Note: Confirm BRAF V600 mutation status (in tumor specimens) prior to trametinib treatment initiation.
Melanoma, adjuvant treatment, with BRAF V600E or BRAF V600K mutation: Oral: 2 mg once daily (in combination with dabrafenib); continue until disease recurrence or unacceptable toxicity for up to 1 year (Ref).
Melanoma, metastatic or unresectable, with BRAF V600E or BRAF V600K mutation: Oral: 2 mg once daily (either as a single-agent or in combination with dabrafenib), continue until disease progression or unacceptable toxicity (Ref).
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 (Ref).
Ovarian carcinoma, serous, low-grade, recurrent (off-label use): Oral: 2 mg once daily until disease progression or unacceptable toxicity (Ref). Refer to protocol for dosage adjustment details.
Solid tumors, unresectable or metastatic, with BRAF V600E mutation: Oral: 2 mg once daily (in combination with dabrafenib) until disease progression or unacceptable toxicity (Ref).
Thyroid cancer, anaplastic, locally advanced or metastatic, with BRAF V600E mutation: Oral: 2 mg once daily (in combination with dabrafenib); continue until disease recurrence or unacceptable toxicity (Ref).
Missed or vomited doses: Do not take a missed dose within 12 hours of the next dose. If a dose is vomited, do not administer an additional dose; administer the next dose at its scheduled time.
eGFR ≥15 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling; however, eGFR ≥15 mL/minute/1.73 m2 does not have a clinically significant effect on trametinib exposure.
eGFR <15 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling.
Mild impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1 to 1.5 times ULN with any AST): No dosage adjustment necessary.
Moderate (bilirubin >1.5 to 3 times ULN and any AST) to severe (bilirubin >3 to 10 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (a recommended dose has not been established).
In a small pharmacokinetic study, patients with moderate impairment who received either 1.5 or 2 mg once daily for up to 3 (28-day) cycles did not experience dose-limiting toxicities. Among patients with severe impairment who received either 1 or 1.5 mg once daily, no dose-limiting toxicities occurred at the 1 mg dose level, although 1 of the 2 patients who received 1.5 mg once daily experienced grade 3 acneiform rash (Ref). According to the manufacturer, moderate or severe hepatic impairment had no significant effect on trametinib exposure or apparent clearance (compared to patients with normal hepatic function); based on the limited number of patients and doses studied, assess risks versus benefits with respect to dosing in patients with moderate or severe hepatic impairment.
Note: If using combination therapy, refer to Dabrafenib monograph for recommended dabrafenib dose modifications.
Usual (initial) dose |
2 mg once daily |
First dose reduction |
1.5 mg once daily |
Second dose reduction |
1 mg once daily |
If unable to tolerate 1 mg once daily, permanently discontinue trametinib. |
Adverse reaction |
Description/severity |
Trametinib dosage modification |
---|---|---|
a LVEF = left ventricular ejection fraction; DVT = deep vein thrombosis; PE = pulmonary embolism. | ||
Cardiomyopathy |
Asymptomatic, absolute decrease in LVEF ≥10% from baseline and is below institutional LLN from pretreatment value |
Interrupt trametinib for up to 4 weeks. If LVEF improves to normal within 4 weeks, resume trametinib at a lower dose. If LVEF does not improve to normal, permanently discontinue trametinib. |
Symptomatic cardiomyopathy |
Permanently discontinue trametinib. | |
Absolute decrease in LVEF of >20% from baseline that is below institutional LLN | ||
Dermatologic toxicity |
Intolerable grade 2 toxicity or grade 3 or 4 toxicity |
Interrupt trametinib for up to 3 weeks. If toxicity improves within 3 weeks, resume trametinib at a lower dose. If toxicity does not improve, permanently discontinue trametinib. |
New primary cutaneous malignancy |
No trametinib dosage modification is necessary. | |
Severe cutaneous adverse reactions |
Permanently discontinue trametinib. | |
Febrile reaction |
Fever of 38°C to 40°C (100.4°F to 104°F), or first symptoms in case of recurrence |
Interrupt trametinib therapy until fever resolves and then resume at the same or lower dose. |
Fever >40°C (104°F) or fever (any severity) complicated by rigors, hypotension, dehydration, or renal failure |
Interrupt trametinib therapy until febrile reaction resolves for at least 24 hours, then resume trametinib at a lower dose or permanently discontinue trametinib. Administer antipyretics (as secondary prophylaxis) upon trametinib resumption if patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (eg, prednisone 10 mg daily or equivalent) for at least 5 days for second or subsequent episode of pyrexia if temperature does not return to baseline within 3 days of onset of fever, or for fever associated with complications (eg, dehydration, hypotension, renal failure, severe chills/rigors with no evidence of active infection). | |
Hemophagocytic lymphohistiocytosis |
Suspected |
Interrupt trametinib treatment. |
Confirmed |
Discontinue trametinib and manage as appropriate. | |
Hemorrhage |
Grade 3 hemorrhage |
Interrupt trametinib therapy. If hemorrhage improves, resume trametinib at a lower dose. If hemorrhage does not improve, permanently discontinue trametinib. |
Grade 4 hemorrhage |
Permanently discontinue trametinib. | |
Hyperglycemia |
Hyperglycemia may require initiation or optimization of insulin or oral hypoglycemic agent therapy (as clinically indicated). | |
Ocular toxicity |
Uveitis |
No trametinib dosage modification necessary. |
Retinal pigment epithelial detachment |
Interrupt trametinib for up to 3 weeks. If improves within 3 weeks, resume trametinib at the same or lower dose. If not improved, resume trametinib at a reduced dose or permanently discontinue trametinib. | |
Retinal vein occlusion |
Permanently discontinue trametinib. | |
Pulmonary |
New or progressive pulmonary symptoms/findings (including cough, dyspnea, hypoxia, plural effusion, infiltrates) |
Withhold trametinib and assess. |
Interstitial lung disease/pneumonitis |
Permanently discontinue trametinib. | |
Venous thromboembolic events |
Uncomplicated DVT or PE |
Interrupt trametinib therapy for up to 3 weeks. If toxicity improves to ≤ grade 1 within 3 weeks, resume trametinib at a lower dose. If toxicity does not improve, permanently discontinue trametinib. |
Life-threatening PE |
Permanently discontinue trametinib. | |
Other |
Intolerable grade 2 adverse reaction or any grade 3 adverse reaction |
Interrupt trametinib. If toxicity improves to ≤ grade 1, resume trametinib at a lower dose. If toxicity does not improve, permanently discontinue trametinib. |
Grade 4 adverse reaction, first occurrence |
Interrupt trametinib therapy until toxicity improves to ≤ grade 1, then resume trametinib at lower dose or permanently discontinue trametinib. | |
Grade 4 adverse reaction, recurrent |
Permanently discontinue trametinib. | |
New primary noncutaneous malignancy |
No trametinib dosage reduction is necessary. |
(For additional information see "Trametinib: Pediatric drug information")
Note: Confirm BRAF V600 mutation status (in tumor specimens) prior to trametinib treatment initiation. Trametinib is available as tablets and oral solution; weight-band dosing is product specific in patients <18 years of age due to product strengths.
Low-grade glioma (LGG) (with BRAF V600E mutation): Note: Use in combination with dabrafenib and continue therapy until disease progression or unacceptable toxicity.
Weight-directed dosing: Limited data available: Note: In clinical trial experience, both dosage forms, oral solution and tablets, were used based on patient's ability to swallow capsules (Ref).
Children 1 to <6 years: Oral: 0.032 mg/kg/dose every 24 hours; maximum dose: 2 mg/dose (Ref).
Children ≥6 years and Adolescents <18 years: Oral: 0.025 mg/kg/dose every 24 hours; maximum dose: 2 mg/dose (Ref).
Weight-band dosing: Children ≥1 year and Adolescents: Oral:
Weight |
Oral solution (0.05 mg/mL) once daily dose |
Tablets once daily dose |
---|---|---|
8 to <9 kg |
0.3 mg |
N/A |
9 to <11 kg |
0.35 mg |
N/A |
11 to <12 kg |
0.4 mg |
N/A |
12 to <14 kg |
0.45 mg |
N/A |
14 to <18 kg |
0.55 mg |
N/A |
18 to <22 kg |
0.7 mg |
N/A |
22 to <26 kg |
0.85 mg |
N/A |
26 to <30 kg |
0.9 mg |
1 mg |
30 to <34 kg |
1 mg | |
34 to <38 kg |
1.15 mg | |
38 to <42 kg |
1.25 mg |
1.5 mg |
42 to <46 kg |
1.4 mg | |
46 to <51 kg |
1.6 mg | |
≥51 kg |
2 mg |
2 mg |
Solid tumors, unresectable or metastatic (with BRAF V600E mutation):
Note: For use in patients who have progressed following prior treatment and have no satisfactory alternative treatment options; approval from an accelerated process and subject to change as data evolves. Use in combination with dabrafenib and continue therapy until disease progression or unacceptable toxicity.
Children ≥1 year and Adolescents <18 years:
Weight |
Oral solution (0.05 mg/mL) once daily dose |
Tablets once daily dose |
---|---|---|
8 to <9 kg |
0.3 mg |
N/A |
9 to <11 kg |
0.35 mg |
N/A |
11 to <12 kg |
0.4 mg |
N/A |
12 to <14 kg |
0.45 mg |
N/A |
14 to <18 kg |
0.55 mg |
N/A |
18 to <22 kg |
0.7 mg |
N/A |
22 to <26 kg |
0.85 mg |
N/A |
26 to <30 kg |
0.9 mg |
1 mg |
30 to <34 kg |
1 mg | |
34 to <38 kg |
1.15 mg | |
38 to <42 kg |
1.25 mg |
1.5 mg |
42 to <46 kg |
1.4 mg | |
46 to <51 kg |
1.6 mg | |
≥51 kg |
2 mg |
2 mg |
Adolescents ≥18 years: Oral: 2 mg once daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity:
Dose reduction levels: Note: In patients <18 years of age, dosage adjustments are dosage form specific (oral solution or tablets).
Oral solution (0.05 mg/mL): Oral:
Patient Weight (Usual Once Daily Dose) |
First Dose Reduction |
Second Dose Reduction |
---|---|---|
a Trametinib oral solution should be permanently discontinued if unable to tolerate a maximum of 2 dose reductions. | ||
<8 kg (0.032 mg/kg once daily) |
Refer to protocols for specific dose reduction |
Refer to protocols for specific dose reduction |
8 kg to <9 kg (0.3 mg once daily) |
0.25 mg once daily |
0.15 mg once daily |
9 to <11 kg (0.35 mg once daily) |
0.25 mg once daily |
0.2 mg once daily |
11 kg to <12 kg (0.4 mg once daily) |
0.3 mg once daily |
0.2 mg once daily |
12 to <14 kg (0.45 mg once daily) |
0.35 mg once daily |
0.25 mg once daily |
14 to <18 kg (0.55 mg once daily) |
0.4 mg once daily |
0.3 mg once daily |
18 to <22 kg (0.7 mg once daily) |
0.55 mg once daily |
0.35 mg once daily |
22 to <26 kg (0.85 mg once daily) |
0.65 mg once daily |
0.45 mg once daily |
26 to <30 kg (0.9 mg once daily) |
0.7 mg once daily |
0.45 mg once daily |
30 to <34 kg (1 mg once daily) |
0.75 mg once daily |
0.5 mg once daily |
34 to <38 kg (1.15 mg once daily) |
0.85 mg once daily |
0.6 mg once daily |
38 to <42 kg (1.25 mg once daily) |
0.95 mg once daily |
0.65 mg once daily |
42 to <46 kg (1.4 mg once daily) |
1.05 mg once daily |
0.7 mg once daily |
46 to <51 kg (1.6 mg once daily) |
1.2 mg once daily |
0.8 mg once daily |
≥51 kg (2 mg once daily) |
1.5 mg once daily |
1 mg once daily |
Tablets: Oral:
Children and Adolescents <18 years: | |||
Patient Weight (Usual Dose) |
First Dose Reduction |
Second Dose Reduction |
Subsequent Modifications |
26 to <38 kg (1 mg/day) |
0.5 mg once daily |
Permanently discontinue if unable to tolerate 0.5 mg/day. | |
38 to <51 kg (1.5 mg/day) |
1 mg once daily |
0.5 mg once daily |
Permanently discontinue if unable to tolerate 2 trametinib dose reductions. |
≥51 kg (2 mg/day) |
1.5 mg once daily |
1 mg once daily |
Permanently discontinue if unable to tolerate 2 trametinib dose reductions. |
Adolescents ≥18 years: | |||
Usual Dose |
First Dose Reduction |
Second Dose Reduction |
Subsequent Modifications |
2 mg/day |
1.5 mg once daily |
1 mg once daily |
Permanently discontinue if unable to tolerate 2 trametinib dose reductions. |
Dosage adjustments: Note: If using combination therapy with dabrafenib, other adverse reactions related to dabrafenib may occur; refer to Dabrafenib monograph for detailed information.
Adverse Reaction |
Description/Severity |
Trametinib Dosage Modification |
---|---|---|
a LVEF = left ventricular ejection fraction; DVT = deep vein thrombosis; PE = pulmonary embolism. | ||
Cardiomyopathy |
Asymptomatic, absolute decrease in LVEF 10% to 20% from baseline and is below institutional LLN from pretreatment value |
Interrupt trametinib for up to 4 weeks. If LVEF improves to normal within 4 weeks, resume trametinib at a lower dose. If LVEF does not improve to normal, permanently discontinue trametinib. |
Symptomatic cardiomyopathy |
Permanently discontinue trametinib. | |
Absolute decrease in LVEF of >20% from baseline that is below institutional LLN | ||
Dermatologic toxicity |
Intolerable grade 2 toxicity or grade 3 or 4 toxicity |
Interrupt trametinib for up to 3 weeks. If toxicity improves within 3 weeks, resume trametinib at a lower dose. If toxicity does not improve, permanently discontinue trametinib. |
New primary cutaneous malignancy |
No trametinib dosage modification is necessary. | |
Severe cutaneous adverse reactions |
Permanently discontinue trametinib. | |
Febrile reaction |
Fever of 38°C to 40°C (100.4°F to 104°F), or first symptoms in case of recurrence |
Interrupt trametinib therapy until fever resolves and then resume at the same or lower dose. |
Fever >40°C (104°F) or fever (any severity) complicated by rigors, hypotension, dehydration, or kidney failure |
Interrupt trametinib therapy until febrile reaction resolves for at least 24 hours, then resume trametinib at a lower dose or permanently discontinue trametinib. Administer antipyretics (as secondary prophylaxis) upon trametinib resumption if patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (eg, the equivalent of prednisone 10 mg daily in adults) for at least 5 days for second or subsequent episode of pyrexia if temperature does not return to baseline within 3 days of onset of fever, or for fever associated with complications (eg, dehydration, hypotension, kidney failure, severe chills/rigors with no evidence of active infection). | |
Hemorrhage |
Grade 3 hemorrhage |
Interrupt trametinib therapy. If hemorrhage improves, resume trametinib at a lower dose. If hemorrhage does not improve, permanently discontinue trametinib. |
Grade 4 hemorrhage |
Permanently discontinue trametinib. | |
Hyperglycemia |
N/A |
Hyperglycemia may require initiation or optimization of insulin or oral hypoglycemic agent therapy (as clinically indicated). |
Ocular toxicity |
Uveitis |
No trametinib dosage modification necessary. |
Retinal pigment epithelial detachment |
Interrupt trametinib for up to 3 weeks. If improves within 3 weeks, resume trametinib at the same or lower dose. If not improved, resume trametinib at a reduced dose or permanently discontinue trametinib. | |
Retinal vein occlusion |
Permanently discontinue trametinib. | |
Pulmonary |
New or progressive pulmonary symptoms/findings (including cough, dyspnea, hypoxia, plural effusion, infiltrates) |
Withhold trametinib and assess. |
Interstitial lung disease/pneumonitis |
Permanently discontinue trametinib. | |
Venous thromboembolism |
Uncomplicated DVT or PE |
Interrupt trametinib therapy for up to 3 weeks. If toxicity improves to ≤ grade 1 within 3 weeks, resume trametinib at a lower dose. If toxicity does not improve, permanently discontinue trametinib. |
Life-threatening PE |
Permanently discontinue trametinib. | |
Other |
Intolerable grade 2 adverse reaction or any grade 3 adverse reaction |
Interrupt trametinib. If toxicity improves to ≤ grade 1, resume trametinib at a lower dose. If toxicity does not improve, permanently discontinue trametinib. |
Grade 4 adverse reaction, first occurrence |
Interrupt trametinib therapy until toxicity improves to ≤ grade 1, then resume trametinib at a lower dose or permanently discontinue trametinib. | |
Grade 4 adverse reaction, recurrent |
Permanently discontinue trametinib. | |
New primary noncutaneous malignancy |
No trametinib dosage reduction is necessary. |
Children and Adolescents: Oral:
eGFR ≥15 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling; however, eGFR ≥15 mL/minute/1.73 m2 does not have a clinically significant effect on trametinib exposure.
eGFR <15 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling.
Children and Adolescents: Oral:
Mild impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1 to 1.5 times ULN with any AST): No dosage adjustment necessary.
Moderate (bilirubin >1.5 to 3 times ULN and any AST) to severe (bilirubin >3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling (a recommended dose has not been established). According to the manufacturer, moderate or severe hepatic impairment had no significant effect on trametinib exposure or apparent clearance (compared to patients with normal hepatic function); based on the limited number of patients and doses studied, assess risks versus benefits with respect to dosing in patients with moderate or severe hepatic impairment.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Edema (including peripheral edema: ≤32%), hypertension (15%)
Dermatologic: Acneiform eruption (19%), skin rash (57%), xeroderma (11%)
Endocrine & metabolic: Hypoalbuminemia (42%)
Gastrointestinal: Abdominal pain (13%), diarrhea (43%), stomatitis (15%; grades 3/4: 2%)
Hematologic & oncologic: Anemia (38%; grades 3/4: 2%), hemorrhage (13%; grades 3/4: <1%), lymphedema (≤32%; grades 3/4: 1%)
Hepatic: Increased serum alanine aminotransferase (39%), increased serum alkaline phosphatase (24%), increased serum aspartate aminotransferase (60%)
1% to 10%:
Cardiovascular: Bradycardia
Dermatologic: Cellulitis, folliculitis, paronychia (10%), pruritus (10%), pustular rash
Gastrointestinal: Dysgeusia, xerostomia
Nervous system: Dizziness
Neuromuscular & skeletal: Rhabdomyolysis
Ophthalmic: Blurred vision, dry eye syndrome
Respiratory: Interstitial lung disease (≤2%), pneumonitis (≤2%)
<1%:
Gastrointestinal: Colitis, gastrointestinal perforation
Ophthalmic: Retinal vein occlusion
Frequency not defined:
Cardiovascular: Decreased left ventricular ejection fraction
Ophthalmic: Retinal detachment
Renal: Renal failure syndrome
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to trametinib or any component of the formulation.
Concerns related to adverse effects:
• Cardiac events: Cardiomyopathy, including heart failure, may occur with trametinib (including when used in combination with dabrafenib). Cardiomyopathy was defined as a decrease in left ventricular ejection fraction ≥10% from baseline and below the institutional LLN). Cardiomyopathy resolved in most patients receiving trametinib in combination with dabrafenib following dose adjustments, treatment interruption, and/or permanent discontinuation.
• Dermatologic toxicity: Severe cutaneous adverse reactions, including Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported; may be life-threatening or fatal. Other serious dermatologic toxicities may also occur.
• 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. Fever commonly occurred.
• GI events: Colitis and GI perforation, including fatal cases, have been reported with monotherapy and when administered concomitantly with dabrafenib.
• Hemophagocytic lymphohistiocytosis: Hemophagocytic lymphohistiocytosis, a life-threatening immune system reaction, has been reported when trametinib is used in combination with dabrafenib.
• Hemorrhage: Hemorrhage (including major hemorrhage), defined as symptomatic bleeding in a critical area/organ, may occur with trametinib; may be fatal. Bleeding events included intracranial hemorrhage (including fatal cerebral and brainstem hemorrhages) and GI hemorrhage.
• Hyperglycemia: Hyperglycemia may occur with trametinib/dabrafenib combination therapy, including some grade 3 or 4 events.
• Hypertension: May cause hypertension.
• Malignancy: Cutaneous squamous cell carcinomas (cuSCCs) and keratoacanthoma, basal cell carcinoma, and new primary melanoma all occurred in a small percentage of patients when used in combination with dabrafenib. There are reports of noncutaneous malignancies with combination therapy.
• Ocular toxicity: Retinal pigment epithelial detachments and retinal vein occlusion may occur with trametinib (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.
• Pulmonary toxicity: Interstitial lung disease and pneumonitis were observed in clinical trials; pulmonary signs/symptoms may include cough, dyspnea, hypoxia, pleural effusion, and infiltrates.
• Venous thromboembolism: Deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred with combination therapy. Patients should seek immediate medical attention with symptoms of DVT or PE (shortness of breath, chest pain, arm/leg swelling).
Other warnings/precautions:
• Appropriate use: Prior to initiating therapy, confirm BRAF V600K and/or 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Oral:
Mekinist: 0.05 mg/mL (90 mL) [contains methylparaben; strawberry flavor]
Tablet, Oral:
Mekinist: 0.5 mg, 2 mg
No
Solution (reconstituted) (Mekinist Oral)
0.05 mg/mL (per mL): $22.31
Tablets (Mekinist Oral)
0.5 mg (per each): $185.88
2 mg (per each): $542.39
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Oral:
Mekinist: 0.05 mg/mL (180 mL) [contains methylparaben]
Tablet, Oral:
Mekinist: 0.5 mg, 2 mg
Oral: Tablets: Administer at least 1 hour before or 2 hours after a meal. Trametinib doses should be administered ~24 hours apart (at approximately the same time each day), 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. Swallow tablets whole; do not open, crush, or break.
Oral: Administer at least 1 hour before or 2 hours after a meal. 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.
Oral solution: Administer dose with an oral syringe; may also administer through feeding tube.
Missed doses: Do not take a missed dose within 12 hours of the next dose.
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
An FDA-approved patient medication guide, which is available with the product information and at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204114s004lbl.pdf#page=32, must be dispensed with this medication.
Glioma, low-grade, with BRAF V600E mutation: Treatment of low-grade glioma with a BRAF V600E mutation (in combination with dabrafenib) in pediatric patients ≥1 year of age who require systemic therapy.
Melanoma, adjuvant treatment, with BRAF V600E or BRAF V600K mutation: 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.
Melanoma, metastatic or unresectable, with BRAF V600E or BRAF V600K mutation : 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, with BRAF V600E mutation: Treatment of metastatic non-small cell lung cancer in patients with BRAF V600E mutation as detected by an approved test (in combination with dabrafenib).
Solid tumors, unresectable or metastatic, with BRAF V600E mutation: Treatment (in combination with dabrafenib) of unresectable or metastatic solid tumors with a BRAF V600E mutation in adults and pediatric patients ≥1 year of age who have progressed following prior treatment and have no satisfactory alternative treatment options.
Thyroid cancer, anaplastic, locally advanced or metastatic, with BRAF V600E mutation: 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.
Limitations of use: Trametinib is not indicated for treatment of colorectal cancer because of known intrinsic resistance to BRAF inhibition.
Ovarian carcinoma, serous, low-grade, recurrent
Trametinib may be confused with binimetinib, cobimetinib, dabrafenib, encorafenib, selumetinib, tepotinib, trilaciclib, tucatinib, vemurafenib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its lists of drug classes which have a heightened risk of causing significant patient harm when used in error.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Dabrafenib: Trametinib may enhance the adverse/toxic effect of Dabrafenib. Trametinib may increase the serum concentration of Dabrafenib. Risk C: Monitor therapy
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Administration of a single trametinib dose with a high-fat, high-calorie meal (~1,000 calories) decreased AUC by 24%, Cmax by 70%, and delayed Tmax by ~4 hours. Management: Administer 1 hour before or 2 hours after a meal.
Verify pregnancy status prior to treatment initiation in patients who could become pregnant. Patients who could become pregnant 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 partners who could become pregnant should use condoms during trametinib treatment and for 4 months after the last trametinib dose.
Based on its mechanism of action and on findings in animal reproduction studies, in utero exposure to trametinib may cause fetal harm.
It is not known if trametinib is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during trametinib treatment and for 4 months after the last trametinib dose.
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 while on treatment. Verify pregnancy status prior to treatment initiation (in patients who could become pregnant). Perform ophthalmological evaluation (including retinal evaluation) periodically during treatment; if patient-reported loss of vision or other visual disturbances occur, urgently (within 24 hours) perform ophthalmological exam. Monitor for signs/symptoms of new or progressive pulmonary toxicity (eg, cough dyspnea, hypoxia, pleural effusion, or infiltrates). Monitor for new or worsening dermatologic toxicity and secondary skin infections. Monitor BP. Monitor for signs/symptoms of bleeding/hemorrhage, diarrhea, colitis, GI perforations, and hemophagocytic lymphohistiocytosis. Monitor adherence.
For patients receiving combination therapy with dabrafenib: Blood glucose (baseline and periodically in patients with preexisting diabetes or hyperglycemia). Monitor for signs/symptoms of fever or febrile reactions. Dermatologic exams should be performed prior to treatment initiation, every 2 months while receiving combination treatment, and for up to 6 months following combination therapy discontinuation. Monitor for signs/symptoms of venous thromboembolism, cutaneous and noncutaneous malignancies, and uveitis/iritis.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Cardiovascular monitoring specifics: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]). Assess BP at baseline and each clinical visit (as well as outpatient monitoring weekly for initial 3 months, then monthly thereafter), obtain a baseline echocardiography in high- and very-high risk patients scheduled to receive BRAF-MEK inhibitor combination therapy (consider repeating every 4 months during the first year); consider echocardiography in low- and moderate-risk patients scheduled to receive BRAF-MEK inhibitor combination therapy (ESC [Lyon 2022]).
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). Induction of EGFR-mediated MAPK pathway reactivation in the setting of BRAF-mutant colorectal cancer has been identified as a mechanism of intrinsic resistance to BRAF inhibitors.
Absorption: Rapid; decreased with a high-fat, high-calorie meal (~1,000 calories).
Distribution: 214 L.
Protein binding: ~97% to plasma proteins.
Metabolism: Predominantly deacetylation (via hydrolytic enzymes) alone or with mono-oxygenation or in combination with glucuronidation.
Bioavailability: Tablets: 72%; Oral solution: 81%.
Half-life elimination: ~4 to 5 days.
Time to peak: 1.5 hours; delayed with a high-fat, high-calorie meal (~1,000 calories).
Excretion: Feces (>80%); urine (<20% with <0.1% as unchanged drug).
Clearance: 4.9 L/hour.
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