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Trametinib

Pronunciation

(tra ME ti nib)

Index Terms

  • GSK1120212
  • Trametinib Dimethyl Sulfoxide

Dosage Forms

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

Tablet, Oral:

Mekinist: 0.5 mg, 2 mg

Brand Names: U.S.

  • Mekinist

Pharmacologic Category

  • Antineoplastic Agent, MEK Inhibitor

Pharmacology

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, 2012).

Absorption

Rapid; decreased with a high-fat, high-calorie meal

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

Half-Life Elimination

4 to 5 days

Protein Binding

~97% to plasma proteins

Use: Labeled Indications

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

Limitations of use: Trametinib is not indicated for use in patients who have received prior BRAF-inhibitor therapy.

Contraindications

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

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

Dosing: Adult

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.

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

Dosing: Renal Impairment

Mild to moderate impairment (GFR ≥30 mL/minute/1.73 m2): No dosage adjustment necessary.

Severe impairment (GFR <30 mL/minute/1.73 m2): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, renal excretion is low and is unlikely to affect drug exposure.

Dosing: Hepatic Impairment

Mild impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 times ULN with any AST): No dosage adjustment necessary.

Moderate to severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

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

Cardiac:

Asymptomatic, 10% or greater absolute decrease in LVEF from baseline and LVEF is below institutional lower limits of normal (LLN) from pretreatment value: Interrupt trametinib therapy for up to 4 weeks. If LVEF improves to normal within 4 weeks following therapy interruption, resume at a lower dose level. 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 heart failure: Permanently discontinue trametinib.

Dermatologic:

US labeling:

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

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

Canadian labeling:

Grade 2 rash: Reduce dose by 0.5 mg; if taking 1 mg daily, discontinue trametinib.

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

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 at the same or a lower dose level. May require prophylactic antipyretics (secondary prophylaxis) upon resumption. Administer corticosteroids (eg, prednisone 10 mg daily or equivalent) for at least 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, resume at a lower dose level. If hemorrhage does not improve following therapy interruption, permanently discontinue trametinib.

Grade 4 hemorrhage: Permanently discontinue trametinib.

Ocular:

Uveitis and iritis:

US labeling: No trametinib dosage modification necessary.

Canadian labeling: Uveitis that does not improve despite ocular therapy: Interrupt trametinib therapy until uveitis resolves, then resume at the same or lower dose level.

Retinal pigment epithelial detachments (RPED):

US labeling: Interrupt trametinib therapy for up to 3 weeks. If improves within 3 weeks following therapy interruption, resume at the same or lower dose level. If RPED does not improve within 3 weeks following therapy interruption, reduce dose or permanently discontinue trametinib.

Canadian labeling:

RPED, grade 2 or 3: Interrupt trametinib therapy for up to 3 weeks. If improves within 3 weeks following therapy interruption, resume at a lower dose level. If RPED does not improve to at least grade 1 within 3 weeks following therapy interruption, permanently discontinue trametinib.

Recurrence of RPED (any grade) after dose reduction/therapy interruption: 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 up to 3 weeks. If improves to ≤ grade 1 within 3 weeks following therapy interruption, resume at a lower dose level. 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 at a lower dose level. If toxicity does not improve following therapy interruption, permanently discontinue trametinib.

Grade 4 adverse reaction:

US labeling:

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

Recurrence: Permanently discontinue trametinib.

Canadian labeling: Permanently discontinue trametinib.

Grade 4 adverse reaction, recurrent: 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. When administered in combination with dabrafenib, take the once daily trametinib dose at the same time each day with either the morning or evening dose of dabrafenib.

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single gloving for administration of intact tablets (NIOSH 2014).

Storage

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

Drug Interactions

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

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%; defined as cardiac failure, decreased left ventricular ejection fraction, or left ventricular dysfunction)

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%; grades 3/4: 8%), acneiform eruption (19%; grades 3/4: <1%), xeroderma (11%)

Endocrine & metabolic: Hypoalbuminemia (42%)

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

Hematologic & oncologic: Anemia (38%; grades 3/4: 2%), lymphedema (32%; includes edema, peripheral edema; grades 3/4: 1%), hemorrhage (13%; includes epistaxis, gingival bleeding, hematochezia, rectal hemorrhage, melena, vaginal hemorrhage, hemorrhoidal hemorrhage, hematuria, conjunctival hemorrhage; grades 3/4: <1%)

Hepatic: Increased serum AST (60%), increased serum ALT (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%; grades 3/4: 2%), cellulitis, folliculitis, pustular rash

Gastrointestinal: Dysgeusia, xerostomia

Neuromuscular & skeletal: Rhabdomyolysis

Ophthalmic: Blurred vision, dry eye syndrome

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

<1% (Limited to important or life-threatening): 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: Headache (30% to 33%), chills (31%; grades 3/4: <1%), dizziness (11% to 14%)

Dermatologic: Skin toxicity (55% any skin toxicity; severe toxicity: <1%), skin rash (32% to 42%; includes generalized rash, pruritic rash, erythematous rash, papular rash, vesicular rash, macular rash, maculopapular rash, folliculitis rash; grades 3/4: ≤1%), xeroderma (10% to 12%)

Endocrine & metabolic: Hyperglycemia (60% to 65%; grades 3/4: 5% to 6%), hypoalbuminemia (48% to 53%), hypophosphatemia (38%), exacerbation of diabetes mellitus (27%), hyponatremia (24% to 25%)

Gastrointestinal: Nausea (34% to 35%), diarrhea (30% to 31%), vomiting (25% to 27%), abdominal pain (18% to 26%), constipation (13%)

Hematologic & oncologic : Neutropenia (46% to 50%; grades 3/4: 6% to 7%), anemia (43%; grades 3/4: 2%), lymphocytopenia (32% to 38%; grades 3/4: 8% to 9%), thrombocytopenia (19% to 21%; grades 3/4: <1%), hemorrhage (18% to 19%; includes epistaxis, hematochezia, decreased hemoglobin, purpura, rectal hemorrhage; grades 3/4: 2%; includes hepatic hematoma, duodenal ulcer hemorrhage)

Hepatic: Increased serum AST (59% to 60%), increased serum alkaline phosphatase (49% to 50%), increased serum ALT (44% to 48%)

Neuromuscular & skeletal: Arthralgia (25% to 26%), myalgia (13% to 15%)

Respiratory: Cough (20% to 21%)

Miscellaneous: Fever (54% to 57%; grades 3/4: 5% to 7%), 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%), 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%)

Respiratory: Pneumonitis (1%)

<1% (Limited to important or life-threatening): 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. Monitor complete blood counts at baseline and as clinically needed during therapy.

• 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). The median time to onset of cardiomyopathy for single-agent trametinib was ~2 months (range: 16 to 156 days) and ~8 months (range: ~1 to 25 months) when used in combination with dabrafenib. In some patients, cardiomyopathy developed within the first month of treatment. Assess LVEF (by echocardiogram or MUGA scan) prior to therapy initiation, at one month, and then at 2- to 3-month intervals 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. The median time to onset and resolution of skin toxicity for single-agent trametinib was 15 days (range: 1 to 221 days) and 48 days (range: 1 to 282 days), respectively. The median time to onset and resolution of skin toxicity for combination therapy was 2 months (range: 1 day to 22 months) and 1.2 months (range: 1 day to ~24 months), respectively. 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. The incidence and severity were higher with combination therapy than with single-agent dabrafenib; the median time to onset of fever was ~30 days and duration was 3 days for patients receiving combination therapy. Withhold trametinib for fever >104°F (if using in combination, withhold dabrafenib for fever ≥101.3°F) or for any fever with rigors/chills, hypotension, dehydration, or renal failure (evaluate for infection); may require prophylactic antipyretics as secondary prophylaxis upon therapy resumption. 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).

• 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 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: While not reported with single-agent trametinib, hyperglycemia may occur while on combination therapy with dabrafenib; 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. Instruct patients to report symptoms of severe hyperglycemia (eg, polydipsia, polyuria).

• 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) is ~3% for combination therapy versus 6% for single-agent dabrafenib. The median time to BCC diagnosis ranged from ~3 to 24 months for patients receiving combination therapy. Cutaneous squamous cell carcinomas (SCC), including keratoacanthoma, occurred at a lower rate for combination therapy compared to single-agent dabrafenib (3% vs 10%, respectively), with a median time to diagnosis ranging from ~2 to 17 months for combination therapy. 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, including pancreatic cancer (KRAS mutation-positive), colorectal cancer (recurrent NRAS mutation-positive), hand and neck cancer, and glioblastoma, 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.

• Ophthalmic effects: Retinal pigment epithelial detachments (RPED) and retinal vein occlusion were seen in clinical trials (rare). Detachments were typically bilateral and multifocal and occurred in the central macular area of 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 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; median time to initial presentation was ~5 months (range: 2 to ~6 months). 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.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).

Other warnings/precautions:

• Appropriate use: Prior to initiating therapy, confirm BRAF mutation status with an approved test; approved for use in patients with BRAF V600K and BRAF V600E mutations. Current data regarding use in patients with BRAF V600K mutation is limited; compared to BRAF V600E mutation, lower response rates have been observed with BRAF V600K mutation. Data regarding other less common BRAF V600 mutations is lacking.

Monitoring Parameters

BRAF V600K or V600E mutation status (prior to treatment); CBC and liver function tests at baseline and periodically; assess LVEF (by echocardiogram or MUGA scan) at baseline, 1 month after therapy initiation, and then at 2- to 3-month intervals; 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.

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.

Pregnancy Considerations

Adverse effects were observed in animal reproduction studies. Based on its mechanism of action, trametinib would be expected to cause fetal harm if administered to a pregnant woman. Females of reproductive potential should use a highly effective contraceptive during therapy and for 4 months after treatment is complete. When trametinib is used in combination with dabrafenib, a highly effective nonhormonal contraceptive method should be used (dabrafenib may diminish efficacy of hormonal contraceptives). Fertility may also be impaired in females. Due to a risk for impaired spermatogenesis, males who may want to father a child should seek fertility/family planning counseling prior to initiating combination therapy with dabrafenib.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dry skin, nail changes, abdominal pain, mouth sores, nausea, or vomiting. Have patient report immediately to prescriber signs of blood clots (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; angina; shortness of breath; fast heartbeat; or coughing up blood), signs of bleeding (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 bleeding that is very bad or that will not stop), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of heart problems (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, skin rash, redness or irritation of palms of hands or soles of feet, shortness of breath, difficulty breathing, cough, severe loss of strength and energy, chills, dizziness, passing out, severe headache, severe diarrhea, blurred vision, blindness, vision changes, or visual halos or bright light (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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