Verzenio (abemaciclib)
Antineoplastic- Cyclin-Dependent Kinase (CDK) 4/6 Inhibitors Oral Tablet
Last reviewed · Source: First Databank (FDB) drug data
Overview
Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6), is an antineoplastic agent.
Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6), is an antineoplastic agent. Several mechanisms contribute to the dysregulation of the cell cycle during the G1 into S phase, including amplification or overexpression of the cyclin D oncogene or the loss of intrinsic CDK inhibitors (i.e., p16, p15, p18, p19, p21, p27, p57) in breast cancer. Abemaciclib specifically inhibits CDK4 and CDK6 and blocks the interaction of CDK4 and CDK6 with cyclin D, resulting in inhibition of phosphorylation of the tumor suppressor protein retinoblastoma and inhibition of progression of the cell cycle from the G1 into S phase.
In vitro, abemaciclib has demonstrated decreased phosphorylation of retinoblastoma protein and reduced cellular proliferation of breast cancer cell lines by inhibiting the G1 into S phase of the cell cycle. The combination of abemaciclib with an antiestrogen agent or as a single-agent demonstrated reduced tumor volume in xenograft models of breast cancer.
Area under the serum concentration-time curve (AUC) and peak plasma concentrations of abemaciclib are dose proportional over a dosage range of 50-200 mg. Peak plasma concentrations of abemaciclib are achieved in a median of 8 hours following oral administration of the drug. Following repeated doses of abemaciclib twice daily, steady-state concentrations of the drug are achieved in 5 days and the mean accumulation ratio for the drug based on AUC or peak plasma concentration is 3.2 or 2.3, respectively.
Oral administration of abemaciclib with a high-fat, high-calorie meal (approximately 800-1000 calories with fat accounting for over 50% of the caloric content) increases systemic exposure and peak plasma concentrations of abemaciclib and its active metabolites by 9 and 26%, respectively. Abemaciclib and its active metabolites are highly bound (more than 93%) to plasma proteins, albumin, and alpha1-acid glycoprotein. Abemaciclib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.
The main circulating metabolites, M-2 (an N-desethyl metabolite), M-18 (a hydroxy-N-desethyl metabolite), and M-20 (a hydroxy metabolite) have been shown to be equipotent to abemaciclib, and these metabolites account for 25, 13, and 26%, respectively, of total plasma concentrations of the drug. In patients with advanced cancer, including breast cancer, CSF concentrations of abemaciclib and its active metabolites M-2 and M-20 are similar to unbound plasma concentrations. Following oral administration of a single radiolabeled dose of abemaciclib, approximately 81% of the radioactivity was recovered in feces (mainly as metabolites) and approximately 3% was recovered in urine.
The mean plasma elimination half-life of the drug is 18.3 hours.
Population pharmacokinetic analysis indicated that age (24-91 years), gender, and body weight (36-175 kg) do not have clinically important effects on the exposure of abemaciclib.
USES: This medication is used to treat certain types of breast cancer. Abemaciclib works by slowing or stopping the growth of cancer cells. It belongs to a class of drugs known as kinase inhibitors.
Generic name: abemaciclib
Pronunciation: (a-BEM-a-SYE-klib)
Drug class: Antineoplastic- Cyclin-Dependent Kinase (CDK) 4/6 Inhibitors
Therapeutic class: Antineoplastics
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
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Indications
The following indications are listed for Verzenio:
- Er-Positive, Her2-Negative, Esr1-Mutated Breast Cancer
- Hormone Receptor (Hr)-Positive, Her2-Negative Advanced Breast Cancer
- Hormone Receptor (Hr)-Positive, Her2-Negative Early-Stage Breast Cancer
Also known as: Hormone Receptor (Hr)-Positive, Her2-Negative Metastatic Breast Cancer, Hormone Receptor(+), Her2(-) Early Breast Cancer, Hr+, Her2- Early Breast Ca, Hr-Positive, Human Epidermal Growth Factor Receptor 2 (Her2)-Negative Advanced Breast Cancer, Hr-Positive, Human Epidermal Growth Factor Receptor 2 (Her2)-Negative Metastatic Breast Cancer.
Dosing
Dosage interruption and/or reduction or discontinuance of abemaciclib therapy may be necessary based on severity of adverse reactions. The following table on Dosage Modifications for Abemaciclib Toxicity indicates the recommended dosage modifications for abemaciclib during monotherapy or combination therapy with fulvestrant or an aromatase inhibitor.
Table 1: Dosage Modifications for Abemaciclib Toxicity
Toxicity Occurrence Dosage Modification after Recovery from Toxicity Single-agent Abemaciclib Abemaciclib in (Starting Dosage = 200 Combination with mg twice daily) Fulvestrant, Tamoxifen, or an Aromatase Inhibitor (Starting Dosage = 150 mg twice daily) First Restart at 150 mg twice Restart at 100 mg twice daily daily Second Restart at 100 mg twice Restart at 50 mg twice daily daily Third Restart at 50 mg twice Discontinue abemaciclib daily Fourth Discontinue abemaciclib
Concomitant use of abemaciclib with ketoconazole, a potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A (CYP3A), must be avoided; however, when abemaciclib is used concomitantly with other potent CYP3A inhibitors, the manufacturer recommends reducing the initial dosage of abemaciclib (200 or 150 mg twice daily depending on indication) to 100 mg twice daily or, in those already receiving a reduced dosage of abemaciclib (100 mg twice daily), further reducing the dosage of abemaciclib to 50 mg twice daily. When concomitant use of the potent CYP3A inhibitor is discontinued, the abemaciclib dosage should be returned (after at least 3-5 elimination half-lives of the CYP3A inhibitor) to the dosage used prior to initiation of the potent CYP3A inhibitor.
Patients receiving abemaciclib concomitantly with moderate CYP3A inhibitors should be monitored for signs of abemaciclib toxicity and dosage modifications for adverse reactions (see Table 1) should be considered.
Abemaciclib is administered orally without regard to food at approximately the same time each day. The tablets should be swallowed intact and should not be broken, chewed, crushed, or split.
If a dose of abemaciclib is missed or vomited, patients should not take an extra dose. The next dose should be taken at the regularly scheduled time.
Store abemaciclib at 20-25oC (excursions permitted to 15-30oC).
| Drug label | Dosing type | Instructions |
|---|---|---|
| Verzenio 50 Mg Tablet | Maintenance | Take 1 tablet (50 mg) by oral route 2 times per day at approximately the same times each day. |
| Verzenio 100 Mg Tablet | Maintenance | Take 1 tablet (100 mg) by oral route 2 times per day at approximatelythe same times each day. |
| Verzenio 150 Mg Tablet | Maintenance | Take 1 tablet (150 mg) by oral route 2 times per day at approximatelythe same times each day. |
| Verzenio 200 Mg Tablet | Maintenance | Take 1 tablet (200 mg) by oral route 2 times per day at approximatelythe same times each day. |
No dosing information is available for this tab.
Drug interactions
Metabolism of abemaciclib to the active N-desethyl (M-2), hydroxy-N-desethyl (M-18), and hydroxy (M-20) metabolites is mediated principally by cytochrome P-450 (CYP) isoenzyme 3A4.
Autoinhibition of abemaciclib metabolism via CYP3A4 has not been observed.
In vitro studies indicate that abemaciclib inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Abemaciclib and its major active metabolites also inhibit organic cation transporter (OCT) 2, multidrug and toxic compound extrusion protein (MATE) 1, and MATE2K, but do not inhibit OCT1, organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, and OAT3 at clinically relevant concentrations. In vitro, the drug is a substrate for P-gp and BCRP, but the drug and its major active metabolites are not substrates for OCT1, OATP1B1, or OATP1B3.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Abemaciclib/Ketoconazole
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: Abemaciclib is a substrate of CYP3A4. Ketoconazole, a strong inhibitor of CYP3A4, may inhibit the metabolism of abemaciclib.(1)
CLINICAL EFFECTS: Concurrent use of ketoconazole, a strong inhibitor of CYP3A4, may result in increased levels and toxicity from abemaciclib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of abemaciclib states to avoid concurrent administration with ketoconazole, a strong CYP3A4 inhibitor.(1) The manufacturer of abemaciclib recommends a dose reduction of abemaciclib if concurrent use with other strong CYP3A4 inhibitors (other than ketoconazole). In patients on the recommended starting dose of abemaciclib 200 mg twice daily or 150 mg twice daily, reduce the abemaciclib dose to 100 mg twice daily. In patients who have had a dose reduction of abemaciclib to 100 mg twice daily due to adverse reactions, further reduce the dose to 50 mg twice daily with concurrent use of a strong CYP3A4 inhibitor.(1) If the concurrent strong CYP3A4 inhibitor is discontinued, increase the abemaciclib dose after 3-5 half-lives of the inhibitor to the dose that was used prior to starting the strong inhibitor.(1) Monitor patient for signs and symptoms of abemaciclib toxicity with concurrent use.
DISCUSSION: Abemaciclib is a substrate of CYP3A4.(1) Concurrent administration of ketoconazole (a strong CYP3A4 inhibitor) is predicted to increase the area-under-curve (AUC) of abemaciclib up to 16-fold.(1) Concurrent administration of itraconazole (a strong CYP3A4 inhibitor) is predicted to increase the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 2.2-fold.(1) Concurrent administration of clarithromycin (500 mg twice daily, a strong CYP3A4 inhibitor) with a single dose of 50 mg of abemaciclib increased the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 1.7-fold.(1)
Abemaciclib/Strong Cyp3a4 Inducers
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Abemaciclib is a substrate of CYP3A4. Strong inducers of CYP3A4 may induce the metabolism of abemaciclib.(1)
CLINICAL EFFECTS: Concurrent use of a strong inducer of CYP3A4 may result in decreased levels and effectiveness of abemaciclib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of abemaciclib states to avoid concurrent administration with strong CYP3A4 inducers and consider alternative agents.(1)
DISCUSSION: Abemaciclib is a substrate of CYP3A4.(1) Concurrent administration of rifampin (600 mg once daily, a strong CYP3A4 inducer) with a single 200 mg dose of abemaciclib decreased the relative potency adjusted unbound area-under-curve (AUC) of abemaciclib and its active metabolites (M2, M18, and M20) by 67% in healthy subjects.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2-3)
Abemaciclib/Strong Cyp3a4 Inhibitors
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Abemaciclib is a substrate of CYP3A4. Strong inhibitors of CYP3A4 may inhibit the metabolism of abemaciclib.(1)
CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 may result in increased levels and toxicity from abemaciclib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Recommendations for management of this interaction vary in different regions. The US manufacturer of abemaciclib states to avoid concurrent administration with ketoconazole, a strong CYP3A4 inhibitor.(1) The US manufacturer of abemaciclib recommends a dose reduction of abemaciclib if concurrent use with other strong CYP3A4 inhibitors (other than ketoconazole). In patients on the recommended starting dose of abemaciclib 200 mg twice daily or 150 mg twice daily, reduce the abemaciclib dose to 100 mg twice daily. In patients who have had a dose reduction of abemaciclib to 100 mg twice daily due to adverse reactions, further reduce the dose to 50 mg twice daily with concurrent use of a strong CYP3A4 inhibitor.(1) The Australian manufacturer of abemaciclib recommends specific dose recommendations based on the concomitant strong CYP3A4 inhibitor. If given with ketoconazole, the recommended abemaciclib dose is 50 mg once daily. If given with itraconazole, the recommended abemaciclib dose is 50 mg twice daily. If given with clarithromycin, the recommended abemaciclib dose is 100 mg twice daily. For other strong CYP3A4 inhibitors, the recommended abemaciclib dose is 50 mg twice daily.(2) If the concurrent strong CYP3A4 inhibitor is discontinued, increase the abemaciclib dose after 3-5 half-lives of the inhibitor to the dose that was used prior to starting the strong inhibitor.(1,2) Monitor patient for signs and symptoms of abemaciclib toxicity with concurrent use.
DISCUSSION: Abemaciclib is a substrate of CYP3A4.(1) Concurrent administration of ketoconazole (a strong CYP3A4 inhibitor) is predicted to increase the area-under-curve (AUC) of abemaciclib up to 16-fold.(1) Concurrent administration of itraconazole (a strong CYP3A4 inhibitor) is predicted to increase the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 2.2-fold.(1) Concurrent administration of clarithromycin (500 mg twice daily, a strong CYP3A4 inhibitor) with a single dose of 50 mg of abemaciclib increased the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 1.7-fold.(1) Strong CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, levoketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, posaconazole, relacorilant, ribociclib, ritonavir, saquinavir, telaprevir, telithromycin, tucatinib, troleandomycin, and voriconazole.(3,4)
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)
Oct2 Inhibitors/Dofetilide
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of dofetilide by OCT2 in the kidneys.(1)
CLINICAL EFFECTS: Concurrent use of OCT2 inhibitors may result in increased levels of and toxicities of dofetilide, including potentially life-threatening cardiac arrhythmias, like torsades de pointes (TdP).(1-3)
PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) Renal impairment may increase risk for excessive QTc prolongation as dofetilide is primarily renally eliminated. To prevent increased serum levels and risk for ventricular arrhythmias, dofetilide must be dose adjusted for creatinine clearance < or = to 60 mL/min.(1)
PATIENT MANAGEMENT: The manufacturer of dofetilide states that all renal cation transport inhibitors are contraindicated. If dofetilide is to be discontinued, a washout of at least 2 days is recommended prior to starting OCT2 inhibitors.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Dofetilide is primarily excreted in the urine via both glomerular filtration and active tubular secretion via the cation transport system. The concurrent administration of dofetilide (500 mcg twice daily) with cimetidine (an OCT2 inhibitor)(400 mg twice daily) resulted in an increase in dofetilide plasma levels by 58%. The concurrent administration of dofetilide (500 mcg single dose) with cimetidine (100 mg twice daily) resulted in an increase in dofetilide plasma levels by 13%.(1) In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(3) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(4) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, brepocitinib, givinostat, isavuconazole, trilaciclib, tucatinib, and vimseltinib. (5)
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.
Abemaciclib/Moderate Cyp3a4 Inducers
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Abemaciclib is a substrate of CYP3A4. Moderate inducers of CYP3A4 may induce the metabolism of abemaciclib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inducer of CYP3A4 may result in decreased levels and effectiveness of abemaciclib.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The manufacturer of abemaciclib states to avoid concurrent administration with moderate CYP3A4 inducers and consider alternative agents.(1)
DISCUSSION: Abemaciclib is a substrate of CYP3A4.(1) Concurrent administration of rifampin (600 mg once daily, a strong CYP3A4 inducer) with a single 200 mg dose of abemaciclib decreased the relative potency adjusted unbound area-under-curve (AUC) of abemaciclib and its active metabolites (M2, M18, and M20) by 70% in healthy subjects.(1) Concurrent administration of efavirenz, bosentan, and modafinil (moderate CYP3A4 inducers) are predicted to decrease the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 53%, 41%, and 29%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, tipranavir/ritonavir and tovorafenib.(2,3)
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 Cyp3a4 Substrates/Crizotinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Crizotinib inhibits CYP3A4, and thus may inhibit the metabolism of agents processed by this isoenzyme.(1)
CLINICAL EFFECTS: Concurrent use of crizotinib with drugs primarily metabolized by CYP3A4 may lead to elevated drug levels and increased side effects of these agents.(1) Drugs with a narrow therapeutic window that are metabolized by this isoenzyme include: abemaciclib, cisapride, cyclosporine, felodipine, hydroquinidine, lovastatin, midazolam, nisoldipine, quinidine, simvastatin, and sirolimus.(1-2)
PREDISPOSING FACTORS: Greater risk for adverse events would be expected for drugs with a narrow therapeutic window, or for drugs especially sensitive to CYP3A4 inhibition.
PATIENT MANAGEMENT: Avoid coadministration of sensitive CYP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoidable, dosage adjustment of the CYP3A4 substrate should be considered when initiating or discontinuing crizotinib.(1) Patients maintained on crizotinib may need lower initial doses of the CYP3A4 substrate. Monitor patients receiving concurrent therapy for adverse effects. Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(3)
DISCUSSION: Crizotinib (250 mg twice daily for 28 days) increased the area-under-curve (AUC) of oral midazolam by 3.7-fold.(1) Thus, crizotinib is expected to increase levels of abemaciclib, cisapride, cyclosporine, felodipine, hydroquinidine, lovastatin, midazolam, nisoldipine, quinidine, and simvastatin.
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)
Selected Sensitive Cyp3a4 Substrates/Oral Lefamulin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,3)
CLINICAL EFFECTS: Concurrent use of oral lefamulin may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)
PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)
PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate.(1) Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(2)
DISCUSSION: In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates linked to this monograph include: abemaciclib, acalabrutinib, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, ticagrelor, triazolam, and ulipristal.(1,3,5)
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.
Abemaciclib/Moderate Cyp3a4 Inhibitors
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Abemaciclib is a substrate of CYP3A4. Moderate inhibitors of CYP3A4 may inhibit the metabolism of abemaciclib.(1)
CLINICAL EFFECTS: Concurrent use of a moderate inhibitor of CYP3A4 may result in increased levels and toxicity from abemaciclib.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of abemaciclib recommends monitoring for adverse reactions and consider a dose reduction of abemaciclib dose in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(1) Monitor patient for signs and symptoms of abemaciclib toxicity with concurrent use.
DISCUSSION: Abemaciclib is a substrate of CYP3A4.(1) Concurrent administration of verapamil and diltiazem (moderate CYP3A4 inhibitors) are predicted to increase the relative adjusted unbound area-under-curve (AUC) of abemaciclib and its active metabolites (M2, M18, and M20) by approximately 1.6-fold and 2.4-fold, respectively.(1) Concurrent administration of ketoconazole (a strong CYP3A4 inhibitor) is predicted to increase the AUC of abemaciclib up to 16-fold.(1) Concurrent administration of itraconazole (a strong CYP3A4 inhibitor) is predicted to increase the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 2.2-fold.(1) Concurrent administration of clarithromycin (500 mg twice daily, a strong CYP3A4 inhibitor) with a single dose of 50 mg of abemaciclib increased the relative potency adjusted unbound AUC of abemaciclib and its active metabolites (M2, M18, and M20) by 2.5-fold.(1) Moderate CYP3A4 inhibitors linked to this monograph include: amprenavir, aprepitant, avacopan, berotralstat, clofazimine, conivaptan, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosnetupitant, imatinib, isavuconazonium, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, and verapamil.(2,3)
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)
Mate Inhibitors/Flecainide
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may interfere with the renal elimination of flecainide.(1)
CLINICAL EFFECTS: Concurrent use of MATE renal transporter inhibitors may result in increased levels of and toxicity from flecainide.(1)
PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)
PATIENT MANAGEMENT: Monitor serum flecainide concentrations and observe the patients for signs of toxicity. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a pharmacokinetic study, concurrent use of cimetidine (1 gram daily) increased flecainide levels by 30% and increased half-life by 10%.(1) MATE inhibitors linked include: abemaciclib, bictegravir, brepocitinib, cimetidine, isavuconazole, pyrimethamine, risdiplam, trimethoprim, and tucatinib.(4,5)
Mate Inhibitors/Oxaliplatin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Inhibitors of the Multidrug and Toxin Extrusion (MATE) protein transporters in the kidneys may inhibit the renal transport of oxaliplatin.(1) Oxaliplatin is a MATE substrate.(2,3)
CLINICAL EFFECTS: Concurrent use of MATE renal transporter inhibitors may result in increased levels of and toxicity from oxaliplatin, including QT prolongation and neutropenia.(1)
PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4)
PATIENT MANAGEMENT: Concurrent use of oxaliplatin with MATE renal transporter inhibitors should be approached with caution and monitored closely. If concurrent use is warranted, monitor for toxicities of oxaliplatin and consider dosage reduction based on toxicity dose recommendations.(1) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: Oxaliplatin is a MATE substrate.(2,3) MATE inhibitors include: abemaciclib, bictegravir, cimetidine, isavuconazole, pyrimethamine, risdiplam, trimethoprim, and tucatinib.(6,7)
Oct2 Inhibitors/Cisplatin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of cisplatin by OCT2 in the kidneys.(1,2)
CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicities from cisplatin, including nephrotoxicity, ototoxicity, neuropathy, and myelosuppression.(1,2)
PREDISPOSING FACTORS: Pre-existing renal insufficiency, advanced age, and dehydration may increase the risk of nephrotoxicity.
PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of cisplatin with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor closely for toxicities of cisplatin and consider dosage reduction of cisplatin.(1,2)
DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, bictegravir, brepocitinib, dolutegravir, givinostat, isavuconazole, ranolazine, trilaciclib, trimethoprim, tucatinib, and vimseltinib.(3)
Oct2 Inhibitors/Clofarabine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of clofarabine by OCT2 in the kidneys.(1,2)
CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicity from clofarabine, including myelosuppression, serious hemorrhages, enterocolitis, nephrotoxicity, and hepatotoxicity.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of clofarabine with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor for toxicities of the clofarabine and consider dosage reduction of clofarabine.(1)
DISCUSSION: In an animal study, cimetidine, an OCT2 inhibitor, decreased the clearance of clofarabine in rats by 61%. The clinical implications of this finding are unclear.(1,2) In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(3) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(4) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, bictegravir, brepocitinib, cimetidine, dolutegravir, givinostat, isavuconazole, ranolazine, trilaciclib, trimethoprim, tucatinib, and vimseltinib.(5)
Oct2 Inhibitors/Dalfampridine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of dalfampridine by OCT2 in the kidneys.(1,2)
CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicity from dalfampridine.(1,2)
PREDISPOSING FACTORS: The risk of seizures from dalfampridine may be increased in patients with a history of head trauma or prior seizure; CNS tumor; CNS infections; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).
PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of dalfampridine with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor for toxicities of dalfampridine and consider dosage reduction of dalfampridine.(1,2)
DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, bictegravir, brepocitinib, givinostat, isavuconazole, ranolazine, trilaciclib, trimethoprim, tucatinib, and vimseltinib.(3)
Oct2 Inhibitors/Procainamide
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of procainamide by OCT2 in the kidneys.(1,2)
CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicities of procainamide,(1,2) including potentially life-threatening cardiac arrhythmias, like torsades de pointes (TdP).(3)
PREDISPOSING FACTORS: Risk factors for QT prolongation include: cardiovascular disease (e.g. heart failure, recent myocardial infarction, history of torsades de pointes, congenital long QT syndrome), female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, advanced age, and concurrent use of agents known to cause QT prolongation.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3)
PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of procainamide with OCT2 renal transport inhibitors. If concurrent use is appropriate, check procainamide and N-acetylprocainamide (NAPA) levels, monitor for toxicities of procainamide and consider dosage reduction of procainamide.(1) Since other H-2 antagonists (e.g., ranitidine, famotidine) do not appear to interact, substituting cimetidine with one of these agents may be desirable. However, if a patient is already receiving this combination and is not experiencing adverse effects, substitution is probably not necessary. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.
DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, bictegravir, brepocitinib, cimetidine, dolutegravir, givinostat, isavuconazole, trilaciclib, tucatinib, and vimseltinib.(4)
Contraindications
The manufacturer states there are no known contraindications to the use of abemaciclib.
- Lactation
- Child-pugh class C hepatic impairment
- Disease of liver
- Interstitial lung disease
- Neutropenic disorder
- Pregnancy
- Severe diarrhea
- Thromboembolic disorder
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in 20% or more of patients treated with abemaciclib include diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.
More Frequent
- Anemia
- Diarrhea
- Infection
- Leukopenia
- Neutropenic disorder
- Thrombocytopenic disorder
Less Frequent
- Deep venous thrombosis
- Dehydration
- Increased alanine transaminase
- Increased aspartate transaminase
- Pneumonia
- Venous thrombosis
Rare or Very Rare
- Acute myocardial infarction
- Arterial thrombosis
- Cardiac arrest
- Cerebral thrombosis
- Cerebrovascular accident
- Heart failure
- Hypoxia
- Interstitial lung disease
- Interstitial pneumonitis
- Intracerebral hemorrhage
- Mesenteric artery thrombosis
- Neutropenic sepsis
- Pulmonary fibrosis
- Pulmonary thromboembolism
- Thrombosis of pelvic vein
- Ventricular fibrillation
More Frequent
- Acute abdominal pain
- Alopecia
- Anorexia
- Fatigue
- Headache disorder
- Hypercholesterolemia
- Hypertriglyceridemia
- Hypokalemia
- Lymphopenia
- Nausea
- Vomiting
Less Frequent
- Arthralgia
- Cough
- Dizziness
- Dysgeusia
- Fever
- Peripheral edema
- Pruritus of skin
- Skin rash
- Stomatitis
- Weight loss
Precautions
No enhanced messaging available.
Safety and efficacy of abemaciclib have not been established in pediatric patients.
Abemaciclib may cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.
Verify pregnancy status prior to initiation of abemaciclib therapy.
It is not known whether abemaciclib is distributed into human milk. Because of the potential for serious adverse reactions to abemaciclib in nursing infants, women should be advised to discontinue nursing during and for at least 3 weeks after discontinuance of abemaciclib therapy. The effects of the drug on nursing infants or on milk production are unknown.
In the monarchE study, 15% of patients were 65 years of age or older and 2.7% were 75 years of age or older.
In the MONARCH-1, MONARCH-2, and MONARCH-3 studies, 38% of patients were 65 years of age or older and 10% were 75 years of age or older. No overall differences in safety and efficacy were observed between geriatric patients and younger adults. Grade 3 or 4 adverse reactions occurring in at least 5% of geriatric patients in MONARCH-1, MONARCH-2, and MONARCH-3 were neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infection, and elevated serum ALT concentrations.
Among patients 24-91 years of age, age did not appear to substantially affect systemic exposure to abemaciclib.
ICD codes
| Code | Type | Description |
|---|---|---|
| Er-positive, HEr2-negative, ESr1-mutated breast cancer | ||
| C50.011 | ICD10CM | Malignant neoplasm of nipple and areola, right female breast |
| C50.012 | ICD10CM | Malignant neoplasm of nipple and areola, left female breast |
| C50.019 | ICD10CM | Malignant neoplasm of nipple and areola, unspecified female breast |
| C50.021 | ICD10CM | Malignant neoplasm of nipple and areola, right male breast |
| C50.022 | ICD10CM | Malignant neoplasm of nipple and areola, left male breast |
| C50.029 | ICD10CM | Malignant neoplasm of nipple and areola, unspecified male breast |
| C50.111 | ICD10CM | Malignant neoplasm of central portion of right female breast |
| C50.112 | ICD10CM | Malignant neoplasm of central portion of left female breast |
| C50.119 | ICD10CM | Malignant neoplasm of central portion of unspecified female breast |
| C50.121 | ICD10CM | Malignant neoplasm of central portion of right male breast |
| C50.122 | ICD10CM | Malignant neoplasm of central portion of left male breast |
| C50.129 | ICD10CM | Malignant neoplasm of central portion of unspecified male breast |
| C50.211 | ICD10CM | Malignant neoplasm of upper-inner quadrant of right female breast |
| C50.212 | ICD10CM | Malignant neoplasm of upper-inner quadrant of left female breast |
| C50.219 | ICD10CM | Malignant neoplasm of upper-inner quadrant of unspecified female breast |
| C50.221 | ICD10CM | Malignant neoplasm of upper-inner quadrant of right male breast |
| C50.222 | ICD10CM | Malignant neoplasm of upper-inner quadrant of left male breast |
| C50.229 | ICD10CM | Malignant neoplasm of upper-inner quadrant of unspecified male breast |
| C50.311 | ICD10CM | Malignant neoplasm of lower-inner quadrant of right female breast |
| C50.312 | ICD10CM | Malignant neoplasm of lower-inner quadrant of left female breast |
| C50.319 | ICD10CM | Malignant neoplasm of lower-inner quadrant of unspecified female breast |
| C50.321 | ICD10CM | Malignant neoplasm of lower-inner quadrant of right male breast |
| C50.322 | ICD10CM | Malignant neoplasm of lower-inner quadrant of left male breast |
| C50.329 | ICD10CM | Malignant neoplasm of lower-inner quadrant of unspecified male breast |
| C50.411 | ICD10CM | Malignant neoplasm of upper-outer quadrant of right female breast |
| C50.412 | ICD10CM | Malignant neoplasm of upper-outer quadrant of left female breast |
| C50.419 | ICD10CM | Malignant neoplasm of upper-outer quadrant of unspecified female breast |
| C50.421 | ICD10CM | Malignant neoplasm of upper-outer quadrant of right male breast |
| C50.422 | ICD10CM | Malignant neoplasm of upper-outer quadrant of left male breast |
| C50.429 | ICD10CM | Malignant neoplasm of upper-outer quadrant of unspecified male breast |
| C50.511 | ICD10CM | Malignant neoplasm of lower-outer quadrant of right female breast |
| C50.512 | ICD10CM | Malignant neoplasm of lower-outer quadrant of left female breast |
| C50.519 | ICD10CM | Malignant neoplasm of lower-outer quadrant of unspecified female breast |
| C50.521 | ICD10CM | Malignant neoplasm of lower-outer quadrant of right male breast |
| C50.522 | ICD10CM | Malignant neoplasm of lower-outer quadrant of left male breast |
| C50.529 | ICD10CM | Malignant neoplasm of lower-outer quadrant of unspecified male breast |
| C50.611 | ICD10CM | Malignant neoplasm of axillary tail of right female breast |
| C50.612 | ICD10CM | Malignant neoplasm of axillary tail of left female breast |
| C50.619 | ICD10CM | Malignant neoplasm of axillary tail of unspecified female breast |
| C50.621 | ICD10CM | Malignant neoplasm of axillary tail of right male breast |
| C50.622 | ICD10CM | Malignant neoplasm of axillary tail of left male breast |
| C50.629 | ICD10CM | Malignant neoplasm of axillary tail of unspecified male breast |
| C50.811 | ICD10CM | Malignant neoplasm of overlapping sites of right female breast |
| C50.812 | ICD10CM | Malignant neoplasm of overlapping sites of left female breast |
| C50.819 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified female breast |
| C50.821 | ICD10CM | Malignant neoplasm of overlapping sites of right male breast |
| C50.822 | ICD10CM | Malignant neoplasm of overlapping sites of left male breast |
| C50.829 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified male breast |
| C50.911 | ICD10CM | Malignant neoplasm of unspecified site of right female breast |
| C50.912 | ICD10CM | Malignant neoplasm of unspecified site of left female breast |
| C50.919 | ICD10CM | Malignant neoplasm of unspecified site of unspecified female breast |
| C50.921 | ICD10CM | Malignant neoplasm of unspecified site of right male breast |
| C50.922 | ICD10CM | Malignant neoplasm of unspecified site of left male breast |
| C50.929 | ICD10CM | Malignant neoplasm of unspecified site of unspecified male breast |
| Hormone receptor (Hr)-positive, HEr2-negative advanced breast cancer | ||
| C50 | ICD10CM | Malignant neoplasm of breast |
| C50.1 | ICD10CM | Malignant neoplasm of central portion of breast |
| C50.11 | ICD10CM | Malignant neoplasm of central portion of breast, female |
| C50.111 | ICD10CM | Malignant neoplasm of central portion of right female breast |
| C50.112 | ICD10CM | Malignant neoplasm of central portion of left female breast |
| C50.119 | ICD10CM | Malignant neoplasm of central portion of unspecified female breast |
| C50.12 | ICD10CM | Malignant neoplasm of central portion of breast, male |
| C50.121 | ICD10CM | Malignant neoplasm of central portion of right male breast |
| C50.122 | ICD10CM | Malignant neoplasm of central portion of left male breast |
| C50.129 | ICD10CM | Malignant neoplasm of central portion of unspecified male breast |
| C50.2 | ICD10CM | Malignant neoplasm of upper-inner quadrant of breast |
| C50.21 | ICD10CM | Malignant neoplasm of upper-inner quadrant of breast, female |
| C50.211 | ICD10CM | Malignant neoplasm of upper-inner quadrant of right female breast |
| C50.212 | ICD10CM | Malignant neoplasm of upper-inner quadrant of left female breast |
| C50.219 | ICD10CM | Malignant neoplasm of upper-inner quadrant of unspecified female breast |
| C50.22 | ICD10CM | Malignant neoplasm of upper-inner quadrant of breast, male |
| C50.221 | ICD10CM | Malignant neoplasm of upper-inner quadrant of right male breast |
| C50.222 | ICD10CM | Malignant neoplasm of upper-inner quadrant of left male breast |
| C50.229 | ICD10CM | Malignant neoplasm of upper-inner quadrant of unspecified male breast |
| C50.3 | ICD10CM | Malignant neoplasm of lower-inner quadrant of breast |
| C50.31 | ICD10CM | Malignant neoplasm of lower-inner quadrant of breast, female |
| C50.311 | ICD10CM | Malignant neoplasm of lower-inner quadrant of right female breast |
| C50.312 | ICD10CM | Malignant neoplasm of lower-inner quadrant of left female breast |
| C50.319 | ICD10CM | Malignant neoplasm of lower-inner quadrant of unspecified female breast |
| C50.32 | ICD10CM | Malignant neoplasm of lower-inner quadrant of breast, male |
| C50.321 | ICD10CM | Malignant neoplasm of lower-inner quadrant of right male breast |
| C50.322 | ICD10CM | Malignant neoplasm of lower-inner quadrant of left male breast |
| C50.329 | ICD10CM | Malignant neoplasm of lower-inner quadrant of unspecified male breast |
| C50.4 | ICD10CM | Malignant neoplasm of upper-outer quadrant of breast |
| C50.41 | ICD10CM | Malignant neoplasm of upper-outer quadrant of breast, female |
| C50.411 | ICD10CM | Malignant neoplasm of upper-outer quadrant of right female breast |
| C50.412 | ICD10CM | Malignant neoplasm of upper-outer quadrant of left female breast |
| C50.419 | ICD10CM | Malignant neoplasm of upper-outer quadrant of unspecified female breast |
| C50.42 | ICD10CM | Malignant neoplasm of upper-outer quadrant of breast, male |
| C50.421 | ICD10CM | Malignant neoplasm of upper-outer quadrant of right male breast |
| C50.422 | ICD10CM | Malignant neoplasm of upper-outer quadrant of left male breast |
| C50.429 | ICD10CM | Malignant neoplasm of upper-outer quadrant of unspecified male breast |
| C50.5 | ICD10CM | Malignant neoplasm of lower-outer quadrant of breast |
| C50.51 | ICD10CM | Malignant neoplasm of lower-outer quadrant of breast, female |
| C50.511 | ICD10CM | Malignant neoplasm of lower-outer quadrant of right female breast |
| C50.512 | ICD10CM | Malignant neoplasm of lower-outer quadrant of left female breast |
| C50.519 | ICD10CM | Malignant neoplasm of lower-outer quadrant of unspecified female breast |
| C50.52 | ICD10CM | Malignant neoplasm of lower-outer quadrant of breast, male |
| C50.521 | ICD10CM | Malignant neoplasm of lower-outer quadrant of right male breast |
| C50.522 | ICD10CM | Malignant neoplasm of lower-outer quadrant of left male breast |
| C50.529 | ICD10CM | Malignant neoplasm of lower-outer quadrant of unspecified male breast |
| C50.6 | ICD10CM | Malignant neoplasm of axillary tail of breast |
| C50.61 | ICD10CM | Malignant neoplasm of axillary tail of breast, female |
| C50.611 | ICD10CM | Malignant neoplasm of axillary tail of right female breast |
| C50.612 | ICD10CM | Malignant neoplasm of axillary tail of left female breast |
| C50.619 | ICD10CM | Malignant neoplasm of axillary tail of unspecified female breast |
| C50.62 | ICD10CM | Malignant neoplasm of axillary tail of breast, male |
| C50.621 | ICD10CM | Malignant neoplasm of axillary tail of right male breast |
| C50.622 | ICD10CM | Malignant neoplasm of axillary tail of left male breast |
| C50.629 | ICD10CM | Malignant neoplasm of axillary tail of unspecified male breast |
| C50.8 | ICD10CM | Malignant neoplasm of overlapping sites of breast |
| C50.81 | ICD10CM | Malignant neoplasm of overlapping sites of breast, female |
| C50.811 | ICD10CM | Malignant neoplasm of overlapping sites of right female breast |
| C50.812 | ICD10CM | Malignant neoplasm of overlapping sites of left female breast |
| C50.819 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified female breast |
| C50.82 | ICD10CM | Malignant neoplasm of overlapping sites of breast, male |
| C50.821 | ICD10CM | Malignant neoplasm of overlapping sites of right male breast |
| C50.822 | ICD10CM | Malignant neoplasm of overlapping sites of left male breast |
| C50.829 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified male breast |
| C50.9 | ICD10CM | Malignant neoplasm of breast of unspecified site |
| C50.91 | ICD10CM | Malignant neoplasm of breast of unspecified site, female |
| C50.911 | ICD10CM | Malignant neoplasm of unspecified site of right female breast |
| C50.912 | ICD10CM | Malignant neoplasm of unspecified site of left female breast |
| C50.919 | ICD10CM | Malignant neoplasm of unspecified site of unspecified female breast |
| C50.92 | ICD10CM | Malignant neoplasm of breast of unspecified site, male |
| C50.921 | ICD10CM | Malignant neoplasm of unspecified site of right male breast |
| C50.922 | ICD10CM | Malignant neoplasm of unspecified site of left male breast |
| C50.929 | ICD10CM | Malignant neoplasm of unspecified site of unspecified male breast |
| Z17.0 | ICD10CM | Estrogen receptor positive status [Er+] |
| Z19.1 | ICD10CM | Hormone sensitive malignancy status |
| Hormone receptor (Hr)-positive, HEr2-negative early-stage breast cancer | ||
| C50 | ICD10CM | Malignant neoplasm of breast |
| C50.1 | ICD10CM | Malignant neoplasm of central portion of breast |
| C50.11 | ICD10CM | Malignant neoplasm of central portion of breast, female |
| C50.111 | ICD10CM | Malignant neoplasm of central portion of right female breast |
| C50.112 | ICD10CM | Malignant neoplasm of central portion of left female breast |
| C50.119 | ICD10CM | Malignant neoplasm of central portion of unspecified female breast |
| C50.12 | ICD10CM | Malignant neoplasm of central portion of breast, male |
| C50.121 | ICD10CM | Malignant neoplasm of central portion of right male breast |
| C50.122 | ICD10CM | Malignant neoplasm of central portion of left male breast |
| C50.129 | ICD10CM | Malignant neoplasm of central portion of unspecified male breast |
| C50.2 | ICD10CM | Malignant neoplasm of upper-inner quadrant of breast |
| C50.21 | ICD10CM | Malignant neoplasm of upper-inner quadrant of breast, female |
| C50.211 | ICD10CM | Malignant neoplasm of upper-inner quadrant of right female breast |
| C50.212 | ICD10CM | Malignant neoplasm of upper-inner quadrant of left female breast |
| C50.219 | ICD10CM | Malignant neoplasm of upper-inner quadrant of unspecified female breast |
| C50.22 | ICD10CM | Malignant neoplasm of upper-inner quadrant of breast, male |
| C50.221 | ICD10CM | Malignant neoplasm of upper-inner quadrant of right male breast |
| C50.222 | ICD10CM | Malignant neoplasm of upper-inner quadrant of left male breast |
| C50.229 | ICD10CM | Malignant neoplasm of upper-inner quadrant of unspecified male breast |
| C50.3 | ICD10CM | Malignant neoplasm of lower-inner quadrant of breast |
| C50.31 | ICD10CM | Malignant neoplasm of lower-inner quadrant of breast, female |
| C50.311 | ICD10CM | Malignant neoplasm of lower-inner quadrant of right female breast |
| C50.312 | ICD10CM | Malignant neoplasm of lower-inner quadrant of left female breast |
| C50.319 | ICD10CM | Malignant neoplasm of lower-inner quadrant of unspecified female breast |
| C50.32 | ICD10CM | Malignant neoplasm of lower-inner quadrant of breast, male |
| C50.321 | ICD10CM | Malignant neoplasm of lower-inner quadrant of right male breast |
| C50.322 | ICD10CM | Malignant neoplasm of lower-inner quadrant of left male breast |
| C50.329 | ICD10CM | Malignant neoplasm of lower-inner quadrant of unspecified male breast |
| C50.4 | ICD10CM | Malignant neoplasm of upper-outer quadrant of breast |
| C50.41 | ICD10CM | Malignant neoplasm of upper-outer quadrant of breast, female |
| C50.411 | ICD10CM | Malignant neoplasm of upper-outer quadrant of right female breast |
| C50.412 | ICD10CM | Malignant neoplasm of upper-outer quadrant of left female breast |
| C50.419 | ICD10CM | Malignant neoplasm of upper-outer quadrant of unspecified female breast |
| C50.42 | ICD10CM | Malignant neoplasm of upper-outer quadrant of breast, male |
| C50.421 | ICD10CM | Malignant neoplasm of upper-outer quadrant of right male breast |
| C50.422 | ICD10CM | Malignant neoplasm of upper-outer quadrant of left male breast |
| C50.429 | ICD10CM | Malignant neoplasm of upper-outer quadrant of unspecified male breast |
| C50.5 | ICD10CM | Malignant neoplasm of lower-outer quadrant of breast |
| C50.51 | ICD10CM | Malignant neoplasm of lower-outer quadrant of breast, female |
| C50.511 | ICD10CM | Malignant neoplasm of lower-outer quadrant of right female breast |
| C50.512 | ICD10CM | Malignant neoplasm of lower-outer quadrant of left female breast |
| C50.519 | ICD10CM | Malignant neoplasm of lower-outer quadrant of unspecified female breast |
| C50.52 | ICD10CM | Malignant neoplasm of lower-outer quadrant of breast, male |
| C50.521 | ICD10CM | Malignant neoplasm of lower-outer quadrant of right male breast |
| C50.522 | ICD10CM | Malignant neoplasm of lower-outer quadrant of left male breast |
| C50.529 | ICD10CM | Malignant neoplasm of lower-outer quadrant of unspecified male breast |
| C50.6 | ICD10CM | Malignant neoplasm of axillary tail of breast |
| C50.61 | ICD10CM | Malignant neoplasm of axillary tail of breast, female |
| C50.611 | ICD10CM | Malignant neoplasm of axillary tail of right female breast |
| C50.612 | ICD10CM | Malignant neoplasm of axillary tail of left female breast |
| C50.619 | ICD10CM | Malignant neoplasm of axillary tail of unspecified female breast |
| C50.62 | ICD10CM | Malignant neoplasm of axillary tail of breast, male |
| C50.621 | ICD10CM | Malignant neoplasm of axillary tail of right male breast |
| C50.622 | ICD10CM | Malignant neoplasm of axillary tail of left male breast |
| C50.629 | ICD10CM | Malignant neoplasm of axillary tail of unspecified male breast |
| C50.8 | ICD10CM | Malignant neoplasm of overlapping sites of breast |
| C50.81 | ICD10CM | Malignant neoplasm of overlapping sites of breast, female |
| C50.811 | ICD10CM | Malignant neoplasm of overlapping sites of right female breast |
| C50.812 | ICD10CM | Malignant neoplasm of overlapping sites of left female breast |
| C50.819 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified female breast |
| C50.82 | ICD10CM | Malignant neoplasm of overlapping sites of breast, male |
| C50.821 | ICD10CM | Malignant neoplasm of overlapping sites of right male breast |
| C50.822 | ICD10CM | Malignant neoplasm of overlapping sites of left male breast |
| C50.829 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified male breast |
| C50.9 | ICD10CM | Malignant neoplasm of breast of unspecified site |
| C50.91 | ICD10CM | Malignant neoplasm of breast of unspecified site, female |
| C50.911 | ICD10CM | Malignant neoplasm of unspecified site of right female breast |
| C50.912 | ICD10CM | Malignant neoplasm of unspecified site of left female breast |
| C50.919 | ICD10CM | Malignant neoplasm of unspecified site of unspecified female breast |
| C50.92 | ICD10CM | Malignant neoplasm of breast of unspecified site, male |
| C50.921 | ICD10CM | Malignant neoplasm of unspecified site of right male breast |
| C50.922 | ICD10CM | Malignant neoplasm of unspecified site of left male breast |
| C50.929 | ICD10CM | Malignant neoplasm of unspecified site of unspecified male breast |
| Z17.0 | ICD10CM | Estrogen receptor positive status [Er+] |
| Z19.1 | ICD10CM | Hormone sensitive malignancy status |
ICD code information from First Databank (FDB).
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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