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  • CLASSES

    Small Molecule Antineoplastic Mitogen-Activated Protein Kinase (MEK) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    MEK kinase inhibitor; confirm a BRAF V600 mutation using an FDA-approved test
    Used as a single-agent in BRAF inhibitor-naive, advanced BRAF V600 mutation-positive melanoma or in combination with dabrafenib in other BRAF V600E mutation-positive tumors including advanced melanoma, metastatic non-small cell lung cancer, and locally advanced or metastatic anaplastic thyroid cancer
    Venous thromboembolism and interstitial lung disease have been reported

    COMMON BRAND NAMES

    Mekinist

    HOW SUPPLIED

    Mekinist Oral Tab: 0.5mg, 2mg

    DOSAGE & INDICATIONS

    For the treatment of malignant melanoma.
    NOTE: Confirm the BRAF V600E or V600K mutation prior to starting therapy. Information on FDA-approved tests for the detection of BRAF V600 mutations is available at http://www.fda.gov/CompanionDiagnostics.
    NOTE: Trametinib has been designated as an orphan drug for the treatment of stage IIb to IV melanoma by the FDA as a single-agent or in combination with dabrafenib.
    For the treatment of unresectable or metastatic malignant melanoma in BRAF inhibitor-naive patients with BRAF V600E or V600K mutations, as a single agent.
    Oral dosage
    Adults

    2 mg orally once daily until disease progression. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[60372] Patients with BRAF V600E- or V600K-mutated unresectable stage IIIC or metastatic melanoma received daily oral trametinib (n = 214) or chemotherapy consisting of dacarbazine 1,000 mg/m2 IV every 3 weeks or paclitaxel 175 mg/m2 IV every 3 weeks (n = 108) in a multinational, randomized, phase 3 study. Patients who received up to 1 prior systemic therapy for advanced disease were eligible for enrollment; however, patients who had received prior BRAF- or MEK-inhibitor or ipilimumab therapy were ineligible. Approximately 66% of patients had received no prior chemotherapy for advanced disease before entering this study. Investigator assessed progression-free survival (PFS) time was significantly improved with trametinib compared with chemotherapy (4.8 months vs. 1.5 months; hazard ratio (HR) = 0.45; 95% CI, 0.33 to 0.63; p less than 0.001); PFS results were confirmed on independent radiologic review. Based on this significant PFS improvement and on initial overall survival (OS) results in an unplanned interim analysis, 51% of patients in the chemotherapy arm crossed over to the trametinib arm. Despite this high crossover rate, the 6-month OS rate was 81% in the trametinib arm and 67% in the chemotherapy arm (HR = 0.54; 95% CI, 0.32 to 0.92; p = 0.01).[54815]

    For the treatment of unresectable or metastatic malignant melanoma in patients with the BRAF V600E or V600K mutation, in combination with dabrafenib.
    Oral dosage
    Adults

    2 mg PO once daily in combination with dabrafenib (150 mg PO twice daily) until disease progression. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[60372] Treatment with dabrafenib plus trametinib resulted in significantly improved median progression-free survival (PFS; 11.4 months vs. 7.3 months; hazard ratio (HR) = 0.56; 95% CI, 0.46 to 0.69; p less than 0.001) and overall survival (OS; median not reached vs. 17.2 months; HR = 0. 69; 95%CI, 0.53 to 0.89; p = 0.005) times compared with single-agent vemurafenib in previously untreated patients with unresectable stage IIIC or stage IV melanoma and BRAF V600E or V600K mutations in a planned interim analysis of a randomized, phase 3 study (n = 704; the COMBI-v study). This trial was stopped early based on the significantly improved OS data with combination therapy; cross-over from the vemurafenib to the combination arm was not allowed prior to the interim analysis.[58760] The median PFS (11 months vs. 8.8 months; HR = 0.67; 95% CI, 0.53 to 0.84; p = 0.0004) and OS (25.1 months vs. 18.7 months; HR = 0.71; 95% CI, 0.55 to 0.92; p = 0.0107) times were significantly improved with dabrafenib plus trametinib compared with dabrafenib plus placebo in previously untreated patients with unresectable stage IIIC or stage IV melanoma with BRAF V600E or V600K mutations in a randomized, double-blind, phase 3 study (n = 423; the COMBI-d study). Cross-over from the dabrafenib plus placebo arm to the combination therapy arm was not permitted at the primary analysis.[59946] At a median follow-up time of 22 months (range, 0 to 76 months), the median PFS and OS times were 11.1 months and 25.9 months, respectively, in a pooled analysis of patients with advanced melanoma who received dabrafenib and trametinib in the COMBI-d and COMBI-v trials (n = 563); the 5-year PFS and OS rates were 19% and 37%, respectively.[64436]

    For the treatment of asymptomatic brain metastases in patients with BRAF V600E- or V600K-mutation metastatic melanoma and no previous local brain-directed therapy, in combination with dabrafenib.
    Oral dosage
    Adults

    2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily until disease progression was evaluated in a cohort of 76 patients in a multicenter, phase 2 trial.[62027] Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[60372]

    For adjuvant therapy following complete resection in patients with BRAF V600E or V600K mutation-positive melanoma and lymph node involvement, in combination with dabrafenib.
    Oral dosage
    Adults

    2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily until disease recurrence or for up to 1 year was evaluated in a multinational, randomized, double-blind, placebo-controlled, phase 3 trial (n = 870; the COMBI-AD trial). Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.

    For the treatment of non-small cell lung cancer (NSCLC).
    NOTE: Confirm the BRAF V600E mutation prior to starting therapy. Information on FDA-approved tests for the detection of BRAF V600 mutations is available at http://www.fda.gov/CompanionDiagnostics.
    NOTE: Trametinib in combination with dabrafenib has been designated as an orphan drug by the FDA for the treatment of BRAF mutation-positive NSCLC.
    For the treatment of metastatic BRAF V600E mutation-positive NSCLC, in combination with dabrafenib.
    Oral dosage
    Adults

    2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily until disease progression. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. The investigator-assessed overall response rate (ORR) was 63.2% following treatment with dabrafenib and trametinib in a cohort of patients with previously treated stage IV BRAF V600E-mutant NSCLC (n = 57) in a multinational, nonrandomized, 3-cohort, phase II trial. At a median follow-up of 11.6 months, the median duration of response was 9 months and the median progression-free survival time was 8.6 months (evaluated by an independent review committee). Patients in this cohort (median age, 64 years; range, 58 to 71 years) had received up to 3 prior systemic therapies (1 prior therapy, 67%; 2 or 3 prior therapies, 33%) including at least 1 prior platinum-based chemotherapy regimen; patients who received prior BRAF or MEK inhibitor treatment were excluded from this study. The ORR was 61% in a cohort of patients with treatment-naive stage IV BRAF V600E-mutant NSCLC (n = 36) who received dabrafenib and trametinib

    For the treatment of thyroid cancer.
    For the treatment of locally advanced or metastatic anaplastic thyroid cancer (ATC) in patients with the BRAF V600E mutation who have no satisfactory locoregional treatment options, in combination with dabrafenib.
    NOTE: Confirm the BRAF V600E mutation prior to starting therapy. An FDA-approved test for the detection of BRAF V600E mutation in ATC is not currently available.
    NOTE: Trametinib has been designated as an orphan drug for the treatment of BRAF mutation-positive ATC by the FDA in combination with dabrafenib.
    Oral dosage
    Adults

    2 mg orally once daily plus dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity was evaluated in a subgroup of patients with ATC in a multicenter, nonrandomized phase 2 clinical trial.[62589] Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.[60372]

    MAXIMUM DOSAGE

    Adults

    2 mg/day PO

    Geriatric

    2 mg/day PO

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No trametinib dosage adjustment is recommended in patients with mild hepatic impairment (bilirubin level at the upper limit of normal (ULN) or less and AST level greater than the ULN OR bilirubin level greater than 1- to 1.5-times the ULN and any AST level) based on a population pharmacokinetic analysis. Trametinib has not been studied in patients with moderate (bilirubin level greater than 1.5- to 3-times the ULN and any AST level) to severe (bilirubin level greater than 3- to 10-times the ULN and any AST level) hepatic impairment.[60372]

    Renal Impairment

    No trametinib dosage adjustment is necessary in patients with mild to moderate renal impairment (glomerular filtration rate (GFR), 30 to 89 mL/min/1.73 m2) based on a population pharmacokinetic analysis. Trametinib has not been studied in patients with severe renal impairment (GFR less than 30 mL/min/1.73 m2).[60372]

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Trametinib should be taken at least 1 hour before or 2 hours after a meal.
    Space doses approximately 24 hours apart.
    If a dose is missed, take within 12 hours of missing the dose. If more than 12 hours have passed, skip the dose of the day and take the dose the next day at the scheduled time.

    STORAGE

    Mekinist:
    - Do not freeze
    - Protect from light
    - Protect from moisture
    - Refrigerate (between 36 and 46 degrees F)
    - Store and dispense in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Cardiac arrhythmias, cardiac disease, cardiomyopathy, heart failure, hypertension, QT prolongation, ventricular dysfunction

    Cardiomyopathy, congestive heart failure (CHF), left ventricular dysfunction (LVD), and decreased left ventricular ejection fraction (LVEF)) have been reported in patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma who received trametinib as monotherapy or in combination with dabrafenib. Evaluate cardiac function/LVEF (e.g., echocardiogram or multigated acquisition (MUGA) scan) prior to starting trametinib, at 1 month, and then every 2 to 3 months thereafter. Interruption of therapy, a dose reduction, and/or permanent discontinuation may be necessary in patients who develop LVD. In clinical trials, the time to cardiomyopathy onset with trametinib therapy ranged from 16 days to 24.9 months; most cases resolved. Patients with cardiac disease including recent history of acute coronary syndrome, NYHA class II or greater CHF, QT prolongation, and uncontrolled hypertension or cardiac arrhythmias may be at increased risk for developing serious cardiac toxicity; these patients were excluded from trametinib clinical studies.

    Glaucoma, retinal detachment

    Serious ophthalmic adverse events including retinal pigment epithelial detachments (RPED) and retinal vein occlusion (RVO) have been reported with trametinib therapy in clinical trials. Ophthalmological exams should be performed periodically and promptly in patients who report vision problems. Interruption of therapy, a dose reduction, or permanent therapy discontinuation may be necessary in patients who develop RPED. Permanently discontinue trametinib in patients who develop RVO. RVO may result in macular edema, decreased visual function, neovascularization, and glaucoma. Retinal detachment may be bilateral and multifocal and occur in the macular region of the retina.

    Pleural effusion, pneumonitis, pulmonary disease

    Interstitial lung disease (ILD) and pneumonitis requiring hospitalization have been reported in patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma who received trametinib as monotherapy or in combination with dabrafenib in clinical trials. Hold trametinib therapy in patients who develop pulmonary symptoms such as cough, dyspnea, hypoxia, pleural effusion, or pulmonary infiltrates. Permanently discontinue therapy in patients with confirmed, treatment-related ILD or pneumonitis. The median time to ILD or pneumonitis development was 5.3 months (range, 2 to 5.7 months) in one trial. Patients with pulmonary disease may be at increased risk for developing serious cardiac toxicity.

    Infection, serious rash

    Skin toxicities including serious rash (unspecified) have been reported in patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma who received trametinib as monotherapy or in combination with dabrafenib in clinical trials; hospitalization was required in some patients due to a secondary infection of the skin. Monitor patients for signs of skin toxicity and secondary infections. Interruption of therapy, a dose reduction, and/or permanent discontinuation may be necessary in patients who develop severe skin toxicity. In clinical trials, the time to skin toxicity onset with trametinib therapy ranged from 1 day to 22.1 months.

    New primary malignancy

    New primary malignancy has been reported in patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma who received trametinib in combination with dabrafenib in clinical trials. When trametinib is given in combination with dabrafenib, perform a dermatologic evaluation before starting therapy, every 2 months on therapy, and for up to 6 months after therapy discontinuation; monitor patients closely for signs or symptoms of non-cutaneous malignancies. No trametinib dose adjustment is necessary in patients who develop new primary cutaneous or non-cutaneous malignancies during combination therapy. In a clinical trial, the median times to onset of BCC and cuSCC following trametinib and dabrafenib therapy were 5.1 months (range, 2.8 to 23.9 months) and 7.3 months (range, 1.8 to 16.8 months), respectively.

    Bleeding, GI bleeding, intracranial bleeding

    Bleeding events including GI bleeding and intracranial bleeding have been reported in patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma who received trametinib as monotherapy or in combination with dabrafenib in clinical trials. Interruption of therapy, a dose reduction, or permanent therapy discontinuation may be necessary in patients who develop grade 3 or 4 bleeding.

    Thromboembolic disease

    Venous thromboembolic disease including deep venous thrombosis (DVT) and pulmonary embolism (PE) has been reported in patients with previously untreated, BRAF V600 mutation-positive, unresectable or metastatic melanoma who received trametinib in combination with dabrafenib in a randomized, double-blind, comparative trial. Patients who develop symptoms of DVT or PE, including shortness of breath, chest pain, or leg swelling, should immediately contact their healthcare provider. Interruption of therapy, a dose reduction, or permanent discontinuation of therapy may be necessary in patients who develop venous thromboembolic disease.

    Dehydration, fever, hypotension, renal failure

    Serious fever and febrile reactions including symptoms of hypotension, rigors/chills, dehydration, and/or renal failure have been reported in patients who received trametinib in combination with dabrafenib. Interruption of therapy, a dose reduction, or permanent therapy discontinuation may be necessary in patients who develop a temperature greater than 104 degrees F or a febrile reaction (any fever complicated by chills/rigors, hypotension, dehydration, or renal failure); evaluate these patients for signs and symptoms of infection. If a patient experiences a severe fever or febrile reaction, monitor renal function (e.g., BUN/serum creatinine) during and after the event and give antipyretic agents as secondary prophylaxis when trametinib therapy is resumed. In patients who develop a febrile reaction or a second or subsequent fever that does not resolve within 3 days of onset, give corticosteroids (e.g., prednisone 10 mg/day PO) for at least 5 days; ensure there is no evidence of active infection prior to starting corticosteroid therapy. In one clinical trial, the median time to fever onset was 1.2 months (range, 1 day to 23.5 months) and the median duration of fever was 3 days (range, 1 day to 1.7 months). About one-half of patients who received combination therapy and had fever experienced 3 or more episodes of a febrile reaction.

    Diabetes mellitus, hyperglycemia

    Hyperglycemia has been reported in patients with a history of diabetes mellitus who received trametinib in combination with dabrafenib; some patients may require more intensive hypoglycemic therapy. In patients with pre-existing diabetes or hyperglycemia, monitor serum glucose levels at baseline and as clinically indicated during therapy; advise patients to report symptoms of severe hyperglycemia (e.g., excessive thirst, increased urinary frequency). Initiate or optimize anti-hyperglycemic agents in these patients as necessary.[60372]

    Colitis, GI perforation, inflammatory bowel disease

    Colitis and GI perforation have been reported in patients with BRAF V600 mutation-positive, unresectable or metastatic melanoma who received trametinib as monotherapy or in combination with dabrafenib in clinical trials; some cases were fatal. Monitor patients for signs and symptoms of colitis and GI perforations. Use trametinib with caution in patients with inflammation of the colon (e.g., inflammatory bowel disease).

    Children, infants, neonates

    The safety and effectiveness of trametinib have not been established in adolescents, children, infants, or neonates. In a toxicity study in juvenile rats, decreased bone length and corneal dystrophy occurred at doses the resulted in drug exposures lower (0.3-fold) than those achieved with the recommended human adult dose. A delay in sexual maturation was observed at doses that resulted in drug exposures 1.6-times those achieved at the recommended dose in human adult patients.

    Geriatric

    In clinical trials, peripheral edema and anorexia occurred more often in geriatric patients aged 65 years and older compared with younger patients following treatment with trametinib plus dabrafenib.

    Pregnancy

    Trametinib may cause fetal harm when administered to a pregnant woman, based on its mechanism of action and findings from animal studies. Advise females of reproductive potential to avoid pregnancy while taking trametinib. Discuss the potential hazard to the fetus if trametinib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including decreased fetal weight (rats and rabbits), variations in bone ossification (rabbits), and increased post implantation loss (rabbits) were observed in pregnant animals that received trametinib at doses that resulted in drug exposures that were lower (about 0.3 times the human exposure or less) than those observed with the recommended human dose. An increase in post implantation loss was also seen in pregnant rats who received trametinib at doses that resulted in drug exposures that were 1.8-times higher than those observed with the recommended human dose.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during trametinib therapy. Pregnancy testing should be performed prior to starting trametinib in female patients of reproductive potential. These patients should use effective contraception during and for at least 4 months after the last trametinib dose. Advise women to contact their healthcare provider if pregnancy is suspected or confirmed. Women who become pregnant while receiving trametinib should be apprised of the potential hazard to the fetus. Due to male-mediated teratogenicity, men (including men who have had a vasectomy) with female partners of reproductive potential should use effective contraception (i.e., condoms) during therapy and for at least 4 months following the final trametinib dose. Advise females of reproductive potential of the potential risk for impaired fertility with trametinib therapy. Based on animal studies, infertility or impaired fertility may occur in females who receive trametinib. In female rats, increased follicular cysts and decreased corpora lutea were observed at trametinib doses that achieved about 0.3 times the recommended human exposure. No adverse effects in male reproductive tissues were observed in rats and dogs who received trametinib in a 13-week study.[60372]

    Breast-feeding

    According to the manufacturer, women should discontinue breast-feeding during trametinib therapy and for 4 months after the last dose because of the potential for serious adverse reactions in nursing infants. It is not known if trametinib is secreted in human milk or if it affects the breast fed infant or milk production. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    hyponatremia / Delayed / 0-17.0
    lymphopenia / Delayed / 5.0-14.0
    hypertension / Early / 11.0-12.0
    cardiomyopathy / Delayed / 3.0-11.0
    bradycardia / Rapid / 0-10.0
    rhabdomyolysis / Delayed / 0-10.0
    anemia / Delayed / 0-10.0
    hyperglycemia / Delayed / 0-9.0
    rash / Early / 0-8.0
    leukopenia / Delayed / 0-8.0
    neutropenia / Delayed / 6.0-8.0
    hypophosphatemia / Delayed / 0-7.0
    GI bleeding / Delayed / 0-6.0
    elevated hepatic enzymes / Delayed / 2.0-6.0
    fever / Early / 5.0-5.0
    fatigue / Early / 0-5.0
    asthenia / Delayed / 0-5.0
    malaise / Early / 0-5.0
    thromboembolism / Delayed / 2.0-4.3
    thrombosis / Delayed / 0-4.3
    pulmonary embolism / Delayed / 0-4.3
    new primary malignancy / Delayed / 0-3.3
    vomiting / Early / 0-3.2
    diarrhea / Early / 0-3.2
    bleeding / Early / 0-3.2
    pruritus / Rapid / 0-2.0
    stomatitis / Delayed / 0-2.0
    oral ulceration / Delayed / 0-2.0
    hypoalbuminemia / Delayed / 0-2.0
    intracranial bleeding / Delayed / 0-1.4
    xerosis / Delayed / 0-1.1
    chills / Rapid / 0.5-1.1
    peripheral edema / Delayed / 0-1.0
    edema / Delayed / 0-1.0
    acneiform rash / Delayed / 0-1.0
    abdominal pain / Early / 0-1.0
    nausea / Early / 0-1.0
    headache / Early / 0-1.0
    musculoskeletal pain / Early / 0-1.0
    myalgia / Early / 0-1.0
    arthralgia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-0.7
    renal failure (unspecified) / Delayed / 0.5-0.5
    GI perforation / Delayed / 0.3-0.3
    visual impairment / Early / 0-0.2
    macular edema / Delayed / 0-0.2
    dizziness / Early / 0-0.2
    heart failure / Delayed / Incidence not known
    retinal detachment / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    ocular hemorrhage / Delayed / Incidence not known

    Moderate

    dyspnea / Early / 0-15.0
    blurred vision / Early / 0-10.0
    hypoxia / Early / 0-5.0
    QT prolongation / Rapid / 0.8-3.8
    pneumonitis / Delayed / 0-2.4
    dehydration / Delayed / 1.8-1.8
    colitis / Delayed / 0.6-0.6
    erythema / Early / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    hemoptysis / Delayed / Incidence not known
    hematoma / Early / Incidence not known
    hypotension / Rapid / Incidence not known

    Mild

    anorexia / Delayed / 0-29.0
    cough / Delayed / 0-22.0
    xerophthalmia / Early / 0-10.0
    xerostomia / Early / 0-10.0
    folliculitis / Delayed / 0-10.0
    infection / Delayed / 0-10.0
    dysgeusia / Early / 0-10.0
    syncope / Early / 0.7-0.7
    vesicular rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    purpura / Delayed / Incidence not known

    DRUG INTERACTIONS

    Chloroquine: (Moderate) Concurrent use of chloroquine and trametinib is not recommended as there is an increased risk of retinal toxicity.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of trametinib with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated dasabuvir plasma concentrations. Trametinib inhibits CYP2C8, an enzyme primarily responsible for the metabolism of dasabuvir. Caution and close monitoring are advised if these drugs are administered together.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP2C8 substrate, may be increased when administered concurrently with trametinib, a mild CYP2C8 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP2C8 substrate, may be increased when administered concurrently with trametinib, a mild CYP2C8 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Paclitaxel: (Minor) Paclitaxel is a substrate of CYP2C8; in vitro, trametinib is a mild inhibitor of CYP2C8. If coadministration is necessary, use caution and monitor for increased paclitaxel side effects, including myelosuppression and peripheral neuropathy.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with trametinib. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Velpatasvir is a CYP2C8 substrate; trametinib is a weak in vitro inhibitor of CYP2C8.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with trametinib. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Velpatasvir is a CYP2C8 substrate; trametinib is a weak in vitro inhibitor of CYP2C8.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Trametinib may cause fetal harm when administered to a pregnant woman, based on its mechanism of action and findings from animal studies. Advise females of reproductive potential to avoid pregnancy while taking trametinib. Discuss the potential hazard to the fetus if trametinib is used during pregnancy or if a patient becomes pregnant while taking this drug. Embryo-fetal toxicities including decreased fetal weight (rats and rabbits), variations in bone ossification (rabbits), and increased post implantation loss (rabbits) were observed in pregnant animals that received trametinib at doses that resulted in drug exposures that were lower (about 0.3 times the human exposure or less) than those observed with the recommended human dose. An increase in post implantation loss was also seen in pregnant rats who received trametinib at doses that resulted in drug exposures that were 1.8-times higher than those observed with the recommended human dose.

    Counsel patients about the reproductive risk and contraception requirements during trametinib therapy. Pregnancy testing should be performed prior to starting trametinib in female patients of reproductive potential. These patients should use effective contraception during and for at least 4 months after the last trametinib dose. Advise women to contact their healthcare provider if pregnancy is suspected or confirmed. Women who become pregnant while receiving trametinib should be apprised of the potential hazard to the fetus. Due to male-mediated teratogenicity, men (including men who have had a vasectomy) with female partners of reproductive potential should use effective contraception (i.e., condoms) during therapy and for at least 4 months following the final trametinib dose. Advise females of reproductive potential of the potential risk for impaired fertility with trametinib therapy. Based on animal studies, infertility or impaired fertility may occur in females who receive trametinib. In female rats, increased follicular cysts and decreased corpora lutea were observed at trametinib doses that achieved about 0.3 times the recommended human exposure. No adverse effects in male reproductive tissues were observed in rats and dogs who received trametinib in a 13-week study.[60372]

    MECHANISM OF ACTION

    Trametinib is a reversible inhibitor of mitogen-activated extracellular kinases (MEK)-1 and MEK-2 that has demonstrated activity against BRAF V600-mutated forms of BRAF kinases in melanoma cells in vitro and in vivo. MEK proteins belong to a family of enzymes that lie downstream of the BRAF kinase and upstream of the extracellular receptor kinase (ERK) signaling pathways. Approximately 50% of melanomas have BRAF mutations. Some BRAF mutations (e.g., BRAF V600 mutations) signal mitogen activated protein kinase (MAPK) pathways resulting in the hyperactivation of MEK and ERK leading to melanoma cell proliferation in the absence of growth factors that would normally be required for cell proliferation.
    Potential mechanisms of resistance to trametinib include upregulation of MAPK signaling, phosphatase tensin homologue (PTEN) loss, hepatocyte growth factor (HGF)/MET signaling, amplified cyclin D1 (CCND1), and amplified receptor tyrosine kinase (RTK) signaling through PI3K and mTOR.

    PHARMACOKINETICS

    Trametinib is administered orally. It is highly bound to plasma proteins (97.4%) and has an apparent volume of distribution of 214 liters (L). In vitro, trametinib is metabolized by deacetylation alone (via hydrolytic enzymes such as carboxyl-esterases or amidases), mono-oxygenation, and/or glucuronidation pathways. The estimated trametinib elimination half-life is 3.9 to 4.8 days and the apparent clearance is 4.9 L/hr. The fecal route is the main route of trametinib excretion. Following a radioactive [14C]-trametinib dose, 50% of the radioactivity in the plasma is the parent compound; 80% of the radioactivity was recovered in the feces and less than 20% of the total reactivity was recovered in the urine (< 0.1% as the parent drug). Following repeat trametinib dosing, 75% or more of the parent compound is found in the plasma.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2C8
    Based on in vitro studies, trametinib inhibits CYP2C8 and induces CYP3A4. The effect of trametinib on CYP2C8 substrates is not known. However, there was no clinically significant impact on the Cmax and AUC values of a sensitive CYP3A4 substrate following the administration of trametinib 2 mg/day in a cross-study comparison. In vitro, trametinib is not a substrate for CYP450 isoenzymes or the following drug transporters: breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP1B1, OATP1B3, OATP2B1), organic cation transporter 1 (OCT1), multidrug resistance protein 2 (MRP2), or multidrug and toxin extrusion 1 (MATE1). Additionally, trametinib is not an inhibitor of drug transporters (e.g., P-glycoprotein (P-gp), BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, bile salt extrusion pump (BSEP), MRP2, or MATE1) at clinically relevant systemic concentrations. Trametinib is a substrate of P-gp and BSEP; however, concomitant administration of trametinib with a P-gp inhibitor is unlikely to result in a clinically important increase in trametinib concentrations because trametinib exhibits high passive permeability and bioavailability.

    Oral Route

    The mean absolute oral bioavailability of a trametinib 2 mg tablet is 72%. Following oral administration, the median time to peak plasma concentration (Tmax) is 1.5 hours. Over a dosage range of 0.125 mg to 10 mg, trametinib exhibits dose proportional Cmax following a single dose; however, the AUC is greater than dose proportional. Following repeat daily doses of 0.125 mg to 4 mg, trametinib exhibits dose proportional exposure; inter-subject steady-state Cmax and AUC variability was 28% and 22%, respectively. Administering trametinib with a high-fat, high-calorie meal decreases the Cmax by 70%, decreases the AUC by 24%, and delays the median Tmax by about 4 hours when compared to the fasted state. Take the trametinib dose either at least 1 hour before or at least 2 hours after a meal.