Trametinib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Mekinist: 0.5 mg, 2 mg

Pharmacology

Mechanism of Action

Trametinib reversibly and selectively inhibits mitogen-activated extracellular kinase (MEK) 1 and 2 activation and kinase activity. MEK is a downstream effector of the protein kinase B-raf (BRAF); BRAF V600 mutations result in constitutive activation of the BRAF pathway (including MEK1 and MEK2). Through inhibition of MEK 1 and 2 kinase activity, trametinib causes decreased cellular proliferation, cell cycle arrest, and increased apoptosis (Kim 2013). The combination of trametinib and dabrafenib allows for greater inhibition of the MAPK pathway, resulting in BRAF V600 melanoma cell death (Flaherty 2012a). Trametinib plus dabrafenib has been reported to synergistically inhibit cell growth in lung cancer cell lines which are BRAF V600E-mutant (Planchard 2016).

Pharmacokinetics/Pharmacodynamics

Absorption

Rapid; decreased with a high-fat, high-calorie meal (~1,000 calories)

Distribution

214 L

Metabolism

Predominantly deacetylation (via hydrolytic enzymes) alone or with mono-oxygenation or in combination with glucuronidation

Excretion

Feces (>80%); urine (<20% with <0.1% as unchanged drug)

Time to Peak

1.5 hours; delayed with a high-fat, high-calorie meal (~1,000 calories)

Half-Life Elimination

~4 to 5 days

Protein Binding

~97% to plasma proteins

Use: Labeled Indications

Melanoma:

Adjuvant treatment of melanoma (in combination with dabrafenib) in patients with BRAF V600E or BRAF V600K mutations (as detected by an approved test), and lymph node involvement, following complete resection.

Treatment of unresectable or metastatic melanoma in patients with BRAF V600E or BRAF V600K mutations (as detected by an approved test), either as a single-agent (in BRAF inhibitor treatment-naive patients) or in combination with dabrafenib.

Non-small cell lung cancer (metastatic): Treatment of metastatic non-small cell lung cancer in patients with BRAF V600E mutation as detected by an approved test (in combination with dabrafenib).

Thyroid cancer, anaplastic, locally advanced or metastatic: Treatment of locally advanced or metastatic anaplastic thyroid cancer (in combination with dabrafenib) in patients with BRAF V600E mutation and with no satisfactory locoregional treatment options.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to trametinib or any component of the formulation.

Dosage and Administration

Dosing: Adult

Note: Confirm BRAF V600 mutation status (in tumor specimens) prior to treatment initiation.

Melanoma, adjuvant treatment (with BRAF V600E or BRAF V600K mutations): Oral: 2 mg once daily (in combination with dabrafenib); continue for ≤1 year in the absence of disease progression or unacceptable toxicity (Long 2017).

Melanoma, metastatic or unresectable (with BRAF V600E or BRAF V600K mutations): Oral: 2 mg once daily (either as a single-agent or in combination with dabrafenib), continue until disease progression or unacceptable toxicity.

Non-small cell lung cancer, metastatic (with BRAF V600E mutation): Oral: 2 mg once daily (in combination with dabrafenib); continue until disease progression or unacceptable toxicity (Planchard 2016).

Thyroid cancer, anaplastic, locally advanced or metastatic (with BRAF V600E mutation): Oral: 2 mg once daily (in combination with dabrafenib); continue until disease progression or unacceptable toxicity (Subbiah 2018).

Missed doses: Do not take a missed dose within 12 hours of the next dose.

Dosing: Adjustment for Toxicity

Recommended trametinib dose reductions for toxicity:

First dose reduction: 1.5 mg once daily.

Second dose reduction: 1 mg once daily.

Subsequent modification (if unable to tolerate 1 mg once daily): Permanently discontinue.

Note: If using combination therapy, refer to dabrafenib monograph for recommended dabrafenib dose reductions.

Cardiotoxicity:

Asymptomatic, ≥10% absolute decrease in left ventricular ejection fraction (LVEF) from baseline and LVEF is below institutional lower limits of normal (LLN) from pretreatment value: Interrupt trametinib therapy for ≤4 weeks. If LVEF improves to normal within 4 weeks following therapy interruption, resume trametinib at a lower dose. If LVEF does not improve to normal within 4 weeks following therapy interruption, permanently discontinue trametinib.

>20% absolute decrease in LVEF from baseline and LVEF is below institutional LLN: Permanently discontinue trametinib.

Symptomatic cardiomyopathy: Permanently discontinue trametinib.

Dermatologic:

Intolerable Grade 2 toxicity or Grade 3 or 4 toxicity: Interrupt trametinib therapy for ≤3 weeks. If toxicity improves within 3 weeks, resume trametinib at a lower dose. If toxicity does not improve within 3 weeks following therapy interruption, permanently discontinue trametinib.

New primary cutaneous malignancies: No trametinib dosage modification is necessary.

Fever: Fever >40°C (104°F) or fever (any severity) complicated by rigors, hypotension, dehydration, or renal failure: Interrupt trametinib therapy until fever resolves, then resume trametinib at the same or lower dose. May require prophylactic antipyretics (secondary prophylaxis) upon resumption. Administer corticosteroids (eg, prednisone 10 mg daily or equivalent) for ≥5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of fever, or for fever associated with complications (eg, dehydration, hypotension, severe chills/rigors with no evidence of active infection).

Hemorrhage:

Grade 3 hemorrhage: Interrupt trametinib therapy. If hemorrhage improves to grade 0 or 1, resume trametinib at a lower dose. If hemorrhage does not improve following therapy interruption, permanently discontinue trametinib.

Grade 4 hemorrhage: Permanently discontinue trametinib.

Ocular:

Uveitis and iritis: No trametinib dosage modification necessary.

Retinal pigment epithelial detachments (RPED): Interrupt trametinib therapy for ≤3 weeks. If improves within 3 weeks following therapy interruption, resume trametinib at the same or lower dose. If RPED does not improve within 3 weeks following therapy interruption, reduce trametinib dose or permanently discontinue trametinib.

Retinal vein occlusion: Permanently discontinue trametinib.

Pulmonary: Interstitial lung disease or pneumonitis: Permanently discontinue trametinib.

Venous thromboembolism:

Uncomplicated DVT or PE: Interrupt trametinib therapy for ≤3 weeks. If improves to ≤ grade 1 within 3 weeks following therapy interruption, resume trametinib at a lower dose. If toxicity does not improve within 3 weeks following therapy interruption, permanently discontinue trametinib.

Life-threatening PE: Permanently discontinue trametinib.

Other toxicity:

Intolerable Grade 2 adverse reaction or any Grade 3 adverse reaction: Interrupt therapy. If toxicity improves to ≤ grade 1 following therapy interruption, resume trametinib at a lower dose. If toxicity does not improve following therapy interruption, permanently discontinue trametinib.

Grade 4 adverse reaction:

First occurrence: Interrupt trametinib therapy until improves to ≤ grade 1, then resume trametinib at a lower dose or permanently discontinue trametinib.

Recurrence: Permanently discontinue trametinib.

New primary noncutaneous malignancy: No trametinib dosage modification is necessary.

Administration

Oral: Administer at least 1 hour before or 2 hours after a meal. Administer dose at the same time each day (trametinib doses should be administered ~24 hours apart), whether administered as a single agent or in combination with dabrafenib (when administered in combination with dabrafenib, take the once daily trametinib dose either with the morning or with the evening dabrafenib dose).

Storage

Store refrigerated at 2°C to 8°C (36°F to 46°F). Dispense in original bottle; do not remove desiccant. Protect from light and moisture. Do not transfer to pill boxes.

Drug Interactions

Dabrafenib: Trametinib may enhance the adverse/toxic effect of Dabrafenib. Monitor therapy

Adverse Reactions

Adverse reactions reported with monotherapy:

>10%:

Cardiovascular: Hypertension (15%), cardiomyopathy (7% to 11%)

Dermatologic: Skin toxicity (87%, most commonly dermatitis acneiform rash, palmar-plantar erythrodysesthesia, erythema, skin rash; severe: 12%; severe toxicity and secondary skin infection requiring hospitalization: 6%), skin rash (57%), acneiform eruption (19%), xeroderma (11%)

Endocrine & metabolic: Hypoalbuminemia (42%)

Gastrointestinal: Diarrhea (43%), stomatitis (15%), abdominal pain (13%)

Hematologic & oncologic: Anemia (38%), lymphedema (32%), hemorrhage (13%; grades 3/4: <1%)

Hepatic: Increased serum aspartate aminotransferase (60%), increased serum alanine aminotransferase (39%), increased serum alkaline phosphatase (24%)

1% to 10%:

Cardiovascular: Decreased left ventricular ejection fraction (5%, ≥20% below baseline), bradycardia

Central nervous system: Dizziness

Dermatologic: Paronychia (10%), pruritus (10%), cellulitis, folliculitis, pustular rash

Gastrointestinal: Dysgeusia, xerostomia

Neuromuscular & skeletal: Rhabdomyolysis

Ophthalmic: Blurred vision, dry eye syndrome

Respiratory: Interstitial pulmonary disease (≤2%), pneumonitis (≤2%)

<1%, postmarketing, and/or case reports: Retinal detachment, retinal vein occlusion

Adverse reactions reported with dual therapy (trametinib plus dabrafenib):

>10%:

Cardiovascular: Hypertension (25% to 26%), peripheral edema (21% to 25%; includes edema and lymphedema; grades 3/4: ≤1% ), prolonged Q-T Interval on ECG (4% QTcF increased >60 msec; <1% QTcF prolongation to >500 msec)

Central nervous system: Fatigue (51% to 59%), headache (30% to 39%), chills (23% to 37%), dizziness (11% to 14%)

Dermatologic: Skin toxicity (55%; severe toxicity: <1%), skin rash (28% to 42%), xeroderma (10% to 31%)

Endocrine & metabolic: Hyperglycemia (60% to 71%), hyponatremia (24% to 57%), hypoalbuminemia (25% to 53%), hypophosphatemia (36% to 42%), exacerbation of diabetes mellitus (27%)

Gastrointestinal: Nausea (34% to 45%), vomiting (25% to 33%), diarrhea (30% to 33%), decreased appetite (29%), abdominal pain (18% to 26%), constipation (13%)

Hematologic & oncologic: Neutropenia (44% to 50%; grades 3/4: 6% to 8%), leukopenia (48%; grades 3/4: 8%), anemia (25% to 46%; grades 3/4: ≤10%), lymphocytopenia (26% to 42%; grades 3/4: 5% to 14%), hemorrhage (18% to 23%; grades 3/4: 2% to 3%; includes hepatic hematoma, duodenal ulcer hemorrhage), thrombocytopenia (19% to 21%; grades 3/4: <1%), malignant neoplasm (1%)

Hepatic: Increased serum alkaline phosphatase (38% to 64%), increased serum aspartate aminotransferase (57% to 61%), increased serum alanine aminotransferase (32% to 48%)

Neuromuscular & skeletal: Arthralgia (25% to 28%), myalgia (13% to 20%)

Renal: Increased serum creatinine (21%)

Respiratory: Cough (20% to 22%), dyspnea (20%)

Miscellaneous: Fever (54% to 63%), febrile reaction (complicated with dehydration: 2%, complicated with severe chills/rigors: <1%, complicated with renal failure: <1%, complicated with syncope: <1%)

1% to 10%:

Cardiovascular: Bradycardia (<10%), cardiomyopathy (6%), reduced ejection fraction (5%), venous thromboembolism (3%; deep vein thrombosis, pulmonary embolism), hypertension

Central nervous system: Intracranial hemorrhage (1%)

Gastrointestinal: Gastrointestinal hemorrhage (6%), pancreatitis

Hematologic & oncologic: Basal cell carcinoma (3%), squamous cell carcinoma of skin (3%; including keratoacanthoma)

Neuromuscular & skeletal: Rhabdomyolysis (<10%)

Ophthalmic: Blurred vision (6%)

Respiratory: Pneumonitis (≤2%)

<1%, postmarketing, and/or case reports: Malignant melanoma

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Neutropenia (including grade 3 and 4 events) has been observed when used in combination with dabrafenib.
• Cardiac events: Cardiac events such as heart failure, left ventricular dysfunction, or decreased left ventricular ejection fraction (LVEF) were observed in clinical trials (for single-agent trametinib and when used in combination with dabrafenib). Assess LVEF (by echocardiogram or MUGA scan) prior to therapy initiation, at one month, and then every 2 to 3 months while on therapy. Cardiac dysfunction may require treatment interruption, dosage reduction, or discontinuation; such measures resulted in resolution of cardiomyopathy in some patients.
• Dermatologic toxicity: Dermatologic toxicity (eg, rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema) was commonly observed in trametinib-treated patients (either as a single-agent or when used in combination with dabrafenib); some patients required hospitalization for severe toxicity or for secondary skin infections. Monitor for dermatologic toxicity and signs/symptoms of secondary infections. Treatment interruption, dose reduction, and/or therapy discontinuation may be necessary.
• Febrile reactions: Serious febrile reactions and fever (any severity) accompanied by hypotension, rigors/chills, dehydration, or renal failure may occur when trametinib is used in combination with dabrafenib. Withhold trametinib for fever >104°F (if using in combination, withhold dabrafenib for fever ≥101.3°F), for serious febrile reactions, or for any fever with rigors/chills, hypotension, dehydration, or renal failure (evaluate for infection; also monitor serum creatinine and other evidence of renal function during and after serious fever); may require prophylactic antipyretics as secondary prophylaxis upon therapy resumption (may resume trametinib at the same or lower dose). Administer corticosteroids (eg, prednisone 10 mg daily or equivalent) for at least 5 days for second or subsequent episodes of pyrexia if temperature does not return to baseline within 3 days of fever onset, or for pyrexia associated with complications (eg, dehydration, hypotension, severe chills/rigors with no evidence of active infection).
• Gastrointestinal events: Colitis and GI perforation, including fatal cases, have been reported with monotherapy and when administered concomitantly with dabrafenib; monitor closely for development of colitis and GI perforations.
• Hemorrhage: Hemorrhage, including symptomatic bleeding in a critical area/organ, may occur with trametinib, either as a single agent or in combination with dabrafenib. Major bleeding events (some fatal) included intracranial, subarachnoid, retroperitoneal, or gastrointestinal hemorrhage. May require treatment interruption and dosage reduction; permanently discontinue trametinib (and dabrafenib) for all grade 4 hemorrhagic events and any grade 3 event that does not improve with therapy interruption.
• Hepatotoxicity: Elevated liver function tests have been reported with trametinib, including grade 3 and 4 events. Monitor hepatic function as clinically necessary.
• Hyperglycemia: Hyperglycemia may occur with trametinib/dabrafenib combination therapy; may require initiation of insulin or oral hypoglycemic agent therapy (or an increased dose if already taking). Monitor serum glucose at baseline and as clinically necessary in patients with preexisting diabetes or hyperglycemia.
• Hypertension: May cause hypertension; monitor blood pressure.
• Malignancy: New primary cutaneous malignancies (which are associated with dabrafenib as single-agent therapy) may occur when trametinib is given in combination with dabrafenib. The incidence of basal cell carcinoma (BCC) in melanoma patients is ~3% for combination therapy versus 6% for single-agent dabrafenib; although rare, some patients experienced more than one BCC occurrence. Cutaneous squamous cell carcinomas (cuSCC), including keratoacanthoma, occurred at a lower rate for combination therapy in melanoma patients compared to single-agent dabrafenib. Cases of cuSCC also occurred in patients with NSCLC. New primary melanoma occurred rarely in patients receiving trametinib. Dermatologic exams should be performed prior to initiation of combination therapy, every 2 months while receiving combination treatment, and for up to 6 months following discontinuation. There are case reports of noncutaneous malignancies with combination therapy; monitor for signs/symptoms of noncutaneous malignancies. No trametinib dosage modification is necessary for new primary cutaneous and noncutaneous malignancies; dabrafenib should be permanently discontinued if RAS mutation-positive noncutaneous malignancies develop.
• Ocular toxicity: Retinal pigment epithelial detachments (RPED) and retinal vein occlusion were seen in clinical trials (rare). Detachments may be bilateral and multifocal, occurring in the central macular area of the retina or elsewhere in the retina. Retinal vein occlusion may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Promptly (within 24 hours) refer patients for ophthalmological evaluations if loss of vision or other visual disturbances occur. Ophthalmic exams (including retinal evaluation) should be performed periodically during treatment and with visual disturbances. Interrupt trametinib therapy for RPED; may resume (at the same or reduced dose) if resolves within 3 weeks; reduce the dose or discontinue if not resolved within 3 weeks. Permanently discontinue if retinal vein occlusion develops. Uveitis and iritis have been reported when trametinib is used in combination with dabrafenib and are managed symptomatically with ophthalmic steroid and mydriatic drops (does not require alteration in trametinib therapy).
• Pulmonary toxicity: Interstitial lung disease (ILD) and pneumonitis were observed in clinical trials. Monitor for new or progressive pulmonary symptoms (eg, cough, dyspnea, hypoxia, pleural effusion, infiltrates); withhold treatment if symptoms occur; permanently discontinue with diagnosis of ILD or pneumonitis.
• Venous thromboembolism: Venous thromboembolic events (some fatal) may occur (was observed when used in combination with dabrafenib). DVT and PE occurred at an increased incidence with combination therapy. Patients should seek immediate medical attention with symptoms of DVT or PE (shortness of breath, chest pain, arm/leg swelling). Withhold trametinib for uncomplicated DVT or PE; may resume at a lower dose if improves within 3 weeks; permanently discontinue trametinib for life-threatening PE.

Concurrent drug therapy issues:

• Combination therapy with dabrafenib: Serious adverse reactions (tumor promotion, hemolytic anemia), which occur with single-agent dabrafenib, may also occur when trametinib is administered in combination with dabrafenib. Refer to Dabrafenib monograph for further information.

Other warnings/precautions:

• Appropriate use: Prior to initiating therapy, confirm BRAF V600K and BRAF V600E mutation status (in tumor specimens) with an approved test. Information on approved tests for detection of BRAF V600 mutations is available at http://www.fda.gov/CompanionDiagnostics. An approved test for BRAF V600E mutation detection in anaplastic thyroid cancer is not available.

Monitoring Parameters

BRAF V600K or V600E mutation status (prior to treatment); liver function tests at baseline and periodically; assess left ventricular ejection fraction (LVEF) (by echocardiogram or MUGA scan) at baseline, 1 month after therapy initiation, and then at 2- to 3-month intervals; verify pregnancy status prior to treatment initiation (in females of reproductive potential); ophthalmological evaluation periodically during treatment and with visual disturbances. Monitor for signs/symptoms of pulmonary toxicity (eg, cough dyspnea, hypoxia, pleural effusion, or infiltrates); monitor for dermatologic toxicity and secondary skin infections; blood pressure; diarrhea; signs/symptoms of bleeding, colitis, and GI perforations.

For patients receiving combination therapy with dabrafenib: Blood glucose (baseline and periodically in patients with preexisting diabetes or hyperglycemia); dermatologic exams should be performed prior to treatment initiation, every 2 months while receiving combination treatment, and for up to 6 months following therapy discontinuation. Monitor for signs/symptoms of cutaneous and noncutaneous malignancies and uveitis/iritis.

Monitor adherence.

Pregnancy

Pregnancy Considerations

Based on its mechanism of action and on findings in animal reproduction studies, in utero exposure to trametinib may cause fetal harm.

Verify pregnancy status in females of reproductive potential prior to treatment initiation. Females of reproductive potential should use effective contraceptive during trametinib therapy and for 4 months after the last trametinib dose. Males (including those with vasectomies) with pregnant partners or female partners of reproductive potential should use condoms during trametinib treatment and for ≥4 months after the last trametinib dose.

Patient Education

What is this drug used for?

• It is used to treat skin cancer.
• It is used to treat lung cancer.
• It is used to treat thyroid cancer.

Frequently reported side effects of this drug

• Dry skin
• Nail changes
• Mouth sores
• Mouth irritation
• Lack of appetite
• Vomiting

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out
• Acne
• Severe skin redness
• Persistent skin rash
• Redness or irritation of palms of hands or soles of feet
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse
• Severe loss of strength and energy
• Chills
• Severe dizziness
• Passing out
• Severe headache
• Severe nausea
• Severe diarrhea
• Severe abdominal pain
• Severe abdominal cramps
• Blurred vision
• Blindness
• Vision changes
• Seeing halos or bright colors around lights
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.