ciprofloxacin, glyburide, imatinib, irinotecan, lapatinib, methotrexate, and mitoxantrone.(1-2) |
TABRECTA |
| Inebilizumab/Immunosuppressives; Immunomodulators 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) |
UPLIZNA |
| Baricitinib/Immunosuppressives; Immunomodulators 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) |
OLUMIANT |
| Leflunomide; Teriflunomide/Selected Immunosuppressants 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) |
ARAVA, AUBAGIO, LEFLUNICLO, LEFLUNOMIDE, TERIFLUNOMIDE |
| Ponesimod/Immunosuppressives; Immunomodulators 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) |
PONVORY |
| Sodium Iodide I 131/Myelosuppressives; Immunomodulators 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) |
HICON, SODIUM IODIDE I-131 |
| Fingolimod/Immunosuppressives; Immunomodulators 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) |
FINGOLIMOD, GILENYA, TASCENSO ODT |
| Ozanimod/Immunosuppressives; Immunomodulators 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) |
ZEPOSIA |
| Siponimod/Immunosuppressives; Immunomodulators 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) |
MAYZENT |
| Cladribine/Immunosuppressives; Immunomodulators 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) |
CLADRIBINE, MAVENCLAD |
| Ritlecitinib/Immunosuppressives; Immunomodulators 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) |
LITFULO |
| Etrasimod/Immunosuppressives; Immunomodulators 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) |
VELSIPITY |
| Ropeginterferon alfa-2b/Slt Immunosuppress; Immunomodulator 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) |
BESREMI |
| Deuruxolitinib/Immunosuppressives; Immunomodulators 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) |
LEQSELVI |
| BCRP, OATP1B1, and OATP1B3 Substrates/Leniolisib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Leniolisib is an inhibitor of the BCRP, OATP1B1, and OATP1B3 transporters and may increase the absorption and/or decrease the elimination of drugs that are substrates of these transporters.(1) CLINICAL EFFECTS: Concurrent use of leniolisib with drugs that are substrates of the BCRP, OATP1B1, and OATP1B3 transporters may result in increased toxicity of the substrate.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid coadministration of leniolisib with substrates of BCRP, OATP1B1, and OATP1B3.(1) DISCUSSION: When co-administered, leniolisib increased rosuvastatin (a substrate of BCRP, OATP1B1, and OATP1B3) systemic exposure by 2-fold.(1) Substrates of BCRP, OATP1B1, and OATP1B3 that are linked to this monograph include: diclofenac, fluvastatin, glecaprevir, glyburide, imatinib, irinotecan, letermovir, lovastatin, methotrexate, mitoxantrone, momelotinib, paritaprevir, pitavastatin, pravastatin, repaglinide, simvastatin, and sulfasalazine.(1,2) |
JOENJA |
There are 8 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Ustekinumab/Immunosuppressives; Immunomodulators 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) |
IMULDOSA, OTULFI, PYZCHIVA, SELARSDI, STELARA, STEQEYMA, USTEKINUMAB, USTEKINUMAB-AEKN, USTEKINUMAB-TTWE, WEZLANA, YESINTEK |
| BCRP or OATP1B1 Substrates/Eltrombopag SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Eltrombopag has been shown to inhibit BCRP and OATP1B1.(1-3) Inhibition of BCRP may increase absorption and/or decrease biliary excretion of substrates, while inhibition of OATP1B1 may decrease hepatic uptake of substrates. CLINICAL EFFECTS: Simultaneous use of eltrombopag with BCRP or OATP1B1 substrates may result in increased levels and side effects from the substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of eltrombopag states that concomitant BCRP or OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects, and dose reduction of the substrate should be considered.(1) DISCUSSION: In a clinical trial in 39 healthy subjects, administration of eltrombopag (75 mg daily) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of rosuvastatin (10 mg, a BCRP and OATP1B1 substrate) by 55% and 103%, respectively.(1,4) In a physiologically-based pharmacokinetic (PBPK) model, eltrombopag 75 mg was predicted to increase the AUC and Cmax of pitavastatin 1 mg by approximately 2-fold.(5) BCRP substrates linked to this monograph include: ciprofloxacin, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and topotecan.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, and simvastatin.(1) |
ALVAIZ, ELTROMBOPAG OLAMINE, PROMACTA |
| COVID-19 Vaccines/Immunosuppressives; Immunomodulators 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.(1,2) 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.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: In an effort to optimize COVID-19 vaccine response, the American College of Rheumatology (ACR) published conditional recommendations for administration of COVID-19 vaccines with immunosuppressants and immunomodulators.(1) The CDC also provides clinical considerations for COVID-19 vaccination in patients on immunosuppressants.(2) 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.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose. See below for specific recommendations for certain agents.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(2) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1,2) B-cell depleting agents, including rituximab: 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.(1) 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 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. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(2) 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.(1) Cyclophosphamide: When feasible, administer cyclophosphamide one week after each COVID-19 vaccine dose.(1) 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.(2) 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.(1) The CDC includes these agents in their general recommendation to hold therapy for at least 2 weeks following vaccination.(2) DISCUSSION: 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.(1) 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.(1) 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.(1) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(1) 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.(1) 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.(1) |
COMIRNATY 2024-2025, MODERNA COVID 24-25(6M-11Y)EUA, NOVAVAX COVID 2024-2025 (EUA), PFIZER COVID 2024-25(5-11Y)EUA, PFIZER COVID 2024-25(6M-4Y)EUA, SPIKEVAX 2024-2025 |
| OATP1B1 Substrates/Midostaurin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Midostaurin has been shown to inhibit OATP1B1.(1) Inhibition of OATP1B1 may decrease hepatic uptake of substrates. CLINICAL EFFECTS: Simultaneous use of midostaurin with OATP1B1 substrates may result in increased levels and side effects from the substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of midostaurin states that concomitant OATP1B1 substrates should be used cautiously. Patients on concurrent therapy should be closely monitored for adverse effects as dose adjustments of the substrate may be necessary.(1) DISCUSSION: In a study, single dose midostaurin 100 mg increased the area-under-curve (AUC) of single dose rosuvastatin by 48%. With a 50 mg twice daily dose, midostaurin is predicted to increase the AUC of an OATP1B1 substrate by up to 2-fold.(1) OATP1B1 substrates linked to this monograph include: atorvastatin, bosentan, fluvastatin, glyburide, irinotecan, letermovir, pitavastatin, pravastatin, repaglinide, rosuvastatin and simvastatin. |
RYDAPT |
| Sarilumab/Immunosuppressives; Immunomodulators 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) |
KEVZARA |
| Ublituximab/Immunosuppressives; Immunomodulators 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) |
BRIUMVI |
| Tocilizumab/Immunosuppressives; Immunomodulators 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) |
ACTEMRA, ACTEMRA ACTPEN, TOFIDENCE, TYENNE, TYENNE AUTOINJECTOR |
| Selected BCRP Substrates/Momelotinib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Momelotinib is an inhibitor of the BCRP transporter, which may result in increased absorption and decreased hepatic uptake of BCRP substrates.(1) CLINICAL EFFECTS: Administration of momelotinib with BCRP substrates may result in elevated levels of and toxicity of the BCRP substrates.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of momelotinib states concurrent use with BCRP substrates should be approached with caution. If concurrent use is warranted, consider reducing the dose of the substrate drug according to the product labeling and monitor for adverse reactions.(1) DISCUSSION: Momelotinib increased the area-under-curve (AUC) and maximum concentration (Cmax) of rosuvastatin, a BCRP substrate, by 220% and 170%, respectively.(1) BCRP substrates linked to this monograph include: ciprofloxacin, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, and sulfasalazine.(1-2) |
OJJAARA |
The following contraindication information is available for IRINOTECAN HCL (irinotecan hcl):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 2 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Inflammatory bowel disease |
| Lactation |
There are 11 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Anemia |
| Dehydration |
| Diarrhea |
| Ileus |
| Interstitial lung disease |
| Neutropenic disorder |
| Pregnancy |
| Sepsis |
| Thrombocytopenic disorder |
| Thromboembolic disorder |
| UGt1a1*28 polymorphism |
There are 3 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Chronic obstructive pulmonary disease |
| Disease of liver |
| Hyperbilirubinemia |
The following adverse reaction information is available for IRINOTECAN HCL (irinotecan hcl):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 34 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Anemia Diarrhea Edema Fever Leukopenia Lymphopenia Neutropenic disorder Severe bone marrow depression Severe diarrhea Stomatitis |
Abnormal hepatic function tests Acute renal failure Bacterial sepsis Bradycardia Gastroenteritis Hypotension Increased alanine transaminase Increased aspartate transaminase Miosis Pneumonia |
| Rare/Very Rare |
|---|
|
Acute arterial thromboembolism Acute pancreatitis Anaphylaxis Bacterial infection Deep venous thrombosis Fungal infection Hypersensitivity drug reaction Hyponatremia Interstitial lung disease Myocardial ischemia Thrombocytopenic disorder Thromboembolic disorder Venous thrombosis Viral infection |
There are 30 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abdominal pain with cramps Alopecia Anorexia Constipation Cough Dizziness Dyspnea Fatigue Flushing General weakness Headache disorder Hyperbilirubinemia Nausea Pain Skin rash Vomiting Weight loss |
Abdominal distension Back pain Chills Eye tearing Hyperhidrosis Intestinal hypermotility Rhinitis Sialorrhea |
| Rare/Very Rare |
|---|
|
Dysarthria Insomnia Periorbital edema Pruritus of skin Urticaria |
The following precautions are available for IRINOTECAN HCL (irinotecan hcl):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
No enhanced Pregnancy information available for this drug.
No enhanced Lactation information available for this drug.
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for IRINOTECAN HCL (irinotecan hcl):
WARNING: You will be closely monitored (for example, by having blood tests) by your doctor while using this medication. Keep all medical and lab appointments. Irinotecan may cause severe diarrhea, which can occur during or right after you receive this medication and/or more than 24 hours afterward.
If the diarrhea starts right away, you may also have other side effects such as runny nose, increased saliva, watery eyes, sweating, stomach cramps, or flushing. If the diarrhea starts later, it could be a different type that may not stop and can cause serious (possibly fatal) loss of too much body water (dehydration), mineral imbalance, or serious infection (sepsis). Tell your doctor right away if you have diarrhea and/or any of the symptoms that occur with the early form of diarrhea.
Also tell your doctor if you have stomach/abdominal pain, extreme thirst, very dry mouth, muscle cramps/weakness, fast/slow/irregular heartbeat, fainting, dizziness, lightheadedness, or signs of infection (such as sore throat that doesn't go away, fever, chills). Your doctor should prescribe other medications to treat the diarrhea and other symptoms. This medication may cause very serious (possibly fatal) blood disorders (decreased bone marrow function leading to low number of blood cells such as white cells, red cells, and platelets).
This effect can decrease your body's ability to fight an infection, cause your body to bruise or bleed easier, or cause anemia. Tell your doctor right away if you develop any of the following: signs of infection (such as sore throat that doesn't go away, fever, chills), easy bruising/bleeding, unusual tiredness, fast/pounding heartbeat.
WARNING: You will be closely monitored (for example, by having blood tests) by your doctor while using this medication. Keep all medical and lab appointments. Irinotecan may cause severe diarrhea, which can occur during or right after you receive this medication and/or more than 24 hours afterward.
If the diarrhea starts right away, you may also have other side effects such as runny nose, increased saliva, watery eyes, sweating, stomach cramps, or flushing. If the diarrhea starts later, it could be a different type that may not stop and can cause serious (possibly fatal) loss of too much body water (dehydration), mineral imbalance, or serious infection (sepsis). Tell your doctor right away if you have diarrhea and/or any of the symptoms that occur with the early form of diarrhea.
Also tell your doctor if you have stomach/abdominal pain, extreme thirst, very dry mouth, muscle cramps/weakness, fast/slow/irregular heartbeat, fainting, dizziness, lightheadedness, or signs of infection (such as sore throat that doesn't go away, fever, chills). Your doctor should prescribe other medications to treat the diarrhea and other symptoms. This medication may cause very serious (possibly fatal) blood disorders (decreased bone marrow function leading to low number of blood cells such as white cells, red cells, and platelets).
This effect can decrease your body's ability to fight an infection, cause your body to bruise or bleed easier, or cause anemia. Tell your doctor right away if you develop any of the following: signs of infection (such as sore throat that doesn't go away, fever, chills), easy bruising/bleeding, unusual tiredness, fast/pounding heartbeat.
The following icd codes are available for IRINOTECAN HCL (irinotecan hcl)'s list of indications:
| Metastatic colorectal cancer | |
| C18 | Malignant neoplasm of colon |
| C18.0 | Malignant neoplasm of cecum |
| C18.1 | Malignant neoplasm of appendix |
| C18.2 | Malignant neoplasm of ascending colon |
| C18.3 | Malignant neoplasm of hepatic flexure |
| C18.4 | Malignant neoplasm of transverse colon |
| C18.5 | Malignant neoplasm of splenic flexure |
| C18.6 | Malignant neoplasm of descending colon |
| C18.7 | Malignant neoplasm of sigmoid colon |
| C18.8 | Malignant neoplasm of overlapping sites of colon |
| C18.9 | Malignant neoplasm of colon, unspecified |
| C19 | Malignant neoplasm of rectosigmoid junction |
| C20 | Malignant neoplasm of rectum |
| C21.8 | Malignant neoplasm of overlapping sites of rectum, anus and anal canal |
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