Imfinzi (durvalumab)
Antineoplastic - Anti-Programmed Death-(PD-1/L1) MC Antibody Intravenous Vial (Ml)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Durvalumab, a recombinant fully human anti-programmed-death ligand-1 (anti-PD-L1) monoclonal antibody, is an antineoplastic agent. The drug is an IgG1 kappa immunoglobulin.
Durvalumab, a recombinant fully human anti-programmed-death ligand-1 (anti-PD-L1) monoclonal antibody, is an antineoplastic agent. The drug is an IgG1 kappa immunoglobulin that binds to PD-L1.
The immune-checkpoint receptor programmed-death receptor-1 (PD-1) is expressed on activated T cells, B cells, macrophages, and dendritic cells. Overexpression of PD-1 ligands on the surface of tumor cells results in activation of PD-1 and CD80 (i.e., B7.1) and suppression of cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Durvalumab blocks the interaction between PD-L1 and the receptors PD-1 and CD80, resulting in activation of the antitumor immune response without inducing antibody-dependent cell-mediated cytotoxicity (ADCC).
The drug also has been shown to reduce tumor growth in mouse tumor models.
Pharmacokinetic exposure of durvalumab increased more than dose proportionally at doses <3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses >=3 mg/kg every 2 weeks. Steady state was achieved at approximately 16 weeks. The pharmacokinetics of durvalumab is similar when assessed as a single agent, when in combination with chemotherapy, when in combination with tremelimumab-actl, and when in combination with tremelimumab-actl and platinum-based chemotherapy.
Durvalumab clearance decreases over time. The elimination half-life is approximately 21 days.
There were no clinically important differences in the pharmacokinetics of durvalumab based on body weight, age, sex, race, albumin levels, lactate dehydrogenase levels, soluble PD-L1, tumor type, mild or moderate renal impairment, and mild or moderate hepatic impairment. The effect of severe renal or hepatic impairment on the pharmacokinetics of durvalumab is unknown.
USES: Durvalumab is used to treat various types of cancer. It works by helping your immune system fight the cancer. This medication belongs to a class of drugs known as monoclonal antibodies.
Generic name: durvalumab
Pronunciation: (dur-VAL-ue-mab)
Drug class: Antineoplastic - Anti-Programmed Death-(PD-1/L1) MC Antibody
Therapeutic class: Antineoplastics
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Imfinzi
Indications
The following indications are listed for Imfinzi:
- Biliary Tract Malignancy
- Egfr Negative, Alk Negative, Non-Small Cell Lung Cancer
- Extensive-Stage Small Cell Lung Cancer
- Gastric Cancer
- Gastroesophageal Junction Adenocarcinoma
- Invasive Bladder Cancer
- Liver Cell Carcinoma
- Mismatch Repair Deficient Endometrial Cancer
- Non-Muscle Invasive Bladder Cancer
- Non-Small Cell Lung Cancer
- Small Cell Lung Carcinoma
Also known as: Biliary Cancer, Biliary Malignancy, Dmmr Endometrial Cancer, Egfr-Negative, Alk Mut (-) Non-Small Cell Lung Cancer, Egfr-Negative, Alk-Negative, Nsclc, Extensive Stage Primary Small Cell Carcinoma Of Lung, Gallbladder Or Bile Duct Cancer, Gastric Malignancy, Hepatocarcinoma, Hepatocellular Carcinoma, Invasive Malignancy Of Bladder, Malignant Neoplasm Of Gallbladder Or Bile Ducts, Malignant Neoplasm Of Stomach, Malignant Tumor Of Gallbladder Or Bile Ducts, Malignant Tumor Of Stomach, Muscle Invasive Bladder Cancer, Oat Cell Carcinoma Of The Lung, Primary Adenocarcinoma Of Cardioesophageal Junction, Primary Adenocarcinoma Of Esophagogastric Junction, Small Cell Lung Cancer, Superficial Carcinoma Of Urinary Bladder.
Dosing
If immune-mediated adverse effects or certain other adverse effects occur, temporary or permanent discontinuance of durvalumab may be required based on severity of the reaction. Dosage reductions of durvalumab are not recommended.
In general, withhold durvalumab for severe (grade 3) immune-mediated adverse reactions. Permanently discontinue durvalumab for life-threatening (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dosage to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids. Specific recommendations that differ from these general guidelines are summarized in the Table 1.
Table 1. Recommended Dosage Modification for Adverse Reactions
Type of Reaction Severity Modification Immune-mediated Adverse Reactions Pneumonitis Grade 2 Withhold Grade 3 or 4 Permanently discontinue Colitis Grade 2 Withhold Grade 3 Withhold or permanently discontinue Grade 4 Permanently discontinue Intestinal perforation Any grade Permanently discontinue Hepatitis with no ALT or AST increases to Withhold hepatic tumor >3 and up to 8 times ULN involvement OR total bilirubin increases to >1.5 to 3 times ULN ALT or AST increases to Permanently discontinue >8 times ULN OR total bilirubin increases to >3 times ULN Hepatitis with hepatic ALT or AST increases to Withhold tumor involvement >1 and up to 3 times ULN at baseline and increases to no >5 and up to 10 times ULN OR ALT or AST is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times ULN ALT or AST increases to Permanently discontinue >10 times ULN OR total bilirubin increase to >3 times ULN Endocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with renal Grade 2 or 3 increased Withhold dysfunction blood creatinine Grade 4 increased blood Permanently discontinue creatinine Exfoliative dermatologic Suspected Stevens Withhold conditions Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Confirmed SJS, TEN, or Permanently discontinue DRESS Myocarditis Grade 2, 3, or 4 Permanently discontinue Neurological toxicities Grade 2 Withhold Grade 3 or 4 Permanently discontinue Other Adverse Reactions Infusion-related Grade 1 or 2 Interrupt or slow the reactions infusion rate Grade 3 or 4 Permanently discontinue
Resume in patients with complete or partial resolution (grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating corticosteroids or an inability to reduce corticosteroid dose to 10 mg of prednisone or less per day (or equivalent) within 12 weeks of initiating corticosteroids.
Permanently discontinue for grade 3 colitis when administered as part of a tremelimumab-actl containing regimen.
If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue treatment based on recommendations for hepatitis with no liver involvement.
Administer durvalumab by IV infusion after dilution.
Administer the diluted durvalumab solution through a sterile, low-protein-binding 0.2- or 0.22-microm inline filter.
Store durvalumab refrigerated at 2-8degreesC in the original carton to protect from light. Do not freeze or shake.
Administer diluted solutions of durvalumab immediately after preparation. If the diluted solution is not administered immediately, store it for up to 8 hours at room temperature (up to 25degreesC) or up to 28 days at 2-8degreesC (total storage time from initial vial entry for preparation of the dilution until start of the IV infusion). Do not freeze diluted solutions of the drug.
Discard any unused portion in the vial or infusion bag since durvalumab injection contains no preservative.
Do not administer durvalumab simultaneously through the same IV line with any other drug.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Imfinzi 120 Mg/2.4 Ml Vial | Maintenance | Infuse 10 mg/kg over 60 minute(s) by intravenous route every 2 weeks. |
| Imfinzi 500 Mg/10 Ml Vial | Maintenance | Infuse 10 mg/kg over 60 minute(s) by intravenous route every 2 weeks. |
No dosing information is available for this tab.
Drug interactions
No formal drug interaction studies have been performed to date.
No cytochrome P-450 (CYP) based drug interactions are anticipated since durvalumab is a monoclonal antibody.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Immunosuppressive; Immunomod/Cladribine Onc Inj (10 Mg/5 Ml)
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-2)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The UK and AU manufacturers of Litak state that concomitant use of other myelosuppressive medicinal products with cladribine is contraindicated.(1-2) The Israeli manufacturer of Litak states that cladribine should not be used concomitantly with other myelosuppressive medicinal products.(3)
DISCUSSION: The risk of severe myelotoxicity and long-lasting immunosuppression is increased in patients with a disease-related bone marrow infiltration or a previous myelosuppressive treatment.(1-3)
Immunosuppressives; Immunomodulators/Efalizumab; Natalizumab
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Natalizumab,(1-3) efalizumab,(4) immunosuppressives, and immunomodulators all suppress the immune system.
CLINICAL EFFECTS: Concurrent use of natalizumab(1-3) or efalizumab(4) with immunosuppressives or immunomodulators may result in an increased risk of infections, including progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).
PREDISPOSING FACTORS: Previous JCV infection, longer duration of natalizumab treatment - especially if greater than 2 years, and prior or concomitant treatment with immunosuppressant medication are all independent risk factors which increase the risk for PML.(1,5) The FDA has estimated PML incidence stratified by risk factors: If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment less than 25 months, incidence <1/1,000. If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment less than 25 months, incidence 2/1,000 If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 4/1,000 If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 11/1,000.
PATIENT MANAGEMENT: The US manufacturer of natalizumab states patients with Crohn's disease should not receive concurrent immunosuppressants, with the exception of limited overlap of corticosteroids, due to the increased risk for PML. For new natalizumab patients currently receiving chronic oral corticosteroids for Crohn's Disease, begin corticosteroid taper when therapeutic response to natalizumab has occurred. If corticosteroids cannot be discontinued within six months of starting natalizumab, discontinue natalizumab.(3) The US manufacturer of natalizumab states that natalizumab should not ordinarily be used in multiple sclerosis patients receiving immunosuppressants or immunomodulators due to the increased risk for PML. Immunosuppressives include, but are not limited to azathioprine, cyclophosphamide, cyclosporine, mercaptopurine, methotrexate, mitoxantrone, mycophenolate, and corticosteroids.(3,6) The UK manufacturer of natalizumab states that concurrent use with immunosuppressives or antineoplastic agents is contraindicated.(1) The Canadian manufacturer of natalizumab states that natalizumab should not be used with immunosuppressive or immunomodulatory agents.(2) The US manufacturer of certolizumab states that concurrent therapy with natalizumab is not recommended.(7)
DISCUSSION: Progressive multifocal leukoencephalopathy has been reported in patients receiving concurrent natalizumab were recently or concomitantly taking immunomodulators or immunosuppressants.(1-5,8,9) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(10)
Selected Immunosuppressants/Nadofaragene Firadenovec
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Nadofaragene firadenovec may contain low levels of replication-competent adenovirus.(1)
CLINICAL EFFECTS: Concurrent use of nadofaragene firadenovec in patients receiving immunosuppressive therapy may cause disseminated adenovirus infection.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Individuals who are immunosuppressed or immune-deficient should not receive nadofaragene firadenovec.(1)
DISCUSSION: Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy but may contain low levels of replication-competent adenovirus. Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection.(1)
Selected Immunosuppressants/Talimogene Laherparepvec
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Talimogene laherparepvec is a live, attenuated herpes simplex virus.(1)
CLINICAL EFFECTS: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Talimogene laherparepvec is contraindicated in immunosuppressed patients.(1) The magnitude of immunocompromise and associated risks due to immunosuppressant drugs should be determined by a physician.
DISCUSSION: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)
Selected Immunosuppressive Agents/Live Vaccines; Live Bcg
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: A variety of disease modifying agents suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines or intravesicular BCG. Immune response to vaccines may be decreased during periods of immunocompromise.(1)
CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) After instillation of intravesicular BCG, immunosuppression may interfere with local immune response, or increase the severity of mycobacterial infection following inadvertent systemic exposure.(2)
PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency.
PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) Patients who receive anti-B cell therapies should not receive live vaccines for at least 6 months after such therapies due to a prolonged duration of immunosuppression. An exception is the Zoster vaccine, which can be given at least 1 month after receipt of anti-B cell therapies.(1) The US manufacturer of abatacept states live vaccines should not be given during or for up to 3 months after discontinuation of abatacept.(2) The US manufacturer of live BCG for intravesicular treatment of bladder cancer states use is contraindicated in immunosuppressed patients.(3) The US manufacturer of daclizumab states live vaccines are not recommended during and for up to 4 months after discontinuation of treatment.(4) The US manufacturer of guselkumab states that live vaccines should be avoided during treatment with guselkumab.(5) The US manufacturer of inebilizumab-cdon states that live vaccines are not recommended during treatment and after discontinuation until B-cell repletion. Administer all live vaccinations at least 4 weeks prior to initiation of inebilizumab-cdon.(6) The US manufacturer of ocrelizumab states that live vaccines are not recommended during treatment and until B-cell repletion occurs after discontinuation of therapy. Administer all live vaccines at least 4 weeks prior to initiation of ocrelizumab.(7) The US manufacturer of ozanimod states that live vaccines should be avoided during and for up to 3 months after discontinuation of ozanimod.(8) The US manufacturer of siponimod states that live vaccines are not recommended during treatment and for up to 4 weeks after discontinuation of treatment.(9) The US manufacturer of ustekinumab states BCG vaccines should not be given in the year prior to, during, or the year after ustekinumab therapy.(10) The US manufacturer of satralizumab-mwge states that live vaccines are not recommended during treatment and should be administered at least four weeks prior to initiation of satralizumab-mwge.(11) The US manufacturer of ublituximab-xiiy states that live vaccines are not recommended during treatment and until B-cell recovery. Live vaccines should be administered at least 4 weeks prior to initiation of ublituximab-xiiy.(12) The US manufacturer of etrasimod states that live vaccines should be avoided during and for 5 weeks after treatment. Live vaccines should be administered at least 4 weeks prior to initiation of etrasimod.(13) The US manufacturer of emapalumab-lzsg states that live vaccines should not be administered to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.(14) The US manufacturer of sibeprenlimab-szsi states live vaccines should not be given within 30 days prior to initiation or during treatment with sibeprenlimab-szsi.(15)
DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Biologic Therapies/Anifrolumab
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of anifrolumab with other biologic therapies may result in additive or synergistic effects on the immune system.(1)
CLINICAL EFFECTS: Concurrent use of anifrolumab with other biologic therapies may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of anifrolumab with other biologic therapies is not recommended.(1)
DISCUSSION: The combination of anifrolumab with other biologic therapies has not been studied and is not recommended.(1)
Igg Antibodies And Derivatives/Efgartigimod-Alfa
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Efgartigimod-alfa binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)
CLINICAL EFFECTS: The effectiveness of medicines that bind to FcRn may be decreased.(3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of efgartigimod-alfa states that efgartigimod-alfa should not be combined with long-term use of FcRn-binding medications. If the medication is essential for the patient, efgartigimod-alfa should be discontinued.(3)
DISCUSSION: Clinical drug interaction studies with efgartigimod-alfa have not been performed. Efgartigimod-alfa may decrease concentrations of compounds that bind to the human FcRn.(3)
Igg Antibodies And Derivatives/Nipocalimab-Aahu
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Nipocalimab-aahu binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)
CLINICAL EFFECTS: The effectiveness of medicines that bind to FcRn may be decreased.(3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of nipocalimab-aahu states that nipocalimab-aahu should not be combined with long-term use of FcRn-binding medications. If the medication is essential for the patient, nipocalimab-aahu should be discontinued.(3)
DISCUSSION: Clinical drug interaction studies with nipocalimab-aahu have not been performed. Nipocalimab-aahu may decrease concentrations of compounds that bind to the human FcRn.(3)
Immunosuppres;Immunomodul/Selected Multiple Sclerosis Agents
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ocrelizumab or ofatumumab in combination with immunosuppressives and immune-modulators all suppress the immune system.(1,2)
CLINICAL EFFECTS: Concurrent use of ocrelizumab or ofatumumab with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1,2)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The ocrelizumab US prescribing information states: - Ocrelizumab and other immune-modulating or immunosuppressive therapies, (including immunosuppressant doses of corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with ocrelizumab. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating ocrelizumab.(1) The ofatumumab US prescribing information states: - Ofatumumab and other immunosuppressive therapies (including systemic corticosteroids) may have the potential for increased immunosuppressive effects and increase the risk of infection. When switching between therapies, the duration and mechanism of action of each therapy should be considered due to the potential for additive immunosuppressive effects. Ofatumumab for MS therapy has not been studied in combination with other MS agents that suppress the immune system.(2)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1,2) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(3)
Immunosuppressives; Immunomodulators/Baricitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of baricitinib with other biologic disease-modifying antirheumatic drugs (DMARDs) or potent immunosuppressants such as azathioprine or cyclosporine may result in additive or synergistic effects on the immune system.
CLINICAL EFFECTS: Concurrent use of baricitinib with other biologic DMARDs or potent immunosuppressants such as azathioprine or cyclosporine may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of baricitinib states that concurrent use of baricitinib with biologic DMARDs or potent immunosuppressants is not recommended.(1)
DISCUSSION: Most patients who developed serious infections while being treated with baricitinib were on concomitant immunosuppressants like methotrexate and corticosteroids. The combination of baricitinib with other biologic DMARDs has not been studied.(1)
Immunosuppressives; Immunomodulators/Cladribine Oral
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-2)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US prescribing information states: -Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered. In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of cladribine.(1) The cladribine Canadian prescribing information states: -Use of cladribine in immunocompromised patients is contraindicated because of a risk of additive effects on the immune system. Acute short-term therapy with corticosteroids can be administered during cladribine treatment.(2)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-2)
Immunosuppressives; Immunomodulators/Deuruxolitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Deuruxolitinib, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of deuruxolitinib and potent immunosuppressants may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of deuruxolitinib states that concurrent use of deuruxolitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1) If concurrent use cannot be avoided, patients should be monitored for signs and symptoms of infection. If a patient develops a serious or opportunistic infection, interrupt deuruxolitinib treatment until the infection is controlled.
DISCUSSION: Serious infections have been reported in patients receiving treatment with deuruxolitinib.(1)
Immunosuppressives; Immunomodulators/Etrasimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Etrasimod causes reversible sequestration of lymphocytes in lymphoid tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte count at 52 weeks.(1) Other immunosuppressives and immune-modulators also suppress the immune system.
CLINICAL EFFECTS: Concurrent use of etrasimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious and fatal infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications increases the risk of adverse effects.
PATIENT MANAGEMENT: The etrasimod US prescribing information states etrasimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Concomitant administration of these therapies with etrasimod should be avoided because of the risk of additive immune effects during therapy and in the weeks following administration. Etrasimod's effect on peripheral lymphocytes may persist for up to 5 weeks after discontinuation.(1) When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with other sphingosine-1 phosphate receptor modulators.(1)
Immunosuppressives; Immunomodulators/Filgotinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic disease-modifying antirheumatic drugs (DMARDs), or other Janus kinase (JAK) inhibitors may result in additive or synergistic effects on the immune system.(1)
CLINICAL EFFECTS: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The UK manufacturer of filgotinib states that concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors is not recommended.(1)
DISCUSSION: Serious infections have been reported in patients receiving filgotinib. Caution should be used in patients with a higher incidence of serious infection, including elderly patients aged 75 years and older.(1)
Immunosuppressives; Immunomodulators/Fingolimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Fingolimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-3)
CLINICAL EFFECTS: Concurrent use of fingolimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-3)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for fingolimod regarding this interaction differ between regulatory approving agencies. The fingolimod US prescribing information states: - Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with fingolimod. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating fingolimod.(1) The fingolimod Canadian prescribing information states: - Concurrent use with immunosuppressive or immunomodulatory agents is contraindicated due to the risk of additive immune system effects. However, co-administration of a short course of corticosteroids (up to 5 days) did not increase the overall rate of infection in patients participating Phase III clinical trials.(2) The fingolimod UK specific product characteristics states: - Fingolimod is contraindicated in patients currently receiving immunosuppressive therapies or those immunocompromised by prior therapies. When switching patients from another disease modifying therapy to Gilenya, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimizing the risk of disease activation.(3)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-3)
Immunosuppressives; Immunomodulators/Inebilizumab
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inebilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of inebilizumab with immunosuppressive or immunomodulating agents may result in myelosuppression including neutropenia resulting in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of inebilizumab states that the concurrent use of inebilizumab with immunosuppressive agents, including systemic corticosteroids, may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Inebilizumab has not been studied in combination with other immunosuppressants. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents. The most common infections reported by inebilizumab treated patients in the randomized and open-label clinical trial periods included urinary tract infections (20%), nasopharyngitis (13%), upper respiratory tract infections (8%), and influenza (7%). Although there been no cases of Hepatitis B virus reactivation or progressive multifocal leukoencephalopathy reported in patients taking inebilizumab, these infections have been observed in patients taking other B-cell-depleting antibodies.(1)
Immunosuppressives; Immunomodulators/Ozanimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ozanimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ozanimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The ozanimod US prescribing information state this information regarding this interaction: -Ozanimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ozanimod after alemtuzumab is not recommended. However, ozanimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)
Immunosuppressives; Immunomodulators/Ponesimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ponesimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ponesimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The ponesimod US prescribing information states ponesimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ponesimod after alemtuzumab is not recommended. However, ponesimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)
Immunosuppressives; Immunomodulators/Ritlecitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ritlecitinib, immunosuppressives, and immunomodulators all suppress the immune system.
CLINICAL EFFECTS: Concurrent use of ritlecitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of ritlecitinib states that concurrent use of ritlecitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1)
DISCUSSION: Serious infections have been reported in patients receiving ritlecitinib. Reported infections included appendicitis, COVID-19 infection (including pneumonia), and sepsis. Reports of viral reactivation, including herpes virus reactivation was reported in clinical studies with ritlecitinib.(1)
Immunosuppressives; Immunomodulators/Siponimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Siponimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of siponimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The siponimod US prescribing information state this information regarding this interaction: -Siponimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with siponimod after alemtuzumab is not recommended. However, siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)
Immunosuppressives; Immunomodulators/Tofacitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of tofacitinib and azathioprine, other biologic disease-modifying antirheumatic drugs (DMARDs), or potent immunosuppressants may result in additive or synergistic effects on the immune system.(1)
CLINICAL EFFECTS: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants use may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Tofacitinib should not be used concurrently with azathioprine, other biologic DMARDs, or cyclosporine.(1) Patient should be monitored for decreases in lymphocytes and neutrophils. Therapy should be adjusted based on the indication. - For all indications: If absolute neutrophil count (ANC) or lymphocyte count is less than 500 cells/mm3, discontinue tofacitinib. - For rheumatoid arthritis or psoriatic arthritis and absolute neutrophil count (ANC) 500 to 1000 cells/mm3: interrupt dosing. When ANC is greater than 1000 cells/mm3, resume Xeljanz 5 mg twice daily or Xeljanz XR 11 mg once daily. - For ulcerative colitis and ANC 500 to 1000 cells/mm3: -If taking Xeljanz 10 mg twice daily, decrease to 5 mg twice daily. When ANC is greater than 1000 cells/mm3, increase to 10 mg twice daily based on clinical response. -If taking Xeljanz 5 mg twice daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 5 mg twice daily. -If taking Xeljanz XR 22 mg once daily, decrease to 11 mg once daily. When ANC is greater than 1000 cells/mm3, increase to 22 mg once daily based on clinical response. -If taking Xeljanz XR 11 mg once daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 11 mg once daily. - For polyarticular course juvenile idiopathic arthritis (pcJIA) and ANC 500 to 1000 cells/mm3: interrupt dosing until ANC is greater than 1000 cells/mm3.(1)
DISCUSSION: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants may increase the risk of infection.(1) Serious infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. Some patients presented with disseminated disease and were often taking concomitant immunomodulating agents. In the ulcerative colitis population, a greater risk of serious infections was seen with a higher tofacitinib dose. In 7 placebo-controlled rheumatoid arthritis trials (0-3 months exposure), the overall frequency of infections was 20% in the tofacitinib 5 mg twice daily group and 22% in the tofacitinib 10 mg twice daily group compared to 18% in the placebo group. Serious infections were reported in 11 patients (1.7 events per 100 patient-years) with a rate difference between treatment groups of 1.1 (-0.4, 2.5) events per 100 patient-years for both tofacitinib 5 mg twice daily and 10 mg twice daily. During 0-12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient years) in the tofacitinib 5 mg twice daily group and 33 patients (2.7 events per 100 patient years) in the tofacitinib 10 mg twice daily group.(1)
Immunosuppressives; Immunomodulators/Upadacitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Upadacitinib, immunosuppressives, and immunomodulators all suppress the immune system.
CLINICAL EFFECTS: Concurrent use of upadacitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of upadacitinib states that concurrent use of upadacitinib with immunosuppressives or immunomodulators is not recommended.
DISCUSSION: Serious infections have been reported in patients receiving upadacitinib. Reported infections included pneumonia, cellulitis, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, cryptococcosis. Reports of viral reactivation, including herpes virus reactivation and hepatitis B reactivation, were reported in clinical studies with upadacitinib.(1)
Myelosuppressives; Immunomodulators/Sodium Iodide I 131
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)
DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)
Pd-1 And Pd-L1 Blocking Antibodies/Thalidomide Analogues
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The mechanism of this interaction is not known.
CLINICAL EFFECTS: Concurrent use of a thalidomide analogue with dexamethasone and a PD-1 or PD-L1 blocking antibody may increase the risk of mortality.
PREDISPOSING FACTORS: Concurrent use of dexamethasone may increase the risk of venous thromboembolism (VTE), ischemic heart disease including myocardial infarction, and stroke.
PATIENT MANAGEMENT: Concurrent administration of a thalidomide analogue plus dexamethasone with a PD-1 or PD-L1 blocking antibody is not recommended outside of controlled clinical trials.
DISCUSSION: Two randomized clinical trials in multiple myeloma patients showed an increase in mortality associated with the concurrent use of pembrolizumab, a thalidomide analogue, and dexamethasone. In the first clinical trial, patients were randomized to receive pomalidomide, dexamethasone, and pembrolizumab. In this trial, the relative risk of death was increased by more than 50% in the experimental arm containing pembrolizumab and the hazard ratio for overall survival was 1.61. Causes of death in the experimental arm included myocarditis, Stevens-Johnson syndrome, myocardial infarction, pericardial hemorrhage, cardiac failure, respiratory tract infection, neutropenia sepsis, sepsis, multiple organ dysfunction, and respiratory failure. In the second clinical trial, patients were randomized to receive lenalidomide, dexamethasone, and pembrolizumab. In this trial, the relative risk of death was increased by more than 100% in the experimental arm containing pembrolizumab and the hazard ratio for overall survival was 2.06. Causes of death in the experimental arm included intestinal ischemia, cardio-respiratory arrest, pulmonary embolism, cardiac arrest, pneumonia, sudden death, myocarditis, large intestinal perforation, and cardiac failure. PD-1 and PD-L1 blocking antibodies linked to this monograph include atezolizumab, avelumab, cemiplimab, cosibelimab, dostarlimab, durvalumab, ivonescimab, nivolumab, pembrolizumab, penpulimab, retifanlimab, sintilimab, sugemalimab, and toripalimab.
Selected Immunosuppressants/Leflunomide; Teriflunomide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of leflunomide or teriflunomide and potent immunosuppressants may result in additive or synergistic effects on the immune system.(1,2) Leflunomide is a prodrug and is converted to its active metabolite teriflunomide.(1)
CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide with immunosuppressants may result in an increased risk of serious infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: If leflunomide or teriflunomide is used concurrently with immunosuppressive agents, chronic CBC monitoring should be performed more frequently, every month instead of every 6 to 8 weeks. If bone marrow suppression or a serious infection occurs, leflunomide or teriflunomide should be stopped and rapid drug elimination procedure should be performed.(1,2)
DISCUSSION: Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving leflunomide or teriflunomide alone, but most frequently in patients taking concurrent immunosuppressants.(1,2) Severe and potentially fatal infections, including sepsis, have been reported in patients receiving leflunomide or teriflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Tuberculosis has also been reported.(1,2)
Selected Myelosuppressive Agents/Clozapine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)
CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.
PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.
PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)
DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)
Selected Myelosuppressive Agents/Deferiprone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)
CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.
PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)
PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)
DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)
Selected Myelosuppressive Agents/Dipyrone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)
CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)
DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)
Slt Immunosuppress; Immunomodulator/Ropeginterferon Alfa-2B
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ropeginterferon alfa-2b and immunosuppressives both suppress the immune system.
CLINICAL EFFECTS: Concurrent use of ropeginterferon alfa-2b with immunosuppressives may result in an increased risk of serious infections.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concurrent use of myelosuppressive agents.(1-2) If concurrent use cannot be avoided, monitor for effects of excessive immunosuppression.
DISCUSSION: In clinical trials, 20% of patients experienced leukopenia. Interferon alfa products may cause fatal or life-threatening infections.(1-2)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Biologic Therapies/Belimumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Concurrent use of belimumab with other biologic therapies may result in additive or synergistic effects on the immune system.(1)
CLINICAL EFFECTS: Concurrent use of belimumab with other biologic therapies may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The concurrent use of belimumab with other biologic therapies should be approached with caution.(1)
DISCUSSION: In a randomized, double-blind, placebo-controlled trial, more patients who received belimumab and rituximab experienced serious adverse events, serious infections, and post-injection systemic reactions (22.2%, 9%, and 13.2%, respectively) than patients who received belimumab with placebo (13.9%, 2.8%, 9.7%) or standard therapy (19.7%, 5.3%, 5.3%).(1) The combination of belimumab with other biologic therapies has not been studied and should be used cautiously.(1)
Igg Antibodies And Derivatives/Rozanolixizumab-Noli
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The neonatal Fc receptor (FcRn) prevents catabolism and mediates recycling of IgG and albumin, which leads to their long persistence in the body.(1,2) Rozanolixizumab-noli binds to FcRn and may decrease systemic exposure of other ligands of FcRn, like immunoglobulins and IgG-based antibodies.(3)
CLINICAL EFFECTS: The effectiveness of medications that bind to FcRn may be decreased.(3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of rozanolixizumab-noli states that concurrent use with medications that bind to the human neonatal Fc receptor (FcRn) should be closely monitored for reduced effectiveness of these medications. If long-term use of such medications is essential for the patient, consider discontinuing rozanolixizumab-noli and use alternative therapies.(3)
DISCUSSION: Clinical drug interaction studies with rozanolixizumab-noli have not been performed. Rozanolixizumab-noli may decrease concentrations of compounds that bind to the human FcRn.(3)
Immune Checkpoint Inhibitors/Proton Pump Inhibitors
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The mechanism of this interaction has not been fully investigated. Proposed mechanisms include: 1. Proton pump inhibitor (PPI)-induced changes of the microbiota (dysbiosis) causing resistance to immune checkpoint inhibitors, 2. Co-administration of PPIs with corticosteroids or non steroidal anti-inflammatory drugs (NSAIDs) and immune checkpoint inhibitors resulting in poorer prognosis.(1)
CLINICAL EFFECTS: PPIs may decrease the therapeutic effects of immune checkpoint inhibitors. Several observational studies have shown a reduction in progression free survival (PFS), overall survival (OS), and tumor response in patients on concurrent treatment with immune checkpoint inhibitors and PPIs.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concurrent use of immune checkpoint inhibitors and PPIs should be approached with caution. Manufacturers of immune checkpoint inhibitors do not provide recommendations on the concurrent use of PPIs. Primary literature on the concurrent use of these agents include recommendations to evaluate the risks and benefits of PPI use and consideration of alternative therapy when possible such as histamine H2-receptor antagonists (H2RAs) or antacids.(1-3)
DISCUSSION: A meta analysis of 23 studies evaluating the impact of acid suppressing therapy on the efficacy of immune checkpoint inhibitors found coadministration of a PPI decreased PFS (HR 1.34 [95% confidence interval (CI), 1.13 to 1.58]) and OS (HR 1.43 [95% CI, 1.21 to 1.69]) compared with patients not treated with PPIs. Furthermore, the meta analysis identified that H2RAs did not affect OS. These results were consistent across cancer types.(1) In another meta analysis of 22 studies (5 prospective and 17 retrospective, n=16,072) evaluating the impact of concomitant medications on survival outcomes in patients treated with systemic therapy for advanced unresectable or metastatic renal cell carcinoma, concomitant use of PPIs (n=3959) was significantly associated with worse OS in patients treated with immune checkpoint inhibitors (HR 1.22, P=0.01).(4) A retrospective analysis of 635 patients treated with immune checkpoint inhibitors found PPI use was associated with significantly decreased OS (9 vs 26.5 months), PFS (3.5 vs. 8 months), and tumor response (61% vs. 72%).(5) Analysis of retrospective data from clinical trials of atezolizumab for urothelial carcinoma and non-small-cell lung cancer, among patients using a PPI within 30 days before or after therapy initiation, OS was significantly worse for patients randomized to treatment with atezolizumab than for patients randomized to chemotherapy.(6,7) A retrospective study of 381 patients treated with immune checkpoint inhibitors found use of acid-suppression therapy (n=168 PPIs, n=37 potassium competitive acid blocker, n=13 H2RAs) was associated with significantly shorter PFS and OS (2.9 vs. 6.2 months and 12.3 vs. 24 months, respectively) compared with patients who did not use acid-suppression therapy. However, when stratified by concomitant use of corticosteroids or NSAIDs, use of acid-suppression therapy was not associated with worse progression-free or overall survival.(8) In a retrospective cohort study of patients with advanced non-small-cell lung cancer treated with pembrolizumab, exposure to PPIs was associated with worse OS (HR, 1.13; 95% CI, 1.10-1.17).(9) Analysis of US and Japanese adverse drug event reporting system databases found administration of immune checkpoint inhibitors and PPIs was associated with an increased risk of adverse events including acute kidney injury (10) and congenital, familial and genetic disorders.(11) In a meta analysis of 14 observational studies, the risk of immune checkpoint inhibitor related AKI (ICI-AKI) in cancer patients concurrently using PPIs was found to be significantly higher (pooled OR of 1.84 [95% CI 1.16-2.90]) in comparison to the overall incidence of AKI from all-causes (1.57 [95% CI 1.02-2.40]).(12) In contrast to these findings, other studies have not found a negative effect on PFS or OS when patients are co-administered PPIs and immune checkpoint inhibitors. In a retrospective study of 159 patients treated with ipilimumab, coadministration of PPIs was associated with increased odds of experiencing a partial or complete response to ipilimumab (OR 3.73 [95% CI, 1.26 to 11.04]).(13) In another retrospective study of 233 patients who received nivolumab or pembrolizumab, use of PPI had no effect on OS (HR 1.2 [95% CI, 0.8-1.9]) or PFS (HR 1.1 [95% CI, 0.8 to 1.5]).(14) A nested case-control study of patients (n=38,930) with cancer who were new PPI or immune checkpoint inhibitor users and had no history of AKI before cohort entry, found the risk of AKI in patients treated with both PPIs and immune checkpoint inhibitors was not higher than then additional or multiplication of the risks in those who were treated with PPIs or immune checkpoint inhibitors alone. The study reinforces the association between PPIs and immune checkpoint inhibitors use and the increased risk of AKI and the need for careful monitoring and evaluation of kidney function when treated with both medicines.(15)
Immunosuppressives; Immunomodulators/Cladribine Oncology Inj
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-4)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-4)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US, UK, and Australian prescribing information state: -Caution should be exercised if cladribine injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression.(1-3) The cladribine Canadian prescribing information states: -Proceed carefully in patients with severe bone marrow impairment of any etiology since further suppression of bone marrow function should be anticipated.(4)
DISCUSSION: Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with cladribine injection, especially at high doses.(1-4)
Immunosuppressives; Immunomodulators/Covid-19 Vaccines
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Immunosuppressants and immunomodulators may prevent the immune system from properly responding to the COVID-19 vaccine.(1-3)
CLINICAL EFFECTS: Administration of a COVID-19 vaccine with immunosuppressants or immunomodulators may interfere with vaccine-induced immune response and impair the efficacy of the vaccine. However, patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The Centers for Disease Control and Prevention (CDC),(1) Infectious Diseases Society of America (IDSA),(2) and the American College of Rheumatology (ACR)(3) have published guidances for COVID-19 vaccination in patients on immunosuppressants. The CDC states that all immunocompromised patients over 6 months of age should receive at least 1 dose of COVID-19 vaccine if eligible. See the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for specific recommendations based on age, vaccination history, and vaccine manufacturer.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(1) IDSA recommends timing COVID-19 vaccination at least 2 weeks before starting or at least 3 months after completing immunosuppressive therapy.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose.(3) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted, though the immune response will likely be blunted. COVID-19 vaccines should not be delayed in patients taking immunosuppressive therapies.(1-2) See below for specific recommendations for certain agents. B-cell depleting agents, including rituximab: The CDC states that the utility of B-cell quantification to guide clinical care is not known and is not recommended. Patients who receive B-cell depleting therapy on a continuing basis should receive COVID-19 vaccines about 4 weeks before the next scheduled dose. For patients who received 1 or more doses of COVID-19 vaccine during treatment with B-cell-depleting therapies that were administered over a limited period (e.g., as part of a treatment regimen for certain malignancies), revaccination may be considered according to the current CDC recommendations for unvaccinated patients. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(1) IDSA recommends waiting for at least 3-6 months after the last infusion of B-cell depleting therapy before administering COVID-19 vaccines.(2) The ACR recommends consulting with the rheumatologist to determine optimal timing of COVID-19 vaccination. Measuring CD19 B cells may be considered to determine need for a booster vaccine dose. If B cell levels are not measured, a supplemental vaccine dose 2-4 weeks before the next scheduled dose of rituximab is recommended.(3) Recipients of hematopoietic cell transplant or CAR-T-cell therapy who received one or more doses of COVID-19 vaccine prior to or during treatment should undergo revaccination following the current CDC recommendations for unvaccinated patients. Revaccination should start at least 3 months (12 weeks) after transplant or CAR-T-cell therapy.(1,2) The CDC includes abatacept, cyclophosphamide, and TNF-alpha and cytokine inhibitors in their general recommendation to hold therapy for at least 2 weeks following vaccination (1) while the ACR provides different recommendations:(3) *Abatacept: - Subcutaneous abatacept should be withheld for 1-2 weeks after each vaccine dose, as disease activity allows. - For intravenous abatacept, time administration so that vaccination will occur 1 week before the next abatacept infusion. *Cyclophosphamide: When feasible, administer cyclophosphamide 1 week after each COVID-19 vaccine dose. *TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to reach consensus on whether to modify dosing or timing of these agents with COVID-19 vaccination.
DISCUSSION: IDSA recommendations are based on cohort and case control studies in immunocompromised patients that found low to modest vaccine effectiveness (37-61%) but lower risks of COVID-19 association hospitalization, COVID-19 related mortality, and critical illness.(2) The ACR convened a COVID-19 Vaccine Guidance Task Force to provide guidance on optimal use of COVID-19 vaccines in rheumatology patients. These recommendations are based on limited clinical evidence of COVID-19 vaccines in patients without rheumatic and musculoskeletal disorders and evidence of other vaccines in this patient population.(3) The ACR recommendation for rituximab is based on studies of humoral immunity following receipt of other vaccines. These studies have uncertain generalizability to vaccination against COVID-19, as it is unknown if efficacy is attributable to induction of host T cells versus B cell (antibody-based) immunity.(3) The ACR recommendation for mycophenolate is based on preexisting data of mycophenolate on non-COVID-19 vaccine immunogenicity. Emerging data suggests that mycophenolate may impair SARS-CoV-2 vaccine response in rheumatic and musculoskeletal disease and transplant patients.(3) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(3) The ACR recommendation for JAK inhibitors is based on concerns related to the effects of JAK inhibitors on interferon signaling that may result in a diminished vaccine response.(3) The ACR recommendation for subcutaneous abatacept is based on several studies suggesting a negative effect of abatacept on vaccine immunogenicity. The first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct. CTLA-4 should not inhibit boosts of already primed T cells at the time of the second vaccine dose.(3)
Immunosuppressives; Immunomodulators/Sarilumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Sarilumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of sarilumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of sarilumab recommends caution because the concurrent use of sarilumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Sarilumab was studied as monotherapy and in combination with methotrexate or conventional disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis studies. Sarilumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by sarilumab treated patients in the clinical trial periods included pneumonia and cellulitis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving sarilumab. Cases of tuberculosis, candidiasis, and pneumocystis with sarilumab have been reported.(1)
Immunosuppressives; Immunomodulators/Tocilizumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Tocilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of tocilizumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of tocilizumab recommends caution because the concurrent use of tocilizumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Tocilizumab was studied as monotherapy and in combination with methotrexate, non-biologic DMARDs or corticosteroids, depending on the indication. Tocilizumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by tocilizumab treated patients in the clinical trial periods included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving tocilizumab. Cases of tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis have been reported.(1)
Immunosuppressives; Immunomodulators/Ublituximab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ublituximab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ublituximab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The US manufacturer of ublituximab recommends caution because the concurrent use of ublituximab with immunomodulating or immunosuppressive agents, including immunosuppressant doses of corticosteroids, may increase the risk of infection.(1) If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents. When switching from agents with immune effects, the half-life and mechanism of action of these drugs must be taken into consideration in order to prevent additive immunosuppressive effects.(1)
DISCUSSION: The most common infections reported by ublituximab-treated patients in the clinical trial periods included upper respiratory tract infections and urinary tract infections. Serious, including life-threatening or fatal, bacterial and viral infections were observed in patients receiving ublituximab.(1) Serious and/or fatal bacterial, fungal, and new or reactivated viral infections have been associated with other anti-CD20 B-cell depleting therapies. There were no cases of progressive multifocal leukoencephalopathy (PML) reported during the clinical trials; however, there have been reports of PML during or following completion of other anti-CD20 B-cell depleting therapies.(1)
Immunosuppressives; Immunomodulators/Ustekinumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ustekinumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ustekinumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of ustekinumab recommends caution because the concurrent use of ustekinumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Ustekinumab has not been studied in combination with other immunosuppressants in psoriasis studies. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by ustekinumab treated patients in the clinical trial periods included nasopharyngitis(8%) and upper respiratory tract infection(5%). Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab. Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia resulting in respiratory failure or prolonged hospitalization have been reported in patients receiving ustekinumab.(1)
Contraindications
*None.
- Lactation
- Pregnancy
- Hyperthyroidism
- Hypothyroidism
- Kidney disease with reduction in glomerular filtration rate (GFr)
- Myasthenia gravis
Adverse reactions
Durvalumab with Chemotherapy: The most common adverse reactions (>=20% of patients with resectable, Stage II/III NSCLC (neoadjuvant /adjuvant)) are anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash.
Durvalumab as a Single Agent: The most common adverse reactions (>=20% of patients with unresectable, Stage III NSCLC) are cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. The most common adverse reactions (>=20% of patients with LS-SCLC) are pneumonitis or radiation pneumonitis, and fatigue.
Durvalumab with Tremelimumab-actl and Platinum-Based Chemotherapy: The most common adverse reactions (>=20% of patients with metastatic NSCLC) were nausea, fatigue, musculoskeletal pain, decreased appetite, rash, and diarrhea.
Durvalumab with Platinum-Based Chemotherapy: The most common adverse reactions (>=20% of patients with ES-SCLC) are nausea, fatigue/asthenia, and alopecia.
Durvalumab with Gemcitabine and Cisplatin: The most common adverse reactions (>=20% of patients with BTC) are fatigue, nausea, constipation, decreased appetite, abdominal pain, rash, and pyrexia.
Durvalumab with Tremelimumab-actl: The most common adverse reactions (>=20% of patients with uHCC) are rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.
Durvalumab with Carboplatin and Paclitaxel, followed by Durvalumab as a Single Agent: The most common adverse reactions (>=20% of patients with endometrial cancer) were peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, decreased magnesium, increased ALT, increased AST, diarrhea, vomiting, cough, decreased potassium, dyspnea, headache, and increased alkaline phosphatase.
More Frequent
- Interstitial lung disease
Less Frequent
- Acute kidney injury
- Anemia
- Cholangitis
- Colitis
- Hypersensitivity drug reaction
- Hyperthyroidism
- Hyponatremia
- Increased alanine transaminase
- Increased aspartate transaminase
- Infection
- Interstitial nephritis
- Lymphopenia
- Neutropenic disorder
- Pneumonia
- Pulmonary thromboembolism
- Radiation pneumonitis
- Thyroiditis
Rare or Very Rare
- Acute inflammatory syndrome
- Adenocarcinoma of pancreas
- Adrenocortical insufficiency
- Aortic aneurysm
- Aplastic anemia secondary to drugs
- Aspiration pneumonia
- Autoimmune hemolytic anemia
- Autoimmune hepatitis
- Bacterial sepsis
- Bullous dermatitis
- Cardiac arrest
- Cerebrovascular accident
- Chronic obstructive pulmonary disease
- Colorectal cancer
- Dementia with lewy bodies
- Diabetes mellitus
- Diabetic ketoacidosis
- Drug-induced hepatitis
- Duodenitis
- Elevated serum amylase
- Elevated serum lipase
- Encephalitis
- Encephalopathy
- Gastritis
- Gastrointestinal hemorrhage
- Gastrointestinal perforation
- Graft-versus-host disease
- Guillain-barre syndrome
- Heart failure
- Hemolytic anemia
- Hemophagocytic lymphohistiocytosis
- Hemoptysis
- Hemorrhagic stroke
- Histiocytic necrotizing lymphadenitis
- Hypersensitivity pneumonitis
- Hypoparathyroidism
- Hypophysitis
- Idiopathic thrombocytopenic purpura
- Interstitial pneumonitis
- Intracranial bleeding
- Iritis
- Keratitis
- Meningitis
- Muscle weakness
- Myasthenia gravis
- Myocarditis
- Myositis
- Nephritis
- Neuropathy
- Non-infective meningitis
- Organ transplant rejection
- Osteomyelitis
- Pancreatitis
- Pancytopenia
- Pericarditis
- Pituitary insufficiency
- Polymyalgia rheumatica
- Prostatic carcinoma
- Rhabdomyolysis
- Sarcoidosis
- Sepsis
- Severe infection
- Stevens-johnson syndrome
- Toxic epidermal necrolysis
- Type 1 diabetes mellitus
- Uveitis
- Vasculitis
More Frequent
- Abnormal hepatic function tests
- Acute abdominal pain
- Anorexia
- Constipation
- Cough
- Dysgeusia
- Dysphagia
- Dyspnea
- Fatigue
- Gamma-glutamyl transferase raised
- General weakness
- Hematuria
- Hyperbilirubinemia
- Hypernatremia
- Hypoalbuminemia
- Musculoskeletal pain
- Nausea
- Peripheral edema
- Polyuria
- Thrombocytopenic disorder
- Urinary tract infection
Less Frequent
- Alopecia
- Diarrhea
- Dysuria
- Fever
- Headache disorder
- Hyperkalemia
- Hypertension
- Hypocalcemia
- Hypomagnesemia
- Hypothyroidism
- Insomnia
- Night sweats
- Pruritus of skin
- Skin rash
- Stomatitis
- Upper respiratory infection
- Voice change
- Vomiting
Rare or Very Rare
- Arthritis
- Dizziness
- Edema
- Hyperglycemia
- Peripheral neuropathy
- Vitiligo
Precautions
No enhanced messaging available.
Safety and efficacy of durvalumab have not been established in pediatric patients.
Based on findings from animal studies and the mechanism of action of durvalumab, the drug can cause fetal harm when administered to pregnant women. There are no available data on use of durvalumab in pregnant women.
In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately 6--20 times higher than those observed at the clinical dose of 10 mg/kg based on AUC, resulted in an increase in premature delivery, fetal loss, and premature neonatal death.
Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to a fetus.
There are no data on the presence of durvalumab in human milk, its effects on the breast-fed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local GI exposure and limited systemic exposure in the breast-fed child to durvalumab are unknown.
Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death.
Because of the potential for adverse reactions in a breast-fed child, advise women not to breast-feed during treatment with durvalumab and for 3 months after the last dose.
The manufacturer provides no specific dosage recommendations for geriatric patients.
Of the 401 patients with resectable non-small cell lung cancer (NSCLC) treated with durvalumab in combination with chemotherapy in the AEGEAN study, 209 (52%) patients were >=65 years of age and 49 (12%) patients were >=75 years of age. There were no overall clinically important differences in safety or efficacy between patients >=65 years of age and younger patients.
Of the 476 patients with unresectable, Stage III NSCLC treated with durvalumab in the PACIFIC study, 45% of patients were >=65 years of age while 7.6% were >=75 years of age. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients >=75 years of age to determine whether they respond differently from younger patients.
Of the 330 patients with metastatic NSCLC treated with durvalumab in combination with tremelimumab-actl and platinum-based chemotherapy, 143 (43%) patients were >=65 years of age and 35 (11%) patients were >=75 years of age. There were no clinically important differences in safety or efficacy between patients >=65 years of age and younger patients.
Of the 262 patients with limited-stage small cell lung cancer (LS-SCLC) treated with durvalumab, 103 (39%) patients were >=65 years of age and 15 (6%) were >=75 years of age. There were no clinically important differences in safety and efficacy between patients >=65 years of age and younger patients.
Of the 265 patients with ES-SCLC treated with durvalumab in combination with chemotherapy, 101 (38%) patients were >=65 years of age and 19 (7.2%) patients were >=75 years of age. There were no clinically important differences in safety or efficacy between patients >=65 years of age and younger patients.
Of the 338 patients with BTC treated with durvalumab in combination with chemotherapy in the TOPAZ-1 study, 158 (47%) patients were >=65 years of age and 38 (11%) patients were >=75 years of age. No overall differences in safety or effectiveness of durvalumab have been observed between patients >=65 years of age and younger adults.
Of the 393 patients with unresectable hepatocellular carcinoma (uHCC) treated with durvalumab in combination with tremelimumab-actl, 50% of patients were >=65 years of age and 13% of patients were >=75 years of age. No overall differences in safety or effectiveness of durvalumab have been observed between patients >=65 years of age and younger adults.
Of the 235 patients with endometrial cancer treated with durvalumab with carboplatin and paclitaxel, 49% of patients were >=65 years of age and 12% of patients were >=75 years of age. No overall differences in safety or effectiveness of durvalumab have been observed between patients >=65 years of age and younger adults.
ICD codes
| Code | Type | Description |
|---|---|---|
| Biliary tract malignancy | ||
| C22.1 | ICD10CM | Intrahepatic bile duct carcinoma |
| C23 | ICD10CM | Malignant neoplasm of gallbladder |
| C24 | ICD10CM | Malignant neoplasm of other and unspecified parts of biliary tract |
| C24.0 | ICD10CM | Malignant neoplasm of extrahepatic bile duct |
| C24.1 | ICD10CM | Malignant neoplasm of ampulla of vater |
| C24.8 | ICD10CM | Malignant neoplasm of overlapping sites of biliary tract |
| C24.9 | ICD10CM | Malignant neoplasm of biliary tract, unspecified |
| EGFR negative, ALK negative, non-small cell lung cancer | ||
| C34 | ICD10CM | Malignant neoplasm of bronchus and lung |
| C34.0 | ICD10CM | Malignant neoplasm of main bronchus |
| C34.00 | ICD10CM | Malignant neoplasm of unspecified main bronchus |
| C34.01 | ICD10CM | Malignant neoplasm of right main bronchus |
| C34.02 | ICD10CM | Malignant neoplasm of left main bronchus |
| C34.1 | ICD10CM | Malignant neoplasm of upper lobe, bronchus or lung |
| C34.10 | ICD10CM | Malignant neoplasm of upper lobe, unspecified bronchus or lung |
| C34.11 | ICD10CM | Malignant neoplasm of upper lobe, right bronchus or lung |
| C34.12 | ICD10CM | Malignant neoplasm of upper lobe, left bronchus or lung |
| C34.2 | ICD10CM | Malignant neoplasm of middle lobe, bronchus or lung |
| C34.3 | ICD10CM | Malignant neoplasm of lower lobe, bronchus or lung |
| C34.30 | ICD10CM | Malignant neoplasm of lower lobe, unspecified bronchus or lung |
| C34.31 | ICD10CM | Malignant neoplasm of lower lobe, right bronchus or lung |
| C34.32 | ICD10CM | Malignant neoplasm of lower lobe, left bronchus or lung |
| C34.8 | ICD10CM | Malignant neoplasm of overlapping sites of bronchus and lung |
| C34.80 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified bronchus and lung |
| C34.81 | ICD10CM | Malignant neoplasm of overlapping sites of right bronchus and lung |
| C34.82 | ICD10CM | Malignant neoplasm of overlapping sites of left bronchus and lung |
| C34.9 | ICD10CM | Malignant neoplasm of unspecified part of bronchus or lung |
| C34.90 | ICD10CM | Malignant neoplasm of unspecified part of unspecified bronchus or lung |
| C34.91 | ICD10CM | Malignant neoplasm of unspecified part of right bronchus or lung |
| C34.92 | ICD10CM | Malignant neoplasm of unspecified part of left bronchus or lung |
| Extensive-stage small cell lung cancer | ||
| C34 | ICD10CM | Malignant neoplasm of bronchus and lung |
| C34.0 | ICD10CM | Malignant neoplasm of main bronchus |
| C34.00 | ICD10CM | Malignant neoplasm of unspecified main bronchus |
| C34.01 | ICD10CM | Malignant neoplasm of right main bronchus |
| C34.02 | ICD10CM | Malignant neoplasm of left main bronchus |
| C34.1 | ICD10CM | Malignant neoplasm of upper lobe, bronchus or lung |
| C34.10 | ICD10CM | Malignant neoplasm of upper lobe, unspecified bronchus or lung |
| C34.11 | ICD10CM | Malignant neoplasm of upper lobe, right bronchus or lung |
| C34.12 | ICD10CM | Malignant neoplasm of upper lobe, left bronchus or lung |
| C34.2 | ICD10CM | Malignant neoplasm of middle lobe, bronchus or lung |
| C34.3 | ICD10CM | Malignant neoplasm of lower lobe, bronchus or lung |
| C34.30 | ICD10CM | Malignant neoplasm of lower lobe, unspecified bronchus or lung |
| C34.31 | ICD10CM | Malignant neoplasm of lower lobe, right bronchus or lung |
| C34.32 | ICD10CM | Malignant neoplasm of lower lobe, left bronchus or lung |
| C34.8 | ICD10CM | Malignant neoplasm of overlapping sites of bronchus and lung |
| C34.80 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified bronchus and lung |
| C34.81 | ICD10CM | Malignant neoplasm of overlapping sites of right bronchus and lung |
| C34.82 | ICD10CM | Malignant neoplasm of overlapping sites of left bronchus and lung |
| C34.9 | ICD10CM | Malignant neoplasm of unspecified part of bronchus or lung |
| C34.90 | ICD10CM | Malignant neoplasm of unspecified part of unspecified bronchus or lung |
| C34.91 | ICD10CM | Malignant neoplasm of unspecified part of right bronchus or lung |
| C34.92 | ICD10CM | Malignant neoplasm of unspecified part of left bronchus or lung |
| Gastric cancer | ||
| C16 | ICD10CM | Malignant neoplasm of stomach |
| C16.0 | ICD10CM | Malignant neoplasm of cardia |
| C16.1 | ICD10CM | Malignant neoplasm of fundus of stomach |
| C16.2 | ICD10CM | Malignant neoplasm of body of stomach |
| C16.3 | ICD10CM | Malignant neoplasm of pyloric antrum |
| C16.4 | ICD10CM | Malignant neoplasm of pylorus |
| C16.5 | ICD10CM | Malignant neoplasm of lesser curvature of stomach, unspecified |
| C16.6 | ICD10CM | Malignant neoplasm of greater curvature of stomach, unspecified |
| C16.8 | ICD10CM | Malignant neoplasm of overlapping sites of stomach |
| C16.9 | ICD10CM | Malignant neoplasm of stomach, unspecified |
| Gastroesophageal junction adenocarcinoma | ||
| C16.0 | ICD10CM | Malignant neoplasm of cardia |
| C16.1 | ICD10CM | Malignant neoplasm of fundus of stomach |
| C16.2 | ICD10CM | Malignant neoplasm of body of stomach |
| C16.3 | ICD10CM | Malignant neoplasm of pyloric antrum |
| C16.4 | ICD10CM | Malignant neoplasm of pylorus |
| C16.5 | ICD10CM | Malignant neoplasm of lesser curvature of stomach, unspecified |
| C16.6 | ICD10CM | Malignant neoplasm of greater curvature of stomach, unspecified |
| C16.8 | ICD10CM | Malignant neoplasm of overlapping sites of stomach |
| C16.9 | ICD10CM | Malignant neoplasm of stomach, unspecified |
| Invasive bladder cancer | ||
| C67 | ICD10CM | Malignant neoplasm of bladder |
| C67.0 | ICD10CM | Malignant neoplasm of trigone of bladder |
| C67.1 | ICD10CM | Malignant neoplasm of dome of bladder |
| C67.2 | ICD10CM | Malignant neoplasm of lateral wall of bladder |
| C67.3 | ICD10CM | Malignant neoplasm of anterior wall of bladder |
| C67.4 | ICD10CM | Malignant neoplasm of posterior wall of bladder |
| C67.5 | ICD10CM | Malignant neoplasm of bladder neck |
| C67.6 | ICD10CM | Malignant neoplasm of ureteric orifice |
| C67.7 | ICD10CM | Malignant neoplasm of urachus |
| C67.8 | ICD10CM | Malignant neoplasm of overlapping sites of bladder |
| C67.9 | ICD10CM | Malignant neoplasm of bladder, unspecified |
| Liver cell carcinoma | ||
| C22.0 | ICD10CM | Liver cell carcinoma |
| Mismatch repair deficient endometrial cancer | ||
| C54.1 | ICD10CM | Malignant neoplasm of endometrium |
| Non-muscle invasive bladder cancer | ||
| C67.9 | ICD10CM | Malignant neoplasm of bladder, unspecified |
| Non-small cell lung cancer | ||
| C34 | ICD10CM | Malignant neoplasm of bronchus and lung |
| C34.0 | ICD10CM | Malignant neoplasm of main bronchus |
| C34.00 | ICD10CM | Malignant neoplasm of unspecified main bronchus |
| C34.01 | ICD10CM | Malignant neoplasm of right main bronchus |
| C34.02 | ICD10CM | Malignant neoplasm of left main bronchus |
| C34.1 | ICD10CM | Malignant neoplasm of upper lobe, bronchus or lung |
| C34.10 | ICD10CM | Malignant neoplasm of upper lobe, unspecified bronchus or lung |
| C34.11 | ICD10CM | Malignant neoplasm of upper lobe, right bronchus or lung |
| C34.12 | ICD10CM | Malignant neoplasm of upper lobe, left bronchus or lung |
| C34.2 | ICD10CM | Malignant neoplasm of middle lobe, bronchus or lung |
| C34.3 | ICD10CM | Malignant neoplasm of lower lobe, bronchus or lung |
| C34.30 | ICD10CM | Malignant neoplasm of lower lobe, unspecified bronchus or lung |
| C34.31 | ICD10CM | Malignant neoplasm of lower lobe, right bronchus or lung |
| C34.32 | ICD10CM | Malignant neoplasm of lower lobe, left bronchus or lung |
| C34.8 | ICD10CM | Malignant neoplasm of overlapping sites of bronchus and lung |
| C34.80 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified bronchus and lung |
| C34.81 | ICD10CM | Malignant neoplasm of overlapping sites of right bronchus and lung |
| C34.82 | ICD10CM | Malignant neoplasm of overlapping sites of left bronchus and lung |
| C34.9 | ICD10CM | Malignant neoplasm of unspecified part of bronchus or lung |
| C34.90 | ICD10CM | Malignant neoplasm of unspecified part of unspecified bronchus or lung |
| C34.91 | ICD10CM | Malignant neoplasm of unspecified part of right bronchus or lung |
| C34.92 | ICD10CM | Malignant neoplasm of unspecified part of left bronchus or lung |
| C39.9 | ICD10CM | Malignant neoplasm of lower respiratory tract, part unspecified |
| Small cell lung carcinoma | ||
| C34 | ICD10CM | Malignant neoplasm of bronchus and lung |
| C34.0 | ICD10CM | Malignant neoplasm of main bronchus |
| C34.00 | ICD10CM | Malignant neoplasm of unspecified main bronchus |
| C34.01 | ICD10CM | Malignant neoplasm of right main bronchus |
| C34.02 | ICD10CM | Malignant neoplasm of left main bronchus |
| C34.1 | ICD10CM | Malignant neoplasm of upper lobe, bronchus or lung |
| C34.10 | ICD10CM | Malignant neoplasm of upper lobe, unspecified bronchus or lung |
| C34.11 | ICD10CM | Malignant neoplasm of upper lobe, right bronchus or lung |
| C34.12 | ICD10CM | Malignant neoplasm of upper lobe, left bronchus or lung |
| C34.2 | ICD10CM | Malignant neoplasm of middle lobe, bronchus or lung |
| C34.3 | ICD10CM | Malignant neoplasm of lower lobe, bronchus or lung |
| C34.30 | ICD10CM | Malignant neoplasm of lower lobe, unspecified bronchus or lung |
| C34.31 | ICD10CM | Malignant neoplasm of lower lobe, right bronchus or lung |
| C34.32 | ICD10CM | Malignant neoplasm of lower lobe, left bronchus or lung |
| C34.8 | ICD10CM | Malignant neoplasm of overlapping sites of bronchus and lung |
| C34.80 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified bronchus and lung |
| C34.81 | ICD10CM | Malignant neoplasm of overlapping sites of right bronchus and lung |
| C34.82 | ICD10CM | Malignant neoplasm of overlapping sites of left bronchus and lung |
| C34.9 | ICD10CM | Malignant neoplasm of unspecified part of bronchus or lung |
| C34.90 | ICD10CM | Malignant neoplasm of unspecified part of unspecified bronchus or lung |
| C34.91 | ICD10CM | Malignant neoplasm of unspecified part of right bronchus or lung |
| C34.92 | ICD10CM | Malignant neoplasm of unspecified part of left bronchus or lung |
ICD code information from First Databank (FDB).
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Last reviewed · Source: First Databank (FDB) drug data
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