Tecentriq (atezolizumab)
Antineoplastic - Anti-Programmed Death-(PD-1/L1) MC Antibody Intravenous Vial (Ml)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Atezolizumab, a humanized anti-programmed-death ligand-1 (anti-PD-L1) monoclonal antibody, is an antineoplastic agent.
Atezolizumab, a humanized anti-programmed-death ligand-1 (anti-PD-L1) monoclonal antibody, is an antineoplastic agent. The drug is an IgG1 kappa immunoglobulin.
The immune-checkpoint receptor PD-1 is expressed on activated T-cells, monocytes, B-cells, natural killer (NK) T-cells, and dendritic cells. Overexpression of PD-1 ligands on the surface of tumor cells results in activation of PD-1 and B7.1 and suppression of cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Atezolizumab blocks the interaction between PD-L1 and the receptors PD-1 and B7.1, 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 syngeneic mouse tumor models. In mouse models of cancer, dual inhibition of the PD-1/PD-L1 and MAPK pathways suppresses tumor growth and improves tumor immunogenicity through increased antigen presentation and T-cell infiltration and activation compared to targeted therapy alone.
Systemic exposure to atezolizumab is proportional to dose over the dose range of 1-20 mg/kg, including the fixed dosage of 1.2 g every 3 weeks. Following repeated doses of atezolizumab 1200 mg every 3 weeks, steady-state concentrations are reached by 6-9 weeks; systemic accumulation of the drug is 3.3- or 1.9-fold when administered every 2 or 3 weeks, respectively. Atezolizumab clearance decreases over time by approximately 17% from baseline values; however, this difference is not considered clinically important.
The terminal half-life of atezolizumab is 27 days.
Systemic exposure to atezolizumab does not appear to be affected by age (range of 21-89 years), body weight, sex, serum albumin concentration, tumor burden, geographic region, race, PD-L1 expression, or performance status.
USES: This medication is used to treat various types of cancer. It works by helping your immune system fight the cancer. Atezolizumab belongs to a class of drugs known as monoclonal antibodies.
Generic name: atezolizumab
Pronunciation: (A-te-zoe-LIZ-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 Tecentriq
Indications
The following indications are listed for Tecentriq:
- Alveolar Soft Part Sarcoma
- Invasive Bladder Cancer
- Liver Cell Carcinoma
- Malignant Melanoma With Braf V600 Mutation
- Microsatellite Instability-High Colorectal Cancer
- Non-Small Cell Lung Cancer
- Nonsquamous Non-Small Cell Lung Cancer
- Pd-L1 Positive, Egfr-Negative, Alk-Negative Metastatic Non-Small Cell Lung Cancer
- Small Cell Lung Carcinoma
Also known as: Dmmr Colorectal Cancer, Hepatocarcinoma, Hepatocellular Carcinoma, Invasive Malignancy Of Bladder, Malignant Melanoma With Braf V600 Genetic Mutation, Mismatch Repair Deficient Colorectal Cancer, Msi-H Colorectal Cancer, Muscle Invasive Bladder Cancer, Nonsquamous Nsclc, Oat Cell Carcinoma Of The Lung, Pd-L1 Expressing, Egfr Mutation Negative, Alk Mutation Negative Metastatic Nsclc, Pd-L1 Positive Metastatic Non-Small Cell Lung Cancer With No Egfr Or Alk Mutations, Pd-L1 Positive, Egfr-Negative, Alk-Negative Nsclc, Small Cell Lung Cancer.
Dosing
No dosing information is available for this tab.
Atezolizumab is administered by IV infusion. The initial dose of atezolizumab should be administered as an IV infusion over 60 minutes; if the first infusion is tolerated, subsequent doses may be administered by IV infusion over 30 minutes. The drug should not be administered by rapid IV injection, such as IV push or bolus.
Unopened vials of atezolizumab injection concentrate should be protected from light, stored at 2-8degreesC, and should not be frozen or shaken.
Atezolizumab injection concentrate must be diluted prior to administration. The appropriate vial size should be selected based on the dose required. Prior to dilution and administration, atezolizumab injection concentrate should be inspected visually for particulate matter and discoloration. The undiluted solution should be colorless to slightly yellow; the solution should not be used if it is cloudy or discolored or if particulate matter is present. Atezolizumab is diluted by adding the required volume of atezolizumab injection concentrate (containing 60 mg/mL) to a polyvinyl chloride (PVC), polyethylene, or polyolefin infusion bag containing 0.9% sodium chloride injection. No other diluent should be used. The final concentration of the diluted atezolizumab solution should be 3.2-16.8 mg/mL. The diluted solution should be mixed by gentle inversion and should not be shaken. The manufacturer recommends immediate administration of diluted solutions of the drug. If immediate administration is not possible, the diluted solution of the drug should be stored at room temperature for up to 6 hours from the time of preparation (including infusion time) or 2-8degreesC for up to 24 hours from time of preparation; diluted solutions of the drug should not be frozen.
Atezolizumab should not be administered simultaneously through the same IV line with any other drug. Use of a low-protein-binding 0.2- to 0.22-mcm inline filter is optional. Atezolizumab injection concentrate contains no preservatives and is intended for single use only; any partially used vials should be discarded.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Tecentriq 1,200 Mg/20 Ml Vial | Maintenance | Infuse 1,200 mg over 60 minute(s) by intravenous route every 3 weeks. |
| Tecentriq 840 Mg/14 Ml Vial | Maintenance | Infuse 840 mg over 60 minute(s) by intravenous route on days 1 and 15of a 28 day treatment cycle. |
No dosing information is available for this tab.
Drug interactions
No formal drug interaction studies have been performed to date.
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
The manufacturer states there are no known contraindications to the use of atezolizumab.
- Lactation
- Pregnancy
- Hyperthyroidism
- Hypothyroidism
- Kidney disease with reduction in glomerular filtration rate (GFr)
- Myasthenia gravis
Adverse reactions
Adverse effects reported in 20% or more of patients receiving atezolizumab as a single agent include fatigue or asthenia, nausea, cough, dyspnea, and decreased appetite.
Adverse effects reported in 20% or more of patients with NSCLC or SCLC receiving atezolizumab in combination with other antineoplastic agents include fatigue or asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite.
Adverse effects reported in 20% or more of patients with triple-negative breast cancer receiving atezolizumab in combination with albumin-bound paclitaxel include alopecia, peripheral neuropathy, fatigue, nausea, diarrhea, constipation, cough, headache, vomiting, and decreased appetite; laboratory abnormalities occurring in 50% or more of patients include decreased concentrations of hemoglobin, leukocytes, neutrophils, and lymphocytes.
Adverse effects reported in 20% or more of patients with hepatocellular carcinoma receiving atezolizumab in combination with bevacizumab include hypertension, fatigue, and proteinuria.
Adverse effects reported in 20% or more of patients with melanoma receiving atezolizumab in combination with cobimetinib and vemurafenib include rash, musculoskeletal pain, fatigue, hepatotoxicity, pyrexia, nausea, pruritus, edema, stomatitis, hypothyroidism, and photosensitivity.
More Frequent
- Hypertension
- Infection
- Polyneuropathy
Less Frequent
- Abnormal hepatic function tests
- Acute renal failure
- Atrial fibrillation
- Bacterial sepsis
- Bradycardia
- Colitis
- Dyspnea
- Gastrointestinal obstruction
- Hematuria
- Hemorrhage
- Hyperbilirubinemia
- Hyperkalemia
- Hypersensitivity pneumonitis
- Hyperthyroidism
- Hypothyroidism
- Increased alanine transaminase
- Increased aspartate transaminase
- Interstitial lung disease
- Neutropenic disorder
- Pleural effusions
- Pneumonia
- Pulmonary hemorrhage
- Tachycardia
- Urinary tract obstruction
- Venous thrombosis
- Weight loss
Rare or Very Rare
- Acute inflammatory syndrome
- Adrenocortical insufficiency
- Anaphylaxis
- Aplastic anemia
- Autoimmune hemolytic anemia
- Autoimmune hepatitis
- Bullous dermatitis
- Cytokine release syndrome
- Demyelinating disorder
- Diabetes mellitus
- Encephalitis
- Erythema multiforme
- Facial palsy
- Graft-versus-host disease
- Guillain-barre syndrome
- Hemophagocytic lymphohistiocytosis
- Hepatic veno-occlusive disease
- Herpes simplex encephalitis
- Histiocytic necrotizing lymphadenitis
- Hypersensitivity drug reaction
- Hypophysitis
- Idiopathic thrombocytopenic purpura
- Interstitial nephritis
- Iritis
- Meningitis
- Muscle weakness
- Myasthenia gravis
- Mycobacteriosis
- Myelitis
- Myocarditis
- Myositis
- Nephritis
- Nephrotic syndrome
- Non-infective meningitis
- Organ transplant rejection
- Pancreatitis
- Pemphigoid
- Pericardial effusion
- Pericardial tamponade
- Pericarditis
- Polymyalgia rheumatica
- Rhabdomyolysis
- Sarcoidosis
- Sepsis
- Sjogren's syndrome
- Stevens-johnson syndrome
- Thyroiditis
- Toxic epidermal necrolysis
- Uveitis
- Vasculitis
- Vogt-koyanagi-harada disease
More Frequent
- Anorexia
- Constipation
- Cough
- Diarrhea
- Dysesthesia
- Fatigue
- Fever
- General weakness
- Headache disorder
- Musculoskeletal pain
- Nausea
- Pain in extremities
- Paresthesia
- Peripheral neuropathy
- Peripheral sensory neuropathy
- Urinary tract infection
Less Frequent
- Acute abdominal pain
- Acute cognitive impairment
- Allergic rhinitis
- Alopecia
- Arthralgia
- Dizziness
- Edema
- Flu-like symptoms
- Insomnia
- Peripheral edema
- Proteinuria
- Pruritus of skin
- Skin photosensitivity
- Skin rash
- Stomatitis
- Symptoms of anxiety
- Vomiting
Rare or Very Rare
- Arthritis
- Cystitis
- Elevated serum amylase
- Elevated serum lipase
- Ocular inflammation
- Tenosynovitis
Precautions
No enhanced messaging available.
Safety and efficacy of atezolizumab have not been established in pediatric patients.
Safety and antitumor activity of atezolizumab were assessed, but not established, in 60 pediatric patients 7 months to less than 17 years of age with relapsed or progressive solid tumors or lymphomas in a phase 1/2 study (iMATRIX). No new safety signals were observed in this study. The median duration of atezolizumab therapy was 0.8 months.
The iMATRIX study also compared the pharmacokinetic parameters of atezolizumab in pediatric patients and adults 18-29 years of age. Pediatric patients received a weight-based dose of 15 mg/kg (up to a maximum of 1200 mg per dose) every 3 weeks and adults received a fixed dose of 1200 mg every 3 weeks. Overall, steady-state area under the concentration-time curve (AUC) was similar between patients 12 to less than 18 years of age and adults, but systemic exposure trended lower in pediatric patients younger than 12 years of age. Peak plasma concentrations increased from children to adolescents to young adults. Terminal elimination half-lives of atezolizumab in pediatric patients and young adults were consistent with those estimated in adults.
Atezolizumab may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Pregnancy status should be verified prior to initiation of atezolizumab.
It is not known whether atezolizumab is distributed into human milk. Because human immunoglobulin G (IgG) is distributed into milk and because of the potential for serious adverse reactions to atezolizumab in nursing infants, women should be advised to discontinue nursing during atezolizumab therapy and for at least 5 months after discontinuance of therapy. The effects of the drug on nursing infants or on milk production are unknown.
In clinical studies evaluating single-agent atezolizumab for the treatment of metastatic urothelial carcinoma, metastatic NSCLC, or other tumor types, 49% of patients were 65 years of age or older and 15% were 75 years of age or older. In clinical studies of atezolizumab in combination with other antineoplastic agents for the treatment of SCLC and NSCLC, 48% of patients were 65 years of age or older, and 10% were 75 years of age or older. No overall differences in safety or efficacy were observed between geriatric patients and younger adults.
ICD codes
| Code | Type | Description |
|---|---|---|
| Alveolar soft part sarcoma | ||
| C49.0 | ICD10CM | Malignant neoplasm of connective and soft tissue of head, face and neck |
| C49.10 | ICD10CM | Malignant neoplasm of connective and soft tissue of unspecified upper limb, including shoulder |
| C49.11 | ICD10CM | Malignant neoplasm of connective and soft tissue of right upper limb, including shoulder |
| C49.12 | ICD10CM | Malignant neoplasm of connective and soft tissue of left upper limb, including shoulder |
| C49.20 | ICD10CM | Malignant neoplasm of connective and soft tissue of unspecified lower limb, including hip |
| C49.21 | ICD10CM | Malignant neoplasm of connective and soft tissue of right lower limb, including hip |
| C49.22 | ICD10CM | Malignant neoplasm of connective and soft tissue of left lower limb, including hip |
| C49.3 | ICD10CM | Malignant neoplasm of connective and soft tissue of thorax |
| C49.4 | ICD10CM | Malignant neoplasm of connective and soft tissue of abdomen |
| C49.5 | ICD10CM | Malignant neoplasm of connective and soft tissue of pelvis |
| C49.6 | ICD10CM | Malignant neoplasm of connective and soft tissue of trunk, unspecified |
| C49.8 | ICD10CM | Malignant neoplasm of overlapping sites of connective and soft tissue |
| C49.9 | ICD10CM | Malignant neoplasm of connective and soft tissue, 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 |
| Malignant melanoma with BRAF v600 mutation | ||
| C43 | ICD10CM | Malignant melanoma of skin |
| C43.0 | ICD10CM | Malignant melanoma of lip |
| C43.1 | ICD10CM | Malignant melanoma of eyelid, including canthus |
| C43.10 | ICD10CM | Malignant melanoma of unspecified eyelid, including canthus |
| C43.11 | ICD10CM | Malignant melanoma of right eyelid, including canthus |
| C43.111 | ICD10CM | Malignant melanoma of right upper eyelid, including canthus |
| C43.112 | ICD10CM | Malignant melanoma of right lower eyelid, including canthus |
| C43.12 | ICD10CM | Malignant melanoma of left eyelid, including canthus |
| C43.121 | ICD10CM | Malignant melanoma of left upper eyelid, including canthus |
| C43.122 | ICD10CM | Malignant melanoma of left lower eyelid, including canthus |
| C43.2 | ICD10CM | Malignant melanoma of ear and external auricular canal |
| C43.20 | ICD10CM | Malignant melanoma of unspecified ear and external auricular canal |
| C43.21 | ICD10CM | Malignant melanoma of right ear and external auricular canal |
| C43.22 | ICD10CM | Malignant melanoma of left ear and external auricular canal |
| C43.3 | ICD10CM | Malignant melanoma of other and unspecified parts of face |
| C43.30 | ICD10CM | Malignant melanoma of unspecified part of face |
| C43.31 | ICD10CM | Malignant melanoma of nose |
| C43.39 | ICD10CM | Malignant melanoma of other parts of face |
| C43.4 | ICD10CM | Malignant melanoma of scalp and neck |
| C43.5 | ICD10CM | Malignant melanoma of trunk |
| C43.51 | ICD10CM | Malignant melanoma of anal skin |
| C43.52 | ICD10CM | Malignant melanoma of skin of breast |
| C43.59 | ICD10CM | Malignant melanoma of other part of trunk |
| C43.6 | ICD10CM | Malignant melanoma of upper limb, including shoulder |
| C43.60 | ICD10CM | Malignant melanoma of unspecified upper limb, including shoulder |
| C43.61 | ICD10CM | Malignant melanoma of right upper limb, including shoulder |
| C43.62 | ICD10CM | Malignant melanoma of left upper limb, including shoulder |
| C43.7 | ICD10CM | Malignant melanoma of lower limb, including hip |
| C43.70 | ICD10CM | Malignant melanoma of unspecified lower limb, including hip |
| C43.71 | ICD10CM | Malignant melanoma of right lower limb, including hip |
| C43.72 | ICD10CM | Malignant melanoma of left lower limb, including hip |
| C43.8 | ICD10CM | Malignant melanoma of overlapping sites of skin |
| C43.9 | ICD10CM | Malignant melanoma of skin, unspecified |
| Microsatellite instability-high colorectal cancer | ||
| C18 | ICD10CM | Malignant neoplasm of colon |
| C18.0 | ICD10CM | Malignant neoplasm of cecum |
| C18.1 | ICD10CM | Malignant neoplasm of appendix |
| C18.2 | ICD10CM | Malignant neoplasm of ascending colon |
| C18.3 | ICD10CM | Malignant neoplasm of hepatic flexure |
| C18.4 | ICD10CM | Malignant neoplasm of transverse colon |
| C18.5 | ICD10CM | Malignant neoplasm of splenic flexure |
| C18.6 | ICD10CM | Malignant neoplasm of descending colon |
| C18.7 | ICD10CM | Malignant neoplasm of sigmoid colon |
| C18.8 | ICD10CM | Malignant neoplasm of overlapping sites of colon |
| C18.9 | ICD10CM | Malignant neoplasm of colon, unspecified |
| C19 | ICD10CM | Malignant neoplasm of rectosigmoid junction |
| C20 | ICD10CM | Malignant neoplasm of rectum |
| C21.8 | ICD10CM | Malignant neoplasm of overlapping sites of rectum, anus and anal canal |
| 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 |
| Nonsquamous 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 |
| Pd-l1 positive, EGFr-negative, ALk-negative metastatic 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 |
| 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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