Epkinly (epcoritamab-bysp)
Antineoplastic - Immunotherapy, T-cell Engager Subcutaneous Vial (Ml)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Epcoritamab-bysp, a bispecific CD20-directed CD3 T-cell engager, is an antineoplastic agent.
Epcoritamab-bysp is a bispecific CD20-directed CD3 T-cell engager; it is a humanized bispecific immunoglobulin G (IgG) antibody. Epcoritamab-bysp is a T-cell specific antibody that binds to the CD3 receptor expressed on the surface of T-cells and CD20 expressed on the surface of lymphoma cells and healthy B-lineage cells. In vitro, epcoritamab-bysp activated T-cells, caused the release of proinflammatory cytokines, and induced lysis of B-cells.
Epcoritamab-bysp is manufactured in Chinese hamster ovary cells using recombinant DNA technology.
Circulating B-cells decreased to undetectable levels (<10 cells/microliter) after administration of the approved recommended dose of epcoritamab-bysp in patients who had detectable B-cells at treatment initiation by Cycle 1 Day 15 and the depletion was sustained while patients remained on treatment. Transient elevation of circulating cytokines (interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor-alpha, and interferon-gamma) was observed at dose levels of 0.04 mg and above. After administration of the approved recommended dosages of epcoritamab-bysp, cytokine levels increased within 24 hours after the first dose on Cycle 1 Day 1, generally reached maximum levels after the first 48 mg dose, and returned to baseline prior to the second 48 mg full dose.
Epcoritamab-bysp AUC increased more than proportionally over a full dosage range from 1.5 to 60 mg (0.03125 to 1.25 times the approved recommended dosage). Epcoritamab-bysp maximum concentration (Cmax) is achieved after the first dose of Cycle 4. The median time to maximum concentration (Tmax) of epcoritamab-bysp after the first full dose and the end of Cycle 3 (weekly dosage regimen) treatment doses were 4 (range: 0.3--7) days and 2.3 days (range: 0.3--3.2), respectively.
The half-life of full dose epcoritamab-bysp (48 mg) is approximately 22 days (58%) at the end of Cycle 3. Epcoritamab-bysp is expected to be metabolized into small peptides by catabolic pathways. No clinically significant differences in pharmacokinetic parameters are observed between patients with relapsed or refractory large B-cell lymphoma and patients with relapsed or refractory follicular lymphoma.
No clinically significant differences in the pharmacokinetics of epcoritamab-bysp were observed based on age (range: 20 to 89 years), sex, race, mild to moderate renal impairment (creatinine clearance 30 to <90 mL/minute as estimated by Cockcroft-Gault formula), and mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal, and aspartate aminotransferase greater than the upper limit of normal or total bilirubin 1--1.5 times the upper limit of normal and any aspartate aminotransferase level) accounting for differences in body weight. The effects of severe renal impairment (creatinine clearance 15 to <30 mL/minute), end-stage renal disease (creatinine clearance <15 mL/minute), or moderate to severe hepatic impairment (total bilirubin greater than 1.5 the upper limit of normal and any aspartate aminotransferase level) on the pharmacokinetics of epcoritamab-bysp are unknown. In patients who received the recommended dosage of epcoritamab-bysp, geometric mean average concentration following the first full 48 mg dose was 31% lower in the higher body weight group (85 to 172 kg) and 13% higher in the lower body weight group (39 to 65 kg) compared to patients with a body weight of 65 to <85 kg.
USES: This medication is used to treat certain types of cancer (diffuse large B-cell lymphoma-DLBCL, high-grade B-cell lymphoma, follicular lymphoma). Epcoritamab works by slowing or stopping the growth of cancer cells.
Generic name: epcoritamab-bysp
Pronunciation: (EP-koe-RIT-a-mab)
Drug class: Antineoplastic - Immunotherapy, T-cell Engager
Therapeutic class: Antineoplastics
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Epkinly
Indications
The following indications are listed for Epkinly:
- Diffuse Large B-Cell Lymphoma
- Follicular Lymphoma
Also known as: Follicular B-Cell Lymphoma, Follicular B-Cell Non-Hodgkin's Lymphoma.
Dosing
If cytokine release syndrome (CRS) is suspected, withhold epcoritamab-bysp until resolved. Manage according to the recommendations in Table 8 and consider further management per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS.
At the first signs of immune effector cell-associated neurological toxicity syndrome (ICANS), withhold epcoritamab-bysp and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for ICANS. Manage ICANS according to the recommendations in Table 9 and consider further management per current practice guidelines.
Manage adverse reactions other than CRS and ICANS according to the recommendations in Table 10.
Table 8. Recommendations for Management of Cytokine Release Syndrome
Grade Presenting Symptoms Recommended Actions Grade 1 Temperature >=38degreesC Withhold epcoritamab-bysp and manage per current practice guidelines. Ensure CRS symptoms are resolved prior to next dose of epcoritamab-bysp. Grade 2 Temperature >=38degreesC Withhold with hypotension not epcoritamab-bysp and requiring vasopressors manage per current and/or hypoxia requiring practice guidelines. low-flow oxygen by nasal Ensure CRS symptoms are cannula or blow-by. resolved prior to the next dose of epcoritamab-bysp. Administer premedication prior to next dose of epcoritamab-bysp. For the next dose of epcoritamab-bysp, moni tor more frequently and consider hospitalization. Grade 3 Temperature >=38degreesC Withhold with hypotension epcoritamab-bysp and requiring a vasopressor manage per current (with or without practice guidelines, vasopressin) and/or which may include hypoxia requiring intensive care. Ensure high-flow oxygen by CRS symptoms are nasal cannula, face resolved prior to next mask, non-rebreather dose of mask, or Venturi mask. epcoritamab-bysp. Administer premedication prior to next dose of epcoritamab-bysp. Hospitalize f or the next dose of epcoritamab-bysp. Grade 3 Recurrent Grade 3 CRS Permanently discontinue epcoritamab-bysp. Manage CRS per current practice guidelines and provide supportive therapy, which may include intensive care. Grade 4 Temperature >=38degreesC Permanently discontinue with hypotension epcoritamab-bysp. Manage requiring multiple CRS per current practice vasopressors (excluding guidelines and provide vasopressin) and/or supportive therapy, hypoxia requiring oxygen which may include by positive pressure intensive care. (e.g., CPAP, BiPAP, intubation, and mechanical ventilation).
Based on the American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS.
Premedication may mask fever, therefore if clinical presentation is consistent with CRS, follow these management guidelines.
Low-flow oxygen defined as oxygen delivered at <6L/minute; high-flow oxygen defined as oxygen delivered at >=6 L/minute.
Refer to Table 6 or 7 for information on restarting epcoritamab-bysp after dosage delays.
If Grade 2 or 3 CRS occurs with the second full dose (48 mg) or beyond, administer CRS pre- and post-administration medications with each subsequent dose until an epcoritamab-bysp dose is given without subsequent CRS Grade 2 or higher. Refer to Table 1 for additional information on pre- and post-administration medications.
Table 9. Recommendations for Management of Immune Effector Cell-Associated Neurotoxicity Syndrome
Grade Presenting Symptoms Recommended Actions Grade 1 Immune Effector Withhold Cell-associated epcoritamab-bysp until Encephalopathy (ICE) ICANS resolves. Monitor score 7--9, or depressed neurological symptoms level of consciousness: and consider awakens spontaneously consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medicatio ns for seizure prophylaxis. Grade 2 ICE score 3--6, or Withhold depressed level of epcoritamab-bysp until consciousness: awakens ICANS resolves. to voice Administer dexamethasonef 10 mg IV every 6 hours. Continue dexamethasone until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other spec ialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medications for seizure prophylaxis. Grade 3 ICE score 0--2, Or First occurrence of depressed level of Grade 3 ICANS: withhold consciousness: awakens epcoritamab-bysp until only to tactile stimuli, ICANS resolves. Or seizures, either any Administer dexamethasone clinical seizure, focal 10 mg IV every 6 hours. or generalized, that Continue dexamethasone resolves rapidly, or until resolution to non-convulsive seizures Grade 1 or less, then on electroencephalogram taper. Monitor that resolve with neurologic symptoms and intervention, consider consultati Or raised intracranial on with neurologist and pressure: focal/local other specialists for edema on neuroimaging further evaluation and management, including consideration for starting non-sedating, anti-seizure medications for seizure prophylaxis. Provide supportive therapy, which may include intensive care. Grade 3 Recurrent Grade 3 ICANS Permanently discontinue epcoritamab-bysp. Administer dexamethasone 10 mg IV every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other special ists for further evaluation and management, including consideration for starting non-sedating, anti-seizure medications for seizure prophylaxis. Provide supportive therapy, which may include intensive care. Grade 4 ICE score of 0, Or depressed level of consciousness: either patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse or stupor or coma. Or seizures, either: life-threatening prolonged seizure (> 5 minutes), or repetitive clinical or electrical seizures Permanently discontinue without return to epcoritamab-bysp. baseline in between, Or Administer dexamethasone motor findings: deep 10 mg IV every 6 hours. focal motor weakness, Continue dexamethasone such as hemiparesis or until resolution to paraparesis, Or raised Grade 1 or less, then intracranial taper. Alternatively, pressure/cerebral edema, consider administration with signs/symptoms such of methylprednisolone as diffuse cerebral 1,000 mg IV per day and edema on neuroima continu ging, or decerebrate or e methylprednisolone decorticate posturing, 1,000 mg IV per day for or cranial nerve VI 2 more days. Monitor palsy, or papilledema, neurologic symptoms and or Cushing's triad. consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure m edications for seizure prophylaxis. Provide supportive therapy, which may include intensive care.
Based on American Society for Transplantation and Cellular Therapy 2019 grading for ICANS.
Management is determined by the most severe event not attributable to any other cause.
If patient is arousable and able to perform ICE assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (names 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., ''show me 2 fingers'' or ''close your eyes and stick out your tongue'' = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by 10 = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.
Not attributable to any other cause.
See Table 6 and Table 7 for recommendations on restarting epcoritamab-bysp after dosage delays.
All references to dexamethasone administration are dexamethasone or equivalent.
Table 10. Recommended Dosage Modification for Other Adverse Reactions
Adverse Reaction Severity Recommended Action Infections Grade 1--4 Withhold epcoritamab-bysp in patients with active infection, until the infection resolves. For Grade 4, consider permanent discontinuation of epcoritamab-bysp. Neutropenia Absolute neutrophil Withhold count 500 cells/mm3 epcoritamab-bysp until absolute neutrophil count is 500 cells/mm3 or higher. Thrombocytopenia Platelet count less than Withhold 50,000 cells/mm3 epcoritamab-bysp until platelet count is 50,000 cells/mm or higher. Other Adverse Reactions Grade 3 or higher Withhold epcoritamab-bysp until the toxicity resolves to Grade 1 or baseline.
Based on National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0.
See Table 6 or Table 7 for recommendations on restarting epcoritamab-bysp after dosage delays.
Epcoritamab-bysp is administered by subcutaneous injection only by a healthcare professional with appropriate medical support to manage severe reactions such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome.
Administer epcoritamab-bysp in 28-day cycles until disease progression or unacceptable toxicity.
Epcoritamab-bysp dosages of 0.16 mg and 0.8 mg require dilution prior to administration. Dosages of 3 mg and 48 mg do not require dilution.
Inspect product for particulate matter and discoloration prior to administration, whenever solution and container permit. Epcoritamab-bysp is a clear to slightly opalescent, colorless to slightly yellow solution, free of visible particles.
The epcoritamab-bysp vial should be swirled gently prior to withdrawal of the dose; do not invert, vortex, or vigorously shake the vial. Vials containing unused epcoritamab-bysp should be discarded.
To minimize injection pain, allow epcoritamab-bysp to equilibrate to room temperature for no more than 1 hour prior to administration.
Inject the required volume of epcoritamab-bysp into the subcutaneous tissue of the lower part of the abdomen (preferred location) or the thigh. Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, or not intact.
Change of injection site from the left or right side (or vice versa) is recommended, especially during weekly administrations (Cycles 1 to 3).
Store refrigerated at 2 to 8degreesC. Keep in the original carton to protect from light. Do not freeze. Do not shake.
Administer epcoritamab-bysp solution in the syringe immediately. If not used immediately, store the solution refrigerated at 2 to 8degreesC for up to 24 hours or at room temperature at 20 to 25degreesC for up to 12 hours. The total storage time from the start of dose preparation to administration should not exceed 24 hours. Protect from direct sunlight. Discard unused epcoritamab-bysp solution beyond the allowable storage time.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Epcoritamab-bysp is expected to be metabolized into small peptides by catabolic pathways.
No clinical studies evaluating the drug interaction potential of epcoritamab-bysp have been conducted.
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)
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)
Immunosuppressives; Immunomodulators/Cladribine Oncology Inj
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-4)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-4)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US, UK, and Australian prescribing information state: -Caution should be exercised if cladribine injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression.(1-3) The cladribine Canadian prescribing information states: -Proceed carefully in patients with severe bone marrow impairment of any etiology since further suppression of bone marrow function should be anticipated.(4)
DISCUSSION: Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with cladribine injection, especially at high doses.(1-4)
Immunosuppressives; Immunomodulators/Covid-19 Vaccines
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Immunosuppressants and immunomodulators may prevent the immune system from properly responding to the COVID-19 vaccine.(1-3)
CLINICAL EFFECTS: Administration of a COVID-19 vaccine with immunosuppressants or immunomodulators may interfere with vaccine-induced immune response and impair the efficacy of the vaccine. However, patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The Centers for Disease Control and Prevention (CDC),(1) Infectious Diseases Society of America (IDSA),(2) and the American College of Rheumatology (ACR)(3) have published guidances for COVID-19 vaccination in patients on immunosuppressants. The CDC states that all immunocompromised patients over 6 months of age should receive at least 1 dose of COVID-19 vaccine if eligible. See the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for specific recommendations based on age, vaccination history, and vaccine manufacturer.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(1) IDSA recommends timing COVID-19 vaccination at least 2 weeks before starting or at least 3 months after completing immunosuppressive therapy.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose.(3) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted, though the immune response will likely be blunted. COVID-19 vaccines should not be delayed in patients taking immunosuppressive therapies.(1-2) See below for specific recommendations for certain agents. B-cell depleting agents, including rituximab: The CDC states that the utility of B-cell quantification to guide clinical care is not known and is not recommended. Patients who receive B-cell depleting therapy on a continuing basis should receive COVID-19 vaccines about 4 weeks before the next scheduled dose. For patients who received 1 or more doses of COVID-19 vaccine during treatment with B-cell-depleting therapies that were administered over a limited period (e.g., as part of a treatment regimen for certain malignancies), revaccination may be considered according to the current CDC recommendations for unvaccinated patients. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(1) IDSA recommends waiting for at least 3-6 months after the last infusion of B-cell depleting therapy before administering COVID-19 vaccines.(2) The ACR recommends consulting with the rheumatologist to determine optimal timing of COVID-19 vaccination. Measuring CD19 B cells may be considered to determine need for a booster vaccine dose. If B cell levels are not measured, a supplemental vaccine dose 2-4 weeks before the next scheduled dose of rituximab is recommended.(3) Recipients of hematopoietic cell transplant or CAR-T-cell therapy who received one or more doses of COVID-19 vaccine prior to or during treatment should undergo revaccination following the current CDC recommendations for unvaccinated patients. Revaccination should start at least 3 months (12 weeks) after transplant or CAR-T-cell therapy.(1,2) The CDC includes abatacept, cyclophosphamide, and TNF-alpha and cytokine inhibitors in their general recommendation to hold therapy for at least 2 weeks following vaccination (1) while the ACR provides different recommendations:(3) *Abatacept: - Subcutaneous abatacept should be withheld for 1-2 weeks after each vaccine dose, as disease activity allows. - For intravenous abatacept, time administration so that vaccination will occur 1 week before the next abatacept infusion. *Cyclophosphamide: When feasible, administer cyclophosphamide 1 week after each COVID-19 vaccine dose. *TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to reach consensus on whether to modify dosing or timing of these agents with COVID-19 vaccination.
DISCUSSION: IDSA recommendations are based on cohort and case control studies in immunocompromised patients that found low to modest vaccine effectiveness (37-61%) but lower risks of COVID-19 association hospitalization, COVID-19 related mortality, and critical illness.(2) The ACR convened a COVID-19 Vaccine Guidance Task Force to provide guidance on optimal use of COVID-19 vaccines in rheumatology patients. These recommendations are based on limited clinical evidence of COVID-19 vaccines in patients without rheumatic and musculoskeletal disorders and evidence of other vaccines in this patient population.(3) The ACR recommendation for rituximab is based on studies of humoral immunity following receipt of other vaccines. These studies have uncertain generalizability to vaccination against COVID-19, as it is unknown if efficacy is attributable to induction of host T cells versus B cell (antibody-based) immunity.(3) The ACR recommendation for mycophenolate is based on preexisting data of mycophenolate on non-COVID-19 vaccine immunogenicity. Emerging data suggests that mycophenolate may impair SARS-CoV-2 vaccine response in rheumatic and musculoskeletal disease and transplant patients.(3) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(3) The ACR recommendation for JAK inhibitors is based on concerns related to the effects of JAK inhibitors on interferon signaling that may result in a diminished vaccine response.(3) The ACR recommendation for subcutaneous abatacept is based on several studies suggesting a negative effect of abatacept on vaccine immunogenicity. The first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct. CTLA-4 should not inhibit boosts of already primed T cells at the time of the second vaccine dose.(3)
Immunosuppressives; Immunomodulators/Sarilumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Sarilumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of sarilumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of sarilumab recommends caution because the concurrent use of sarilumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Sarilumab was studied as monotherapy and in combination with methotrexate or conventional disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis studies. Sarilumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by sarilumab treated patients in the clinical trial periods included pneumonia and cellulitis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving sarilumab. Cases of tuberculosis, candidiasis, and pneumocystis with sarilumab have been reported.(1)
Immunosuppressives; Immunomodulators/Tocilizumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Tocilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of tocilizumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of tocilizumab recommends caution because the concurrent use of tocilizumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Tocilizumab was studied as monotherapy and in combination with methotrexate, non-biologic DMARDs or corticosteroids, depending on the indication. Tocilizumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by tocilizumab treated patients in the clinical trial periods included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving tocilizumab. Cases of tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis have been reported.(1)
Immunosuppressives; Immunomodulators/Ublituximab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ublituximab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ublituximab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The US manufacturer of ublituximab recommends caution because the concurrent use of ublituximab with immunomodulating or immunosuppressive agents, including immunosuppressant doses of corticosteroids, may increase the risk of infection.(1) If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents. When switching from agents with immune effects, the half-life and mechanism of action of these drugs must be taken into consideration in order to prevent additive immunosuppressive effects.(1)
DISCUSSION: The most common infections reported by ublituximab-treated patients in the clinical trial periods included upper respiratory tract infections and urinary tract infections. Serious, including life-threatening or fatal, bacterial and viral infections were observed in patients receiving ublituximab.(1) Serious and/or fatal bacterial, fungal, and new or reactivated viral infections have been associated with other anti-CD20 B-cell depleting therapies. There were no cases of progressive multifocal leukoencephalopathy (PML) reported during the clinical trials; however, there have been reports of PML during or following completion of other anti-CD20 B-cell depleting therapies.(1)
Immunosuppressives; Immunomodulators/Ustekinumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ustekinumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ustekinumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of ustekinumab recommends caution because the concurrent use of ustekinumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Ustekinumab has not been studied in combination with other immunosuppressants in psoriasis studies. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by ustekinumab treated patients in the clinical trial periods included nasopharyngitis(8%) and upper respiratory tract infection(5%). Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab. Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia resulting in respiratory failure or prolonged hospitalization have been reported in patients receiving ustekinumab.(1)
Contraindications
*None.
- Lactation
- Progressive multifocal leukoencephalopathy
- Anemia
- Infection
- Neutropenic disorder
- Pregnancy
- Thrombocytopenic disorder
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse effects of epcoritamab-bysp (>=20% of patients) reported in clinical studies for the treatment of large B-cell lymphoma include cytokine release syndrome, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (>=10%) are decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, decreased hemoglobin, and decreased platelets.
The most common adverse effects of epcoritamab-bysp (>=20% of patients) reported in clinical studies for the treatment of follicular lymphoma include injection site reactions, cytokine release syndrome, COVID-19, fatigue, upper respiratory tract infection, musculoskeletal pain, rash, diarrhea, pyrexia, cough, and headache. The most common Grade 3 to 4 laboratory abnormalities (>=10%) are decreased lymphocyte count, decreased neutrophil count, decreased white blood cell count, and decreased hemoglobin.
More Frequent
- Anemia
- Cytokine release syndrome
- Infection
- Leukopenia
- Lymphopenia
- Neutropenic disorder
- Thrombocytopenic disorder
Less Frequent
- Ataxia
- Cardiac arrhythmia
- Cytomegalovirus disease
- Herpes zoster
- Immune effector cell-associated neurotoxicity syndrome
- Increased alanine transaminase
- Increased aspartate transaminase
- Malignancy
- Pleural effusions
- Pneumonia
- Sepsis
- Tumor lysis syndrome
- Upper respiratory infection
- Varicella zoster virus infection
Rare or Very Rare
- Acute myocardial infarction
- Drug-induced hepatitis
- Heart failure
- Hemophagocytic lymphohistiocytosis
- Interstitial pneumonitis
- Progressive multifocal leukoencephalopathy
- Pulmonary thromboembolism
More Frequent
- Acute abdominal pain
- Acute cognitive impairment
- Diarrhea
- Fatigue
- Fever
- Hyperkalemia
- Injection site sequelae
- Musculoskeletal pain
- Nausea
- Supraventricular premature beats
- Urinary tract infection
Less Frequent
- Abnormal hepatic function tests
- Anorexia
- Arthralgia
- Constipation
- Cough
- Dizziness
- Dyspnea
- Edema
- Headache disorder
- Herpes simplex infection
- Hyperbilirubinemia
- Hypokalemia
- Hypomagnesemia
- Hyponatremia
- Hypophosphatemia
- Insomnia
- Peripheral neuropathy
- Skin rash
- Stomatitis
- Tremor
- Tumor flare reaction
- Visual changes
- Vomiting
Rare or Very Rare
- Kidney disease with reduction in glomerular filtration rate (GFr)
Precautions
No enhanced messaging available.
Safety and effectiveness of epcoritamab-bysp in pediatric patients have not been established.
Based on the mechanism of action, epcoritamab-bysp may cause fetal harm when administered to a pregnant woman. There are no available data on the use of epcoritamab-bysp in pregnant women to evaluate a drug-associated risk. No animal reproductive or development toxicity studies have been conducted with epcoritamab-bysp.
Epcoritamab-bysp causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on expression of CD20 on B-cells and the finding of B-cell depletion in non-pregnant animals, epcoritamab-bysp can cause B-cell lymphocytopenia in infants exposed to epcoritamab-bysp in utero.
Human immunoglobulin G (IgG) is known to cross the placenta; therefore, epcoritamab-bysp has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus.
There are no data on the presence of epcoritamab-bysp in human milk, the effects on the breast-fed child, or the effects on milk production. Because maternal IgG is present in human milk, and there is potential for epcoritamab-bysp absorption leading to serious adverse reactions in a breast-fed child, advise women not to breastfeed during treatment with epcoritamab-bysp and for 4 months after the last dose.
The manufacturer makes no specific dosage recommendations for geriatric patients.
In patients with relapsed or refractory large B-cell lymphoma who received epcoritamab-bysp in EPCORE NHL-1, 77 (49%) were 65 years of age and older, and 29 (19%) were 75 years of age and older. No clinically meaningful differences in safety or efficacy were observed between patients with relapsed or refractory large B-cell lymphoma who were 65 years of age and older compared with younger adult patients.
In patients with relapsed or refractory follicular lymphoma who received epcoritamab-bysp in EPCORE NHL-1, 66 (52%) were 65 years of age and older, and 16 (13%) were 75 years of age and older. In patients with relapsed or refractory follicular lymphoma, there was a higher rate of adverse reactions, primarily infections, including COVID-19, in patients older than 65 years of age compared to younger adult patients.
No overall difference in efficacy was observed in patients with relapsed or refractory follicular lymphoma who were 65 years of age and older compared with younger adult patients.
ICD codes
| Code | Type | Description |
|---|---|---|
| Diffuse large b-cell lymphoma | ||
| C83.3 | ICD10CM | Diffuse large b-cell lymphoma |
| C83.30 | ICD10CM | Diffuse large b-cell lymphoma, unspecified site |
| C83.31 | ICD10CM | Diffuse large b-cell lymphoma, lymph nodes of head, face, and neck |
| C83.32 | ICD10CM | Diffuse large b-cell lymphoma, intrathoracic lymph nodes |
| C83.33 | ICD10CM | Diffuse large b-cell lymphoma, intra-abdominal lymph nodes |
| C83.34 | ICD10CM | Diffuse large b-cell lymphoma, lymph nodes of axilla and upper limb |
| C83.35 | ICD10CM | Diffuse large b-cell lymphoma, lymph nodes of inguinal region and lower limb |
| C83.36 | ICD10CM | Diffuse large b-cell lymphoma, intrapelvic lymph nodes |
| C83.37 | ICD10CM | Diffuse large b-cell lymphoma, spleen |
| C83.38 | ICD10CM | Diffuse large b-cell lymphoma, lymph nodes of multiple sites |
| C83.39 | ICD10CM | Diffuse large b-cell lymphoma, extranodal and solid organ sites |
| C83.398 | ICD10CM | Diffuse large b-cell lymphoma of other extranodal and solid organ sites |
| Follicular lymphoma | ||
| C82 | ICD10CM | Follicular lymphoma |
| C82.0 | ICD10CM | Follicular lymphoma grade I |
| C82.00 | ICD10CM | Follicular lymphoma grade i, unspecified site |
| C82.01 | ICD10CM | Follicular lymphoma grade i, lymph nodes of head, face, and neck |
| C82.02 | ICD10CM | Follicular lymphoma grade i, intrathoracic lymph nodes |
| C82.03 | ICD10CM | Follicular lymphoma grade i, intra-abdominal lymph nodes |
| C82.04 | ICD10CM | Follicular lymphoma grade i, lymph nodes of axilla and upper limb |
| C82.05 | ICD10CM | Follicular lymphoma grade i, lymph nodes of inguinal region and lower limb |
| C82.06 | ICD10CM | Follicular lymphoma grade i, intrapelvic lymph nodes |
| C82.07 | ICD10CM | Follicular lymphoma grade i, spleen |
| C82.08 | ICD10CM | Follicular lymphoma grade i, lymph nodes of multiple sites |
| C82.09 | ICD10CM | Follicular lymphoma grade i, extranodal and solid organ sites |
| C82.1 | ICD10CM | Follicular lymphoma grade II |
| C82.10 | ICD10CM | Follicular lymphoma grade Ii, unspecified site |
| C82.11 | ICD10CM | Follicular lymphoma grade Ii, lymph nodes of head, face, and neck |
| C82.12 | ICD10CM | Follicular lymphoma grade Ii, intrathoracic lymph nodes |
| C82.13 | ICD10CM | Follicular lymphoma grade Ii, intra-abdominal lymph nodes |
| C82.14 | ICD10CM | Follicular lymphoma grade Ii, lymph nodes of axilla and upper limb |
| C82.15 | ICD10CM | Follicular lymphoma grade Ii, lymph nodes of inguinal region and lower limb |
| C82.16 | ICD10CM | Follicular lymphoma grade Ii, intrapelvic lymph nodes |
| C82.17 | ICD10CM | Follicular lymphoma grade Ii, spleen |
| C82.18 | ICD10CM | Follicular lymphoma grade Ii, lymph nodes of multiple sites |
| C82.19 | ICD10CM | Follicular lymphoma grade Ii, extranodal and solid organ sites |
| C82.2 | ICD10CM | Follicular lymphoma grade IIi, unspecified |
| C82.20 | ICD10CM | Follicular lymphoma grade IIi, unspecified, unspecified site |
| C82.21 | ICD10CM | Follicular lymphoma grade IIi, unspecified, lymph nodes of head, face, and neck |
| C82.22 | ICD10CM | Follicular lymphoma grade IIi, unspecified, intrathoracic lymph nodes |
| C82.23 | ICD10CM | Follicular lymphoma grade IIi, unspecified, intra-abdominal lymph nodes |
| C82.24 | ICD10CM | Follicular lymphoma grade IIi, unspecified, lymph nodes of axilla and upper limb |
| C82.25 | ICD10CM | Follicular lymphoma grade IIi, unspecified, lymph nodes of inguinal region and lower limb |
| C82.26 | ICD10CM | Follicular lymphoma grade IIi, unspecified, intrapelvic lymph nodes |
| C82.27 | ICD10CM | Follicular lymphoma grade IIi, unspecified, spleen |
| C82.28 | ICD10CM | Follicular lymphoma grade IIi, unspecified, lymph nodes of multiple sites |
| C82.29 | ICD10CM | Follicular lymphoma grade IIi, unspecified, extranodal and solid organ sites |
| C82.3 | ICD10CM | Follicular lymphoma grade IIia |
| C82.30 | ICD10CM | Follicular lymphoma grade IIia, unspecified site |
| C82.31 | ICD10CM | Follicular lymphoma grade IIia, lymph nodes of head, face, and neck |
| C82.32 | ICD10CM | Follicular lymphoma grade IIia, intrathoracic lymph nodes |
| C82.33 | ICD10CM | Follicular lymphoma grade IIia, intra-abdominal lymph nodes |
| C82.34 | ICD10CM | Follicular lymphoma grade IIia, lymph nodes of axilla and upper limb |
| C82.35 | ICD10CM | Follicular lymphoma grade IIia, lymph nodes of inguinal region and lower limb |
| C82.36 | ICD10CM | Follicular lymphoma grade IIia, intrapelvic lymph nodes |
| C82.37 | ICD10CM | Follicular lymphoma grade IIia, spleen |
| C82.38 | ICD10CM | Follicular lymphoma grade IIia, lymph nodes of multiple sites |
| C82.39 | ICD10CM | Follicular lymphoma grade IIia, extranodal and solid organ sites |
| C82.4 | ICD10CM | Follicular lymphoma grade IIib |
| C82.40 | ICD10CM | Follicular lymphoma grade IIib, unspecified site |
| C82.41 | ICD10CM | Follicular lymphoma grade IIib, lymph nodes of head, face, and neck |
| C82.42 | ICD10CM | Follicular lymphoma grade IIib, intrathoracic lymph nodes |
| C82.43 | ICD10CM | Follicular lymphoma grade IIib, intra-abdominal lymph nodes |
| C82.44 | ICD10CM | Follicular lymphoma grade IIib, lymph nodes of axilla and upper limb |
| C82.45 | ICD10CM | Follicular lymphoma grade IIib, lymph nodes of inguinal region and lower limb |
| C82.46 | ICD10CM | Follicular lymphoma grade IIib, intrapelvic lymph nodes |
| C82.47 | ICD10CM | Follicular lymphoma grade IIib, spleen |
| C82.48 | ICD10CM | Follicular lymphoma grade IIib, lymph nodes of multiple sites |
| C82.49 | ICD10CM | Follicular lymphoma grade IIib, extranodal and solid organ sites |
| C82.5 | ICD10CM | Diffuse follicle center lymphoma |
| C82.50 | ICD10CM | Diffuse follicle center lymphoma, unspecified site |
| C82.51 | ICD10CM | Diffuse follicle center lymphoma, lymph nodes of head, face, and neck |
| C82.52 | ICD10CM | Diffuse follicle center lymphoma, intrathoracic lymph nodes |
| C82.53 | ICD10CM | Diffuse follicle center lymphoma, intra-abdominal lymph nodes |
| C82.54 | ICD10CM | Diffuse follicle center lymphoma, lymph nodes of axilla and upper limb |
| C82.55 | ICD10CM | Diffuse follicle center lymphoma, lymph nodes of inguinal region and lower limb |
| C82.56 | ICD10CM | Diffuse follicle center lymphoma, intrapelvic lymph nodes |
| C82.57 | ICD10CM | Diffuse follicle center lymphoma, spleen |
| C82.58 | ICD10CM | Diffuse follicle center lymphoma, lymph nodes of multiple sites |
| C82.59 | ICD10CM | Diffuse follicle center lymphoma, extranodal and solid organ sites |
| C82.6 | ICD10CM | Cutaneous follicle center lymphoma |
| C82.60 | ICD10CM | Cutaneous follicle center lymphoma, unspecified site |
| C82.61 | ICD10CM | Cutaneous follicle center lymphoma, lymph nodes of head, face, and neck |
| C82.62 | ICD10CM | Cutaneous follicle center lymphoma, intrathoracic lymph nodes |
| C82.63 | ICD10CM | Cutaneous follicle center lymphoma, intra-abdominal lymph nodes |
| C82.64 | ICD10CM | Cutaneous follicle center lymphoma, lymph nodes of axilla and upper limb |
| C82.65 | ICD10CM | Cutaneous follicle center lymphoma, lymph nodes of inguinal region and lower limb |
| C82.66 | ICD10CM | Cutaneous follicle center lymphoma, intrapelvic lymph nodes |
| C82.67 | ICD10CM | Cutaneous follicle center lymphoma, spleen |
| C82.68 | ICD10CM | Cutaneous follicle center lymphoma, lymph nodes of multiple sites |
| C82.69 | ICD10CM | Cutaneous follicle center lymphoma, extranodal and solid organ sites |
| C82.8 | ICD10CM | Other types of follicular lymphoma |
| C82.80 | ICD10CM | Other types of follicular lymphoma, unspecified site |
| C82.81 | ICD10CM | Other types of follicular lymphoma, lymph nodes of head, face, and neck |
| C82.82 | ICD10CM | Other types of follicular lymphoma, intrathoracic lymph nodes |
| C82.83 | ICD10CM | Other types of follicular lymphoma, intra-abdominal lymph nodes |
| C82.84 | ICD10CM | Other types of follicular lymphoma, lymph nodes of axilla and upper limb |
| C82.85 | ICD10CM | Other types of follicular lymphoma, lymph nodes of inguinal region and lower limb |
| C82.86 | ICD10CM | Other types of follicular lymphoma, intrapelvic lymph nodes |
| C82.87 | ICD10CM | Other types of follicular lymphoma, spleen |
| C82.88 | ICD10CM | Other types of follicular lymphoma, lymph nodes of multiple sites |
| C82.89 | ICD10CM | Other types of follicular lymphoma, extranodal and solid organ sites |
| C82.9 | ICD10CM | Follicular lymphoma, unspecified |
| C82.90 | ICD10CM | Follicular lymphoma, unspecified, unspecified site |
| C82.91 | ICD10CM | Follicular lymphoma, unspecified, lymph nodes of head, face, and neck |
| C82.92 | ICD10CM | Follicular lymphoma, unspecified, intrathoracic lymph nodes |
| C82.93 | ICD10CM | Follicular lymphoma, unspecified, intra-abdominal lymph nodes |
| C82.94 | ICD10CM | Follicular lymphoma, unspecified, lymph nodes of axilla and upper limb |
| C82.95 | ICD10CM | Follicular lymphoma, unspecified, lymph nodes of inguinal region and lower limb |
| C82.96 | ICD10CM | Follicular lymphoma, unspecified, intrapelvic lymph nodes |
| C82.97 | ICD10CM | Follicular lymphoma, unspecified, spleen |
| C82.98 | ICD10CM | Follicular lymphoma, unspecified, lymph nodes of multiple sites |
| C82.99 | ICD10CM | Follicular lymphoma, unspecified, extranodal and solid organ sites |
ICD code information from First Databank (FDB).
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