Mekinist (trametinib dimethyl sulfoxide)
Antineoplastic - MEK1 and MEK2 Kinase Inhibitors Oral Solution, Reconstituted, Oral; Oral Tablet
Last reviewed · Source: First Databank (FDB) drug data
Overview
Trametinib, an inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK2 in cells with b-Raf serine-threonine kinase (BRAF) V600E or V600K mutations, is an antineoplastic agent.
Trametinib, a selective, reversible inhibitor of mitogen-activated extracellular signal regulated kinase (MEK) 1 and MEK2 activation and kinase activity in cells with b-Raf serine-threonine kinase (BRAF) V600E or V600K mutations, is an antineoplastic agent. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. Approximately 50% of cutaneous melanomas carry a BRAF mutation.
The most common BRAF mutation is the substitution of glutamic acid for valine at codon 600 (BRAF V600E); a less frequently occurring BRAF mutation is the substitution of lysine for valine at codon 600 (BRAF V600K). BRAF V600 mutations result in activation of the BRAF pathway that includes MEK 1 and 2. The mutation of BRAF V600E activates the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) signal transduction pathway, which enhances cell proliferation and tumor progression (e.g., metastasis).
Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo by decreasing cell proliferation, causing cell cycle arrest, and inducing apoptosis. Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.
Clinical resistance to monotherapy with a BRAF inhibitor, generally occurring 6-7 months following initiation of therapy, has been attributed to several possible resistance mechanisms mostly relying on reactivation of the MAPK/ERK pathway. Complete inhibition of the MAPK/ERK pathway resulting in durable responses may be achieved with the use of combination therapy with a BRAF inhibitor (i.e., dabrafenib, encorafenib, vemurafenib) and an MEK inhibitor (i.e., binimetinib, cobimetinib, trametinib). Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of tumor cell lines testing positive for BRAF V600 mutations in vitro.
In addition, combination therapy was associated with prolonged inhibition of tumor growth in tumor xenografts testing positive for BRAF V600 mutations compared with either drug alone.
Following oral administration, the absolute bioavailability of trametinib tablets and oral solution is 72 and 81%, respectively. Peak plasma concentrations of trametinib occur within 1.5 hours after oral administration. Following single and repeated once-daily doses of 0.125-4 mg as tablets, increases in peak plasma concentrations and AUC are dose proportional.
Trametinib is 97.4% bound to plasma proteins. Administration of a single dose of trametinib tablets with a high-fat, high-calorie meal (approximately 1000 calories) decreased peak plasma concentrations and AUC of the drug by 70 and 24%, respectively, and delayed the rate of absorption (time to reach peak concentrations delayed by 4 hours). Trametinib is principally metabolized by deacetylation with or without mono-oxygenation or in combination with glucuronidation in vitro.
The estimated terminal half-life of trametinib is 3.9-4.8 days. Following oral administration of a radiolabeled dose of trametinib, more than 80% of the dose is recovered in feces and less than 20% is recovered in urine. Age (18--93 years), sex, body weight (36--170 kg), and renal impairment (estimated glomerular filtration rate 15--89 mL/minute/1.73 m2) do not have a clinically significant impact on trametinib exposure.
Insufficient data are available to assess whether race or ethnicity affect trametinib exposure. In pediatric patients 1--17 years of age, the pharmacokinetic exposures of trametinib at the recommended weight-adjusted dosage were within the range of those observed in adults. In this population, weight (6--156 kg) was shown to have a substantial impact on oral clearance of trametinib.
USES: Trametinib is used to treat various cancers (such as skin, thyroid, lung, solid tumors, brain). It belongs to a class of drugs known as kinase inhibitors. Trametinib works by slowing or stopping the growth of cancer cells.
Generic name: trametinib dimethyl sulfoxide
Pronunciation: (tra-ME-ti-nib)
Drug class: Antineoplastic - MEK1 and MEK2 Kinase 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 Mekinist:
- Anaplastic Thyroid Carcinoma With Braf V600e Mutation
- Low Grade Glioma With Braf V600e Mutation
- Malignant Melanoma With Braf V600e Mutation
- Malignant Melanoma With Braf V600k Mutation
- Malignant Solid Tumor With Braf V600e Mutation
- Non-Small Cell Lung Cancer With Braf V600e Mutation
Also known as: Anaplastic Thyroid Cancer With Braf V600e Mutation, Melanoma With Braf V600e Genetic Mutation, Nsclc With Braf V600e Mutation.
Dosing
Dosage of trametinib dimethyl sulfoxide is expressed in terms of trametinib.
If an asymptomatic decrease in left ventricular ejection fraction (LVEF) from baseline of 10% or more and to a level below institution-specific lower limit of normal occurs, interrupt trametinib for up to 4 weeks. If LVEF improves to normal values within 4 weeks of withholding trametinib, resume at a reduced dosage. If LVEF does not improve to normal values within 4 weeks of withholding trametinib, permanently discontinue trametinib.
If symptomatic cardiomyopathy or an absolute decrease in LVEF from baseline exceeding 20% and to a level below institution-specific lower limit of normal occurs, permanently discontinue.
If grade 2 skin toxicity develops and is intolerable, interrupt trametinib for up to 3 weeks. If grade 2 toxicity improves within 3 weeks of withholding trametinib, resume at a reduced dosage. If grade 2 skin toxicity does not improve within 3 weeks of withholding trametinib, permanently discontinue trametinib.
If grade 3 or 4 skin toxicity occurs, interrupt trametinib for up to 3 weeks. If grade 3 or 4 skin toxicity does not improve within 3 weeks of withholding trametinib, permanently discontinue trametinib. If grade 3 or 4 skin toxicity improves within 3 weeks of withholding trametinib, resume at a reduced dosage.
If severe cutaneous adverse reactions (SCARs) occur, permanently discontinue trametinib.
If fever (temperature of 38-40degreesC) or any initial symptom of fever recurrence occurs, interrupt trametinib therapy until the adverse reaction resolves. Once fever resolves, trametinib may be resumed at the same or a reduced dosage.
If fever (temperature exceeding 40degreesC) or fever complicated by rigors, hypotension, dehydration, or renal failure occurs, interrupt trametinib treatment until the adverse reaction resolves for at least 24 hours. Once fever has resolved, resume trametinib at the same or reduced dosage or permanently discontinue trametinib.
If grade 3 hemorrhagic events occur, interrupt trametinib treatment. If improvement is observed, resume trametinib at a lower dosage. If grade 3 hemorrhagic events do not improve, permanently discontinue trametinib.
If any grade 4 hemorrhagic events occur, permanently discontinue trametinib.
If new primary cutaneous malignancies occur, no dosage modification of trametinib is recommended.
If new noncutaneous malignancies occur during combination therapy with trametinib and dabrafenib, no dosage modification of trametinib is required.
If retinal pigment epithelial detachment occurs, interrupt trametinib for up to 3 weeks. If retinal pigment epithelial detachment improves within 3 weeks of withholding trametinib, resume at the same or a reduced dosage. If retinal pigment epithelial detachment does not improve within 3 weeks of withholding trametinib, resume at a reduced dosage or permanently discontinue trametinib.
If retinal vein occlusion occurs, permanently discontinue trametinib.
If uveitis occurs during combination therapy with trametinib and dabrafenib, no dosage modification of trametinib is necessary.
If an intolerable grade 2 or any grade 3 adverse reaction occurs, interrupt trametinib treatment. If the adverse reaction improves to grade 0 or 1, resume trametinib at a reduced dosage. If the adverse reaction does not improve to grade 0 or 1, permanently discontinue trametinib.
At the first occurrence of any grade 4 adverse reaction, interrupt trametinib until the adverse reaction improves to grade 0 or 1 and then resume at a reduced dosage. If the grade 4 adverse reaction does not improve to grade 0 or 1, permanently discontinue trametinib. If there is a recurrent grade 4 adverse reaction, permanently discontinue trametinib.
If treatment-related interstitial lung disease or pneumonitis occurs, permanently discontinue trametinib.
Dosage of trametinib may be reduced or therapy temporarily interrupted in patients who develop adverse effects. Up to 2 dosage reductions for toxicity may be made. Recommended dosage modifications for trametinib tablets and oral solutions are presented in Tables 3 and 4, respectively. Permanently discontinue trametinib if the patient is unable to tolerate a maximum of 2 dosage reductions.
Table 3. Trametinib Tablet Dosage Modifications for Toxicity
Recommended 1 mg orally once 1.5 mg orally 2 mg orally once Dosage daily once daily daily First dose 0.5 mg (one 1 mg (two 0.5-mg 1.5 mg (three reduction 0.5-mg tablet) tablets) orally 0.5-mg tablets) orally once daily once daily orally once daily Second dose N/A 0.5 mg (one 1 mg (two 0.5-mg reduction 0.5-mg tablet) tablets) orally orally once daily once daily
Permanently discontinue trametinib if unable to tolerate a maximum of 2 dosage reductions.
Table 4. Trametinib Oral Solution Dosage Modifications for Toxicity
Body Weight and First Dose Reduction Second Dose Reduction Recommended Dosage 8 kg 0.3 mg (6 mL) once 5 mL once daily 3 mL once daily daily 9 kg 0.35 mg (7 mL) once 5 mL once daily 4 mL once daily daily 10 kg 0.35 mg (7 mL) 5 mL once daily 4 mL once daily once daily 11 kg 0.4 mg (8 mL) once 6 mL once daily 4 mL once daily daily 12--13 kg 0.45 mg (9 mL) 7 mL once daily 5 mL once daily once daily 14--17 kg 0.55 mg (11 8 mL once daily 6 mL once daily mL) once daily 18--21 kg 0.7 mg (14 mL) 11 mL once daily 7 mL once daily once daily 22--25 kg 0.85 mg (17 13 mL once daily 9 mL once daily mL) once daily 26--29 kg 0.9 mg (18 mL) 14 mL once daily 9 mL once daily once daily 30--33 kg 1 mg (20 mL) 15 mL once daily 10 mL once daily once daily 34--37 kg 1.15 mg (23 17 mL once daily 12 mL once daily mL) once daily 38--41 kg 1.25 mg (25 19 mL once daily 13 mL once daily mL) once daily 42--45 kg 1.4 mg (28 mL) 21 mL once daily 14 mL once daily once daily 46--50 kg 1.6 mg (32 mL) 24 mL once daily 16 mL once daily once daily >=51 kg 2 mg (40 mL) 30 mL once daily 20 mL once daily once daily
Concentration of trametinib oral solution: 0.05 mg/mL.
Permanently discontinue trametinib if unable to tolerate a maximum of 2 dosage reductions.
If uncomplicated deep-vein thrombosis (DVT) or pulmonary embolism (PE) occurs, interrupt trametinib for up to 3 weeks. If improvement to grade 0 or 1 is observed within 3 weeks, resume trametinib at a lower dosage. If no improvement is observed within 3 weeks, permanently discontinue trametinib.
If life-threatening PE occurs, permanently discontinue trametinib.
Trametinib is administered orally once daily (approximately every 24 hours).
Do not take a missed dose of trametinib within 12 hours of the next dose of trametinib.
If a dose of trametinib is vomited, do not take an additional dose; take the next dose at the regularly scheduled time.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Mekinist 0.5 Mg Tablet | Maintenance | Take 2 tablets (1 mg) by oral route once daily. |
| Mekinist 2 Mg Tablet | Maintenance | Take 1 tablet (2 mg) by oral route once daily. |
| Mekinist 0.05 Mg/Ml Solution | Maintenance | Take 40 milliliters (2 mg) by oral route once daily. |
No dosing information is available for this tab.
Drug interactions
In vitro studies have indicated that trametinib is an inhibitor of cytochrome P-450 (CYP) isoenzyme 2C8.
Trametinib is a substrate of P-glycoprotein (P-gp) and bile salt export pump (BSEP). Pharmacokinetic interactions are unlikely with drugs that inhibit the P-gp transport system since trametinib exhibits high passive permeability and bioavailability.
Trametinib is not a substrate for CYP isoenzymes, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, OATP1B3, OATP2B1, organic cation transporter (OCT) 1, multidrug resistance-associated protein (MRP) 2, or multidrug and toxic compound extrusion 1 (MATE1). Trametinib is not an inhibitor of CYP 1A2, 2A6, 2B6, 2C9, 2C19, or 2D6, and also is not an inhibitor of OATP1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, OCT2, P-gp, BCRP, BSEP, MRP2, or MATE1.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Immunosuppressive; Immunomod/Cladribine Onc Inj (10 Mg/5 Ml)
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-2)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The UK and AU manufacturers of Litak state that concomitant use of other myelosuppressive medicinal products with cladribine is contraindicated.(1-2) The Israeli manufacturer of Litak states that cladribine should not be used concomitantly with other myelosuppressive medicinal products.(3)
DISCUSSION: The risk of severe myelotoxicity and long-lasting immunosuppression is increased in patients with a disease-related bone marrow infiltration or a previous myelosuppressive treatment.(1-3)
Immunosuppressives; Immunomodulators/Efalizumab; Natalizumab
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Natalizumab,(1-3) efalizumab,(4) immunosuppressives, and immunomodulators all suppress the immune system.
CLINICAL EFFECTS: Concurrent use of natalizumab(1-3) or efalizumab(4) with immunosuppressives or immunomodulators may result in an increased risk of infections, including progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).
PREDISPOSING FACTORS: Previous JCV infection, longer duration of natalizumab treatment - especially if greater than 2 years, and prior or concomitant treatment with immunosuppressant medication are all independent risk factors which increase the risk for PML.(1,5) The FDA has estimated PML incidence stratified by risk factors: If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment less than 25 months, incidence <1/1,000. If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment less than 25 months, incidence 2/1,000 If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 4/1,000 If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 11/1,000.
PATIENT MANAGEMENT: The US manufacturer of natalizumab states patients with Crohn's disease should not receive concurrent immunosuppressants, with the exception of limited overlap of corticosteroids, due to the increased risk for PML. For new natalizumab patients currently receiving chronic oral corticosteroids for Crohn's Disease, begin corticosteroid taper when therapeutic response to natalizumab has occurred. If corticosteroids cannot be discontinued within six months of starting natalizumab, discontinue natalizumab.(3) The US manufacturer of natalizumab states that natalizumab should not ordinarily be used in multiple sclerosis patients receiving immunosuppressants or immunomodulators due to the increased risk for PML. Immunosuppressives include, but are not limited to azathioprine, cyclophosphamide, cyclosporine, mercaptopurine, methotrexate, mitoxantrone, mycophenolate, and corticosteroids.(3,6) The UK manufacturer of natalizumab states that concurrent use with immunosuppressives or antineoplastic agents is contraindicated.(1) The Canadian manufacturer of natalizumab states that natalizumab should not be used with immunosuppressive or immunomodulatory agents.(2) The US manufacturer of certolizumab states that concurrent therapy with natalizumab is not recommended.(7)
DISCUSSION: Progressive multifocal leukoencephalopathy has been reported in patients receiving concurrent natalizumab were recently or concomitantly taking immunomodulators or immunosuppressants.(1-5,8,9) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(10)
Selected Immunosuppressants/Nadofaragene Firadenovec
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Nadofaragene firadenovec may contain low levels of replication-competent adenovirus.(1)
CLINICAL EFFECTS: Concurrent use of nadofaragene firadenovec in patients receiving immunosuppressive therapy may cause disseminated adenovirus infection.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Individuals who are immunosuppressed or immune-deficient should not receive nadofaragene firadenovec.(1)
DISCUSSION: Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy but may contain low levels of replication-competent adenovirus. Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection.(1)
Selected Immunosuppressants/Talimogene Laherparepvec
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Talimogene laherparepvec is a live, attenuated herpes simplex virus.(1)
CLINICAL EFFECTS: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Talimogene laherparepvec is contraindicated in immunosuppressed patients.(1) The magnitude of immunocompromise and associated risks due to immunosuppressant drugs should be determined by a physician.
DISCUSSION: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)
Selected Immunosuppressive Agents/Live Vaccines; Live Bcg
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: A variety of disease modifying agents suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines or intravesicular BCG. Immune response to vaccines may be decreased during periods of immunocompromise.(1)
CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) After instillation of intravesicular BCG, immunosuppression may interfere with local immune response, or increase the severity of mycobacterial infection following inadvertent systemic exposure.(2)
PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency.
PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) Patients who receive anti-B cell therapies should not receive live vaccines for at least 6 months after such therapies due to a prolonged duration of immunosuppression. An exception is the Zoster vaccine, which can be given at least 1 month after receipt of anti-B cell therapies.(1) The US manufacturer of abatacept states live vaccines should not be given during or for up to 3 months after discontinuation of abatacept.(2) The US manufacturer of live BCG for intravesicular treatment of bladder cancer states use is contraindicated in immunosuppressed patients.(3) The US manufacturer of daclizumab states live vaccines are not recommended during and for up to 4 months after discontinuation of treatment.(4) The US manufacturer of guselkumab states that live vaccines should be avoided during treatment with guselkumab.(5) The US manufacturer of inebilizumab-cdon states that live vaccines are not recommended during treatment and after discontinuation until B-cell repletion. Administer all live vaccinations at least 4 weeks prior to initiation of inebilizumab-cdon.(6) The US manufacturer of ocrelizumab states that live vaccines are not recommended during treatment and until B-cell repletion occurs after discontinuation of therapy. Administer all live vaccines at least 4 weeks prior to initiation of ocrelizumab.(7) The US manufacturer of ozanimod states that live vaccines should be avoided during and for up to 3 months after discontinuation of ozanimod.(8) The US manufacturer of siponimod states that live vaccines are not recommended during treatment and for up to 4 weeks after discontinuation of treatment.(9) The US manufacturer of ustekinumab states BCG vaccines should not be given in the year prior to, during, or the year after ustekinumab therapy.(10) The US manufacturer of satralizumab-mwge states that live vaccines are not recommended during treatment and should be administered at least four weeks prior to initiation of satralizumab-mwge.(11) The US manufacturer of ublituximab-xiiy states that live vaccines are not recommended during treatment and until B-cell recovery. Live vaccines should be administered at least 4 weeks prior to initiation of ublituximab-xiiy.(12) The US manufacturer of etrasimod states that live vaccines should be avoided during and for 5 weeks after treatment. Live vaccines should be administered at least 4 weeks prior to initiation of etrasimod.(13) The US manufacturer of emapalumab-lzsg states that live vaccines should not be administered to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.(14) The US manufacturer of sibeprenlimab-szsi states live vaccines should not be given within 30 days prior to initiation or during treatment with sibeprenlimab-szsi.(15)
DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Immunosuppres;Immunomodul/Selected Multiple Sclerosis Agents
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ocrelizumab or ofatumumab in combination with immunosuppressives and immune-modulators all suppress the immune system.(1,2)
CLINICAL EFFECTS: Concurrent use of ocrelizumab or ofatumumab with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1,2)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The ocrelizumab US prescribing information states: - Ocrelizumab and other immune-modulating or immunosuppressive therapies, (including immunosuppressant doses of corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with ocrelizumab. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating ocrelizumab.(1) The ofatumumab US prescribing information states: - Ofatumumab and other immunosuppressive therapies (including systemic corticosteroids) may have the potential for increased immunosuppressive effects and increase the risk of infection. When switching between therapies, the duration and mechanism of action of each therapy should be considered due to the potential for additive immunosuppressive effects. Ofatumumab for MS therapy has not been studied in combination with other MS agents that suppress the immune system.(2)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1,2) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(3)
Immunosuppressives; Immunomodulators/Baricitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of baricitinib with other biologic disease-modifying antirheumatic drugs (DMARDs) or potent immunosuppressants such as azathioprine or cyclosporine may result in additive or synergistic effects on the immune system.
CLINICAL EFFECTS: Concurrent use of baricitinib with other biologic DMARDs or potent immunosuppressants such as azathioprine or cyclosporine may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of baricitinib states that concurrent use of baricitinib with biologic DMARDs or potent immunosuppressants is not recommended.(1)
DISCUSSION: Most patients who developed serious infections while being treated with baricitinib were on concomitant immunosuppressants like methotrexate and corticosteroids. The combination of baricitinib with other biologic DMARDs has not been studied.(1)
Immunosuppressives; Immunomodulators/Cladribine Oral
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-2)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US prescribing information states: -Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered. In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of cladribine.(1) The cladribine Canadian prescribing information states: -Use of cladribine in immunocompromised patients is contraindicated because of a risk of additive effects on the immune system. Acute short-term therapy with corticosteroids can be administered during cladribine treatment.(2)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-2)
Immunosuppressives; Immunomodulators/Deuruxolitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Deuruxolitinib, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of deuruxolitinib and potent immunosuppressants may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of deuruxolitinib states that concurrent use of deuruxolitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1) If concurrent use cannot be avoided, patients should be monitored for signs and symptoms of infection. If a patient develops a serious or opportunistic infection, interrupt deuruxolitinib treatment until the infection is controlled.
DISCUSSION: Serious infections have been reported in patients receiving treatment with deuruxolitinib.(1)
Immunosuppressives; Immunomodulators/Etrasimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Etrasimod causes reversible sequestration of lymphocytes in lymphoid tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte count at 52 weeks.(1) Other immunosuppressives and immune-modulators also suppress the immune system.
CLINICAL EFFECTS: Concurrent use of etrasimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious and fatal infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications increases the risk of adverse effects.
PATIENT MANAGEMENT: The etrasimod US prescribing information states etrasimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Concomitant administration of these therapies with etrasimod should be avoided because of the risk of additive immune effects during therapy and in the weeks following administration. Etrasimod's effect on peripheral lymphocytes may persist for up to 5 weeks after discontinuation.(1) When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with other sphingosine-1 phosphate receptor modulators.(1)
Immunosuppressives; Immunomodulators/Filgotinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic disease-modifying antirheumatic drugs (DMARDs), or other Janus kinase (JAK) inhibitors may result in additive or synergistic effects on the immune system.(1)
CLINICAL EFFECTS: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The UK manufacturer of filgotinib states that concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors is not recommended.(1)
DISCUSSION: Serious infections have been reported in patients receiving filgotinib. Caution should be used in patients with a higher incidence of serious infection, including elderly patients aged 75 years and older.(1)
Immunosuppressives; Immunomodulators/Fingolimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Fingolimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-3)
CLINICAL EFFECTS: Concurrent use of fingolimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-3)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for fingolimod regarding this interaction differ between regulatory approving agencies. The fingolimod US prescribing information states: - Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with fingolimod. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating fingolimod.(1) The fingolimod Canadian prescribing information states: - Concurrent use with immunosuppressive or immunomodulatory agents is contraindicated due to the risk of additive immune system effects. However, co-administration of a short course of corticosteroids (up to 5 days) did not increase the overall rate of infection in patients participating Phase III clinical trials.(2) The fingolimod UK specific product characteristics states: - Fingolimod is contraindicated in patients currently receiving immunosuppressive therapies or those immunocompromised by prior therapies. When switching patients from another disease modifying therapy to Gilenya, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimizing the risk of disease activation.(3)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-3)
Immunosuppressives; Immunomodulators/Inebilizumab
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inebilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of inebilizumab with immunosuppressive or immunomodulating agents may result in myelosuppression including neutropenia resulting in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of inebilizumab states that the concurrent use of inebilizumab with immunosuppressive agents, including systemic corticosteroids, may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Inebilizumab has not been studied in combination with other immunosuppressants. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents. The most common infections reported by inebilizumab treated patients in the randomized and open-label clinical trial periods included urinary tract infections (20%), nasopharyngitis (13%), upper respiratory tract infections (8%), and influenza (7%). Although there been no cases of Hepatitis B virus reactivation or progressive multifocal leukoencephalopathy reported in patients taking inebilizumab, these infections have been observed in patients taking other B-cell-depleting antibodies.(1)
Immunosuppressives; Immunomodulators/Ozanimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ozanimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ozanimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The ozanimod US prescribing information state this information regarding this interaction: -Ozanimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ozanimod after alemtuzumab is not recommended. However, ozanimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)
Immunosuppressives; Immunomodulators/Ponesimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ponesimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ponesimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The ponesimod US prescribing information states ponesimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ponesimod after alemtuzumab is not recommended. However, ponesimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)
Immunosuppressives; Immunomodulators/Ritlecitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ritlecitinib, immunosuppressives, and immunomodulators all suppress the immune system.
CLINICAL EFFECTS: Concurrent use of ritlecitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of ritlecitinib states that concurrent use of ritlecitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1)
DISCUSSION: Serious infections have been reported in patients receiving ritlecitinib. Reported infections included appendicitis, COVID-19 infection (including pneumonia), and sepsis. Reports of viral reactivation, including herpes virus reactivation was reported in clinical studies with ritlecitinib.(1)
Immunosuppressives; Immunomodulators/Siponimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Siponimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of siponimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The siponimod US prescribing information state this information regarding this interaction: -Siponimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with siponimod after alemtuzumab is not recommended. However, siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)
Immunosuppressives; Immunomodulators/Tofacitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of tofacitinib and azathioprine, other biologic disease-modifying antirheumatic drugs (DMARDs), or potent immunosuppressants may result in additive or synergistic effects on the immune system.(1)
CLINICAL EFFECTS: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants use may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Tofacitinib should not be used concurrently with azathioprine, other biologic DMARDs, or cyclosporine.(1) Patient should be monitored for decreases in lymphocytes and neutrophils. Therapy should be adjusted based on the indication. - For all indications: If absolute neutrophil count (ANC) or lymphocyte count is less than 500 cells/mm3, discontinue tofacitinib. - For rheumatoid arthritis or psoriatic arthritis and absolute neutrophil count (ANC) 500 to 1000 cells/mm3: interrupt dosing. When ANC is greater than 1000 cells/mm3, resume Xeljanz 5 mg twice daily or Xeljanz XR 11 mg once daily. - For ulcerative colitis and ANC 500 to 1000 cells/mm3: -If taking Xeljanz 10 mg twice daily, decrease to 5 mg twice daily. When ANC is greater than 1000 cells/mm3, increase to 10 mg twice daily based on clinical response. -If taking Xeljanz 5 mg twice daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 5 mg twice daily. -If taking Xeljanz XR 22 mg once daily, decrease to 11 mg once daily. When ANC is greater than 1000 cells/mm3, increase to 22 mg once daily based on clinical response. -If taking Xeljanz XR 11 mg once daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 11 mg once daily. - For polyarticular course juvenile idiopathic arthritis (pcJIA) and ANC 500 to 1000 cells/mm3: interrupt dosing until ANC is greater than 1000 cells/mm3.(1)
DISCUSSION: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants may increase the risk of infection.(1) Serious infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. Some patients presented with disseminated disease and were often taking concomitant immunomodulating agents. In the ulcerative colitis population, a greater risk of serious infections was seen with a higher tofacitinib dose. In 7 placebo-controlled rheumatoid arthritis trials (0-3 months exposure), the overall frequency of infections was 20% in the tofacitinib 5 mg twice daily group and 22% in the tofacitinib 10 mg twice daily group compared to 18% in the placebo group. Serious infections were reported in 11 patients (1.7 events per 100 patient-years) with a rate difference between treatment groups of 1.1 (-0.4, 2.5) events per 100 patient-years for both tofacitinib 5 mg twice daily and 10 mg twice daily. During 0-12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient years) in the tofacitinib 5 mg twice daily group and 33 patients (2.7 events per 100 patient years) in the tofacitinib 10 mg twice daily group.(1)
Immunosuppressives; Immunomodulators/Upadacitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Upadacitinib, immunosuppressives, and immunomodulators all suppress the immune system.
CLINICAL EFFECTS: Concurrent use of upadacitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of upadacitinib states that concurrent use of upadacitinib with immunosuppressives or immunomodulators is not recommended.
DISCUSSION: Serious infections have been reported in patients receiving upadacitinib. Reported infections included pneumonia, cellulitis, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, cryptococcosis. Reports of viral reactivation, including herpes virus reactivation and hepatitis B reactivation, were reported in clinical studies with upadacitinib.(1)
Myelosuppressives; Immunomodulators/Sodium Iodide I 131
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)
DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)
Selected Immunosuppressants/Leflunomide; Teriflunomide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of leflunomide or teriflunomide and potent immunosuppressants may result in additive or synergistic effects on the immune system.(1,2) Leflunomide is a prodrug and is converted to its active metabolite teriflunomide.(1)
CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide with immunosuppressants may result in an increased risk of serious infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: If leflunomide or teriflunomide is used concurrently with immunosuppressive agents, chronic CBC monitoring should be performed more frequently, every month instead of every 6 to 8 weeks. If bone marrow suppression or a serious infection occurs, leflunomide or teriflunomide should be stopped and rapid drug elimination procedure should be performed.(1,2)
DISCUSSION: Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving leflunomide or teriflunomide alone, but most frequently in patients taking concurrent immunosuppressants.(1,2) Severe and potentially fatal infections, including sepsis, have been reported in patients receiving leflunomide or teriflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Tuberculosis has also been reported.(1,2)
Selected Myelosuppressive Agents/Clozapine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)
CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.
PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.
PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)
DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)
Selected Myelosuppressive Agents/Deferiprone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)
CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.
PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)
PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)
DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)
Selected Myelosuppressive Agents/Dipyrone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)
CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)
DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)
Slt Immunosuppress; Immunomodulator/Ropeginterferon Alfa-2B
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ropeginterferon alfa-2b and immunosuppressives both suppress the immune system.
CLINICAL EFFECTS: Concurrent use of ropeginterferon alfa-2b with immunosuppressives may result in an increased risk of serious infections.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concurrent use of myelosuppressive agents.(1-2) If concurrent use cannot be avoided, monitor for effects of excessive immunosuppression.
DISCUSSION: In clinical trials, 20% of patients experienced leukopenia. Interferon alfa products may cause fatal or life-threatening infections.(1-2)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Immunosuppressives; Immunomodulators/Cladribine Oncology Inj
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-4)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-4)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US, UK, and Australian prescribing information state: -Caution should be exercised if cladribine injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression.(1-3) The cladribine Canadian prescribing information states: -Proceed carefully in patients with severe bone marrow impairment of any etiology since further suppression of bone marrow function should be anticipated.(4)
DISCUSSION: Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with cladribine injection, especially at high doses.(1-4)
Immunosuppressives; Immunomodulators/Covid-19 Vaccines
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Immunosuppressants and immunomodulators may prevent the immune system from properly responding to the COVID-19 vaccine.(1-3)
CLINICAL EFFECTS: Administration of a COVID-19 vaccine with immunosuppressants or immunomodulators may interfere with vaccine-induced immune response and impair the efficacy of the vaccine. However, patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The Centers for Disease Control and Prevention (CDC),(1) Infectious Diseases Society of America (IDSA),(2) and the American College of Rheumatology (ACR)(3) have published guidances for COVID-19 vaccination in patients on immunosuppressants. The CDC states that all immunocompromised patients over 6 months of age should receive at least 1 dose of COVID-19 vaccine if eligible. See the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for specific recommendations based on age, vaccination history, and vaccine manufacturer.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(1) IDSA recommends timing COVID-19 vaccination at least 2 weeks before starting or at least 3 months after completing immunosuppressive therapy.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose.(3) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted, though the immune response will likely be blunted. COVID-19 vaccines should not be delayed in patients taking immunosuppressive therapies.(1-2) See below for specific recommendations for certain agents. B-cell depleting agents, including rituximab: The CDC states that the utility of B-cell quantification to guide clinical care is not known and is not recommended. Patients who receive B-cell depleting therapy on a continuing basis should receive COVID-19 vaccines about 4 weeks before the next scheduled dose. For patients who received 1 or more doses of COVID-19 vaccine during treatment with B-cell-depleting therapies that were administered over a limited period (e.g., as part of a treatment regimen for certain malignancies), revaccination may be considered according to the current CDC recommendations for unvaccinated patients. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(1) IDSA recommends waiting for at least 3-6 months after the last infusion of B-cell depleting therapy before administering COVID-19 vaccines.(2) The ACR recommends consulting with the rheumatologist to determine optimal timing of COVID-19 vaccination. Measuring CD19 B cells may be considered to determine need for a booster vaccine dose. If B cell levels are not measured, a supplemental vaccine dose 2-4 weeks before the next scheduled dose of rituximab is recommended.(3) Recipients of hematopoietic cell transplant or CAR-T-cell therapy who received one or more doses of COVID-19 vaccine prior to or during treatment should undergo revaccination following the current CDC recommendations for unvaccinated patients. Revaccination should start at least 3 months (12 weeks) after transplant or CAR-T-cell therapy.(1,2) The CDC includes abatacept, cyclophosphamide, and TNF-alpha and cytokine inhibitors in their general recommendation to hold therapy for at least 2 weeks following vaccination (1) while the ACR provides different recommendations:(3) *Abatacept: - Subcutaneous abatacept should be withheld for 1-2 weeks after each vaccine dose, as disease activity allows. - For intravenous abatacept, time administration so that vaccination will occur 1 week before the next abatacept infusion. *Cyclophosphamide: When feasible, administer cyclophosphamide 1 week after each COVID-19 vaccine dose. *TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to reach consensus on whether to modify dosing or timing of these agents with COVID-19 vaccination.
DISCUSSION: IDSA recommendations are based on cohort and case control studies in immunocompromised patients that found low to modest vaccine effectiveness (37-61%) but lower risks of COVID-19 association hospitalization, COVID-19 related mortality, and critical illness.(2) The ACR convened a COVID-19 Vaccine Guidance Task Force to provide guidance on optimal use of COVID-19 vaccines in rheumatology patients. These recommendations are based on limited clinical evidence of COVID-19 vaccines in patients without rheumatic and musculoskeletal disorders and evidence of other vaccines in this patient population.(3) The ACR recommendation for rituximab is based on studies of humoral immunity following receipt of other vaccines. These studies have uncertain generalizability to vaccination against COVID-19, as it is unknown if efficacy is attributable to induction of host T cells versus B cell (antibody-based) immunity.(3) The ACR recommendation for mycophenolate is based on preexisting data of mycophenolate on non-COVID-19 vaccine immunogenicity. Emerging data suggests that mycophenolate may impair SARS-CoV-2 vaccine response in rheumatic and musculoskeletal disease and transplant patients.(3) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(3) The ACR recommendation for JAK inhibitors is based on concerns related to the effects of JAK inhibitors on interferon signaling that may result in a diminished vaccine response.(3) The ACR recommendation for subcutaneous abatacept is based on several studies suggesting a negative effect of abatacept on vaccine immunogenicity. The first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct. CTLA-4 should not inhibit boosts of already primed T cells at the time of the second vaccine dose.(3)
Immunosuppressives; Immunomodulators/Sarilumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Sarilumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of sarilumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of sarilumab recommends caution because the concurrent use of sarilumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Sarilumab was studied as monotherapy and in combination with methotrexate or conventional disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis studies. Sarilumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by sarilumab treated patients in the clinical trial periods included pneumonia and cellulitis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving sarilumab. Cases of tuberculosis, candidiasis, and pneumocystis with sarilumab have been reported.(1)
Immunosuppressives; Immunomodulators/Tocilizumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Tocilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of tocilizumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of tocilizumab recommends caution because the concurrent use of tocilizumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Tocilizumab was studied as monotherapy and in combination with methotrexate, non-biologic DMARDs or corticosteroids, depending on the indication. Tocilizumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by tocilizumab treated patients in the clinical trial periods included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving tocilizumab. Cases of tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis have been reported.(1)
Immunosuppressives; Immunomodulators/Ublituximab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ublituximab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ublituximab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The US manufacturer of ublituximab recommends caution because the concurrent use of ublituximab with immunomodulating or immunosuppressive agents, including immunosuppressant doses of corticosteroids, may increase the risk of infection.(1) If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents. When switching from agents with immune effects, the half-life and mechanism of action of these drugs must be taken into consideration in order to prevent additive immunosuppressive effects.(1)
DISCUSSION: The most common infections reported by ublituximab-treated patients in the clinical trial periods included upper respiratory tract infections and urinary tract infections. Serious, including life-threatening or fatal, bacterial and viral infections were observed in patients receiving ublituximab.(1) Serious and/or fatal bacterial, fungal, and new or reactivated viral infections have been associated with other anti-CD20 B-cell depleting therapies. There were no cases of progressive multifocal leukoencephalopathy (PML) reported during the clinical trials; however, there have been reports of PML during or following completion of other anti-CD20 B-cell depleting therapies.(1)
Immunosuppressives; Immunomodulators/Ustekinumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ustekinumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ustekinumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of ustekinumab recommends caution because the concurrent use of ustekinumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Ustekinumab has not been studied in combination with other immunosuppressants in psoriasis studies. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by ustekinumab treated patients in the clinical trial periods included nasopharyngitis(8%) and upper respiratory tract infection(5%). Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab. Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia resulting in respiratory failure or prolonged hospitalization have been reported in patients receiving ustekinumab.(1)
Contraindications
*None.
- Lactation
- Cardiomyopathy
- Chronic heart failure
- Deep venous thrombosis
- High fever >101 degrees fahrenheit
- Increased risk of bleeding
- Interstitial lung disease
- Left ventricular failure
- Pregnancy
- Pulmonary thromboembolism
- Retinal detachment
- Colitis
- Gastrointestinal perforation
- Hyperglycemia
Adverse reactions
The most common adverse reactions (>=20%) in adults with unresectable or metastatic melanoma receiving trametinib monotherapy are rash, diarrhea, and lymphedema.
The most common adverse reactions (>= 20%) in adults receiving trametinib in combination with dabrafenib for adjuvant treatment of melanoma include pyrexia, fatigue, nausea, headache, rash, chills, diarrhea, vomiting, arthralgia, and myalgia.
The most common adverse reactions (>= 20%) in adults receiving trametinib in combination with dabrafenib for unresectable or metastatic melanoma include pyrexia, nausea, rash, chills, diarrhea, vomiting, hypertension, and peripheral edema.
The most common adverse reactions (>= 20%) in adults receiving trametinib in combination with dabrafenib for metastatic NSCLC include pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.
The most common adverse reactions (>= 20%) in adults receiving trametinib in combination with dabrafenib for other solid tumors include pyrexia, fatigue, nausea, rash, chills, headache, hemorrhage, cough, vomiting, constipation, diarrhea, myalgia, arthralgia, and edema.
The most common adverse reactions (>= 20%) in pediatric patients receiving trametinib in combination with dabrafenib for solid tumors include pyrexia, rash, vomiting, fatigue, dry skin, cough, diarrhea, dermatitis acneiform, headache, abdominal pain, nausea, hemorrhage, constipation, and paronychia.
The most common adverse reactions (>= 20%) in pediatric patients receiving trametinib in combination with dabrafenib for low-grade glioma (LGG) include pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform.
More Frequent
- Anemia
- Hypoalbuminemia
- Lymphopenia
- Neutropenic disorder
- Palmar-plantar erythrodysesthesia
Less Frequent
- Cardiomyopathy
- Cellulitis
- Deep venous thrombosis
- Folliculitis
- Heart failure
- Hemorrhage
- Hypertension
- Hyponatremia
- Interstitial lung disease
- Interstitial pneumonitis
- Keratoacanthoma
- Pulmonary thromboembolism
- Squamous cell carcinoma of skin
- Thrombocytopenic disorder
- Venous thrombosis
Rare or Very Rare
- Atrioventricular block
- Bundle branch block
- Colitis
- Dehydration
- DRESS syndrome
- Gastrointestinal hemorrhage
- Gastrointestinal perforation
- Hemophagocytic lymphohistiocytosis
- Hypotension
- Intracerebral hemorrhage
- Iritis
- Macular retinal edema
- Malignancy
- Renal failure
- Retinal detachment
- Retinal pigment epithelial detachment
- Retinal vascular occlusion
- Rhabdomyolysis
- Sarcoidosis
- Second primary melanoma
- Stevens-johnson syndrome
- Tear of retinal pigment epithelium
- Tumor lysis syndrome
- Uveitis
- Visual changes
More Frequent
- Acneiform eruption
- Anorexia
- Chills
- Constipation
- Diarrhea
- Dyspnea
- Edema
- Erythema
- Fever
- Hyperglycemia
- Lymphedema
- Myalgia
- Nausea
- Night sweats
- Peripheral edema
- Skin inflammation
- Skin rash
- Vomiting
Less Frequent
- Abnormal hepatic function tests
- Acute abdominal pain
- Arthralgia
- Back pain
- Basal cell carcinoma of skin
- Blurred vision
- Bradycardia
- Central serous chorioretinopathy
- Dizziness
- Dry eye
- Dry skin
- Dysgeusia
- Erysipelas
- Fatigue
- General weakness
- Headache disorder
- Hypercalcemia
- Hypophosphatemia
- Interstitial nephritis
- Pain in oropharynx
- Paronychia
- Pneumonia
- Pruritus of skin
- Skin photosensitivity
- Stomatitis
- Syncope
- Xerostomia
Rare or Very Rare
- Abnormal uterine bleeding
- Epistaxis
- Glaucoma
- Guillain-barre syndrome
- Peripheral neuropathy
- Reduced visual acuity
Precautions
No enhanced messaging available.
Safety and efficacy of trametinib monotherapy have not been established in pediatric patients.
Safety and efficacy of trametinib in combination with dabrafenib have been established in pediatric patients >=1 year of age with BRAF V600E mutation-positive unresectable or metastatic solid tumors who progressed on prior therapy (with no satisfactory treatment options) and BRAF V600E mutation-positive low-grade glioma requiring systemic therapy. The use of trametinib for these indications is supported by evidence from a study in pediatric patients with refractory or recurrent solid tumors (CTMT212X2101), and a study in pediatric patients with low-grade glioma (CDRB436G2201).
Safety and efficacy of trametinib in combination with dabrafenib have not been established for these indications in pediatric patients <1 year of age.
Trametinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings. Verify pregnancy status in females of reproductive potential prior to initiating trametinib.
There are no data on the presence of trametinib in human milk, the effects on the breast-fed infant, or the effects on milk production. Because of the potential for serious adverse reactions to trametinib in breast-fed infants, advise women not to breast-feed while receiving the drug and for 4 months after the last dose.
The manufacturer does not make any specific dosage recommendations for geriatric patients.
Clinical experience with trametinib monotherapy in patients 65 years of age or older with melanoma is insufficient to determine whether geriatric patients respond differently than younger adults.
In clinical studies evaluating trametinib in combination with dabrafenib in patients with melanoma, 21% of patients were 65 years of age or older and 5% were 75 years of age or older. No overall differences in efficacy were observed between geriatric patients and younger adults, but some adverse effects (i.e., peripheral edema, anorexia) occurred more frequently in geriatric patients with metastatic melanoma.
Clinical experience with trametinib in patients 65 years of age or older with NSCLC is insufficient to determine whether geriatric patients respond differently than younger adults.
In clinical studies evaluating trametinib in combination with dabrafenib in anaplastic thyroid cancer, 77% of patients were 65 years of age and older and 31% were 75 years of age or older. An insufficient number of younger adults were included in the study to determine if there are differences in response to trametinib.
ICD codes
| Code | Type | Description |
|---|---|---|
| Anaplastic thyroid carcinoma with BRAF v600E mutation | ||
| C73 | ICD10CM | Malignant neoplasm of thyroid gland |
| Low grade glioma with BRAF v600E mutation | ||
| C71.0 | ICD10CM | Malignant neoplasm of cerebrum, except lobes and ventricles |
| C71.1 | ICD10CM | Malignant neoplasm of frontal lobe |
| C71.2 | ICD10CM | Malignant neoplasm of temporal lobe |
| C71.3 | ICD10CM | Malignant neoplasm of parietal lobe |
| C71.4 | ICD10CM | Malignant neoplasm of occipital lobe |
| C71.5 | ICD10CM | Malignant neoplasm of cerebral ventricle |
| C71.6 | ICD10CM | Malignant neoplasm of cerebellum |
| C71.7 | ICD10CM | Malignant neoplasm of brain stem |
| C71.8 | ICD10CM | Malignant neoplasm of overlapping sites of brain |
| C71.9 | ICD10CM | Malignant neoplasm of brain, unspecified |
| Malignant melanoma with BRAF v600E mutation | ||
| C43 | ICD10CM | Malignant melanoma of skin |
| C43.0 | ICD10CM | Malignant melanoma of lip |
| C43.1 | ICD10CM | Malignant melanoma of eyelid, including canthus |
| C43.10 | ICD10CM | Malignant melanoma of unspecified eyelid, including canthus |
| C43.11 | ICD10CM | Malignant melanoma of right eyelid, including canthus |
| C43.111 | ICD10CM | Malignant melanoma of right upper eyelid, including canthus |
| C43.112 | ICD10CM | Malignant melanoma of right lower eyelid, including canthus |
| C43.12 | ICD10CM | Malignant melanoma of left eyelid, including canthus |
| C43.121 | ICD10CM | Malignant melanoma of left upper eyelid, including canthus |
| C43.122 | ICD10CM | Malignant melanoma of left lower eyelid, including canthus |
| C43.2 | ICD10CM | Malignant melanoma of ear and external auricular canal |
| C43.20 | ICD10CM | Malignant melanoma of unspecified ear and external auricular canal |
| C43.21 | ICD10CM | Malignant melanoma of right ear and external auricular canal |
| C43.22 | ICD10CM | Malignant melanoma of left ear and external auricular canal |
| C43.3 | ICD10CM | Malignant melanoma of other and unspecified parts of face |
| C43.30 | ICD10CM | Malignant melanoma of unspecified part of face |
| C43.31 | ICD10CM | Malignant melanoma of nose |
| C43.39 | ICD10CM | Malignant melanoma of other parts of face |
| C43.4 | ICD10CM | Malignant melanoma of scalp and neck |
| C43.5 | ICD10CM | Malignant melanoma of trunk |
| C43.51 | ICD10CM | Malignant melanoma of anal skin |
| C43.52 | ICD10CM | Malignant melanoma of skin of breast |
| C43.59 | ICD10CM | Malignant melanoma of other part of trunk |
| C43.6 | ICD10CM | Malignant melanoma of upper limb, including shoulder |
| C43.60 | ICD10CM | Malignant melanoma of unspecified upper limb, including shoulder |
| C43.61 | ICD10CM | Malignant melanoma of right upper limb, including shoulder |
| C43.62 | ICD10CM | Malignant melanoma of left upper limb, including shoulder |
| C43.7 | ICD10CM | Malignant melanoma of lower limb, including hip |
| C43.70 | ICD10CM | Malignant melanoma of unspecified lower limb, including hip |
| C43.71 | ICD10CM | Malignant melanoma of right lower limb, including hip |
| C43.72 | ICD10CM | Malignant melanoma of left lower limb, including hip |
| C43.8 | ICD10CM | Malignant melanoma of overlapping sites of skin |
| C43.9 | ICD10CM | Malignant melanoma of skin, unspecified |
| Malignant melanoma with BRAF v600K mutation | ||
| C43 | ICD10CM | Malignant melanoma of skin |
| C43.0 | ICD10CM | Malignant melanoma of lip |
| C43.1 | ICD10CM | Malignant melanoma of eyelid, including canthus |
| C43.10 | ICD10CM | Malignant melanoma of unspecified eyelid, including canthus |
| C43.11 | ICD10CM | Malignant melanoma of right eyelid, including canthus |
| C43.111 | ICD10CM | Malignant melanoma of right upper eyelid, including canthus |
| C43.112 | ICD10CM | Malignant melanoma of right lower eyelid, including canthus |
| C43.12 | ICD10CM | Malignant melanoma of left eyelid, including canthus |
| C43.121 | ICD10CM | Malignant melanoma of left upper eyelid, including canthus |
| C43.122 | ICD10CM | Malignant melanoma of left lower eyelid, including canthus |
| C43.2 | ICD10CM | Malignant melanoma of ear and external auricular canal |
| C43.20 | ICD10CM | Malignant melanoma of unspecified ear and external auricular canal |
| C43.21 | ICD10CM | Malignant melanoma of right ear and external auricular canal |
| C43.22 | ICD10CM | Malignant melanoma of left ear and external auricular canal |
| C43.3 | ICD10CM | Malignant melanoma of other and unspecified parts of face |
| C43.30 | ICD10CM | Malignant melanoma of unspecified part of face |
| C43.31 | ICD10CM | Malignant melanoma of nose |
| C43.39 | ICD10CM | Malignant melanoma of other parts of face |
| C43.4 | ICD10CM | Malignant melanoma of scalp and neck |
| C43.5 | ICD10CM | Malignant melanoma of trunk |
| C43.51 | ICD10CM | Malignant melanoma of anal skin |
| C43.52 | ICD10CM | Malignant melanoma of skin of breast |
| C43.59 | ICD10CM | Malignant melanoma of other part of trunk |
| C43.6 | ICD10CM | Malignant melanoma of upper limb, including shoulder |
| C43.60 | ICD10CM | Malignant melanoma of unspecified upper limb, including shoulder |
| C43.61 | ICD10CM | Malignant melanoma of right upper limb, including shoulder |
| C43.62 | ICD10CM | Malignant melanoma of left upper limb, including shoulder |
| C43.7 | ICD10CM | Malignant melanoma of lower limb, including hip |
| C43.70 | ICD10CM | Malignant melanoma of unspecified lower limb, including hip |
| C43.71 | ICD10CM | Malignant melanoma of right lower limb, including hip |
| C43.72 | ICD10CM | Malignant melanoma of left lower limb, including hip |
| C43.8 | ICD10CM | Malignant melanoma of overlapping sites of skin |
| C43.9 | ICD10CM | Malignant melanoma of skin, unspecified |
| Malignant solid tumor with BRAF v600E mutation | ||
| C16.8 | ICD10CM | Malignant neoplasm of overlapping sites of stomach |
| C17.0 | ICD10CM | Malignant neoplasm of duodenum |
| C17.1 | ICD10CM | Malignant neoplasm of jejunum |
| C17.2 | ICD10CM | Malignant neoplasm of ileum |
| C17.3 | ICD10CM | Meckel's diverticulum, malignant |
| C17.8 | ICD10CM | Malignant neoplasm of overlapping sites of small intestine |
| C17.9 | ICD10CM | Malignant neoplasm of small intestine, unspecified |
| C21.0 | ICD10CM | Malignant neoplasm of anus, unspecified |
| C21.1 | ICD10CM | Malignant neoplasm of anal canal |
| C21.2 | ICD10CM | Malignant neoplasm of cloacogenic zone |
| C21.8 | ICD10CM | Malignant neoplasm of overlapping sites of rectum, anus and anal canal |
| C24.8 | ICD10CM | Malignant neoplasm of overlapping sites of biliary tract |
| C24.9 | ICD10CM | Malignant neoplasm of biliary tract, unspecified |
| C25.0 | ICD10CM | Malignant neoplasm of head of pancreas |
| C25.1 | ICD10CM | Malignant neoplasm of body of pancreas |
| C25.2 | ICD10CM | Malignant neoplasm of tail of pancreas |
| C25.3 | ICD10CM | Malignant neoplasm of pancreatic duct |
| C25.4 | ICD10CM | Malignant neoplasm of endocrine pancreas |
| C25.7 | ICD10CM | Malignant neoplasm of other parts of pancreas |
| C25.8 | ICD10CM | Malignant neoplasm of overlapping sites of pancreas |
| C25.9 | ICD10CM | Malignant neoplasm of pancreas, unspecified |
| C34.00 | ICD10CM | Malignant neoplasm of unspecified main bronchus |
| C34.01 | ICD10CM | Malignant neoplasm of right main bronchus |
| C34.02 | ICD10CM | Malignant neoplasm of left main bronchus |
| C34.10 | ICD10CM | Malignant neoplasm of upper lobe, unspecified bronchus or lung |
| C34.11 | ICD10CM | Malignant neoplasm of upper lobe, right bronchus or lung |
| C34.12 | ICD10CM | Malignant neoplasm of upper lobe, left bronchus or lung |
| C34.2 | ICD10CM | Malignant neoplasm of middle lobe, bronchus or lung |
| C34.30 | ICD10CM | Malignant neoplasm of lower lobe, unspecified bronchus or lung |
| C34.31 | ICD10CM | Malignant neoplasm of lower lobe, right bronchus or lung |
| C34.32 | ICD10CM | Malignant neoplasm of lower lobe, left bronchus or lung |
| C34.80 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified bronchus and lung |
| C34.81 | ICD10CM | Malignant neoplasm of overlapping sites of right bronchus and lung |
| C34.82 | ICD10CM | Malignant neoplasm of overlapping sites of left bronchus and lung |
| C34.90 | ICD10CM | Malignant neoplasm of unspecified part of unspecified bronchus or lung |
| C34.91 | ICD10CM | Malignant neoplasm of unspecified part of right bronchus or lung |
| C34.92 | ICD10CM | Malignant neoplasm of unspecified part of left bronchus or lung |
| C41.1 | ICD10CM | Malignant neoplasm of mandible |
| C43.0 | ICD10CM | Malignant melanoma of lip |
| C43.10 | ICD10CM | Malignant melanoma of unspecified eyelid, including canthus |
| C43.111 | ICD10CM | Malignant melanoma of right upper eyelid, including canthus |
| C43.112 | ICD10CM | Malignant melanoma of right lower eyelid, including canthus |
| C43.121 | ICD10CM | Malignant melanoma of left upper eyelid, including canthus |
| C43.122 | ICD10CM | Malignant melanoma of left lower eyelid, including canthus |
| C43.20 | ICD10CM | Malignant melanoma of unspecified ear and external auricular canal |
| C43.21 | ICD10CM | Malignant melanoma of right ear and external auricular canal |
| C43.22 | ICD10CM | Malignant melanoma of left ear and external auricular canal |
| C43.30 | ICD10CM | Malignant melanoma of unspecified part of face |
| C43.31 | ICD10CM | Malignant melanoma of nose |
| C43.39 | ICD10CM | Malignant melanoma of other parts of face |
| C43.4 | ICD10CM | Malignant melanoma of scalp and neck |
| C43.51 | ICD10CM | Malignant melanoma of anal skin |
| C43.52 | ICD10CM | Malignant melanoma of skin of breast |
| C43.59 | ICD10CM | Malignant melanoma of other part of trunk |
| C43.60 | ICD10CM | Malignant melanoma of unspecified upper limb, including shoulder |
| C43.61 | ICD10CM | Malignant melanoma of right upper limb, including shoulder |
| C43.62 | ICD10CM | Malignant melanoma of left upper limb, including shoulder |
| C43.70 | ICD10CM | Malignant melanoma of unspecified lower limb, including hip |
| C43.71 | ICD10CM | Malignant melanoma of right lower limb, including hip |
| C43.72 | ICD10CM | Malignant melanoma of left lower limb, including hip |
| C43.8 | ICD10CM | Malignant melanoma of overlapping sites of skin |
| C43.9 | ICD10CM | Malignant melanoma of skin, unspecified |
| C48.0 | ICD10CM | Malignant neoplasm of retroperitoneum |
| C48.1 | ICD10CM | Malignant neoplasm of specified parts of peritoneum |
| C48.2 | ICD10CM | Malignant neoplasm of peritoneum, unspecified |
| C48.8 | ICD10CM | Malignant neoplasm of overlapping sites of retroperitoneum and peritoneum |
| C49.A0 | ICD10CM | Gastrointestinal stromal tumor, unspecified site |
| C49.A1 | ICD10CM | Gastrointestinal stromal tumor of esophagus |
| C49.A2 | ICD10CM | Gastrointestinal stromal tumor of stomach |
| C49.A3 | ICD10CM | Gastrointestinal stromal tumor of small intestine |
| C49.A4 | ICD10CM | Gastrointestinal stromal tumor of large intestine |
| C49.A5 | ICD10CM | Gastrointestinal stromal tumor of rectum |
| C49.A9 | ICD10CM | Gastrointestinal stromal tumor of other sites |
| C56.1 | ICD10CM | Malignant neoplasm of right ovary |
| C56.2 | ICD10CM | Malignant neoplasm of left ovary |
| C56.3 | ICD10CM | Malignant neoplasm of bilateral ovaries |
| C56.9 | ICD10CM | Malignant neoplasm of unspecified ovary |
| C71.0 | ICD10CM | Malignant neoplasm of cerebrum, except lobes and ventricles |
| C71.1 | ICD10CM | Malignant neoplasm of frontal lobe |
| C71.2 | ICD10CM | Malignant neoplasm of temporal lobe |
| C71.3 | ICD10CM | Malignant neoplasm of parietal lobe |
| C71.4 | ICD10CM | Malignant neoplasm of occipital lobe |
| C71.5 | ICD10CM | Malignant neoplasm of cerebral ventricle |
| C71.6 | ICD10CM | Malignant neoplasm of cerebellum |
| C71.7 | ICD10CM | Malignant neoplasm of brain stem |
| C71.8 | ICD10CM | Malignant neoplasm of overlapping sites of brain |
| C71.9 | ICD10CM | Malignant neoplasm of brain, unspecified |
| C72.0 | ICD10CM | Malignant neoplasm of spinal cord |
| C72.9 | ICD10CM | Malignant neoplasm of central nervous system, unspecified |
| C73 | ICD10CM | Malignant neoplasm of thyroid gland |
| C7A.1 | ICD10CM | Malignant poorly differentiated neuroendocrine tumors |
| C7A.8 | ICD10CM | Other malignant neuroendocrine tumors |
| Non-small cell lung cancer with BRAF v600E mutation | ||
| C34 | ICD10CM | Malignant neoplasm of bronchus and lung |
| C34.0 | ICD10CM | Malignant neoplasm of main bronchus |
| C34.00 | ICD10CM | Malignant neoplasm of unspecified main bronchus |
| C34.01 | ICD10CM | Malignant neoplasm of right main bronchus |
| C34.02 | ICD10CM | Malignant neoplasm of left main bronchus |
| C34.1 | ICD10CM | Malignant neoplasm of upper lobe, bronchus or lung |
| C34.10 | ICD10CM | Malignant neoplasm of upper lobe, unspecified bronchus or lung |
| C34.11 | ICD10CM | Malignant neoplasm of upper lobe, right bronchus or lung |
| C34.12 | ICD10CM | Malignant neoplasm of upper lobe, left bronchus or lung |
| C34.2 | ICD10CM | Malignant neoplasm of middle lobe, bronchus or lung |
| C34.3 | ICD10CM | Malignant neoplasm of lower lobe, bronchus or lung |
| C34.30 | ICD10CM | Malignant neoplasm of lower lobe, unspecified bronchus or lung |
| C34.31 | ICD10CM | Malignant neoplasm of lower lobe, right bronchus or lung |
| C34.32 | ICD10CM | Malignant neoplasm of lower lobe, left bronchus or lung |
| C34.8 | ICD10CM | Malignant neoplasm of overlapping sites of bronchus and lung |
| C34.80 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified bronchus and lung |
| C34.81 | ICD10CM | Malignant neoplasm of overlapping sites of right bronchus and lung |
| C34.82 | ICD10CM | Malignant neoplasm of overlapping sites of left bronchus and lung |
| C34.9 | ICD10CM | Malignant neoplasm of unspecified part of bronchus or lung |
| C34.90 | ICD10CM | Malignant neoplasm of unspecified part of unspecified bronchus or lung |
| C34.91 | ICD10CM | Malignant neoplasm of unspecified part of right bronchus or lung |
| C34.92 | ICD10CM | Malignant neoplasm of unspecified part of left bronchus or lung |
| C39.9 | ICD10CM | Malignant neoplasm of lower respiratory tract, part unspecified |
ICD code information from First Databank (FDB).
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