Trametinib is a mitogen-activated extracellular signal-regulated kinase (MEK)1 and MEK2 inhibitor. It inhibits cell growth in BRAF V600 mutation-positive tumors by blocking MEK1 and MEK2 which are proteins activated in the BRAF pathway. In adults, it is indicated as a single agent for the treatment of BRAF-inhibitor treatment-naive advanced melanoma and in combination with dabrafenib for melanoma (for advanced disease or as adjuvant therapy), metastatic non-small cell lung cancer, and advanced anaplastic thyroid cancer. Trametinib is also indicated in combination with dabrafenib in adult and pediatric patients 1 year and older for the treatment of progressive, advanced solid tumors that have no satisfactory alternative treatment and in pediatric patients 1 year and older for the treatment of low-grade glioma. Trametinib is not indicated for the treatment of colorectal cancer. Venous thromboembolism and interstitial lung disease have been reported with trametinib therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Emetic Risk
-Minimal/Low
-Administer prn antiemetics as necessary.
Route-Specific Administration
Oral Administration
-Take trametinib at the same time each day, approximately 24 hours apart.
-Take at least 1 hour before or 2 hours after a meal.
-If a dose is missed, take it as soon as possible. If it is less than 12 hours before the next scheduled dose, skip the missed dose and take the next dose at the regular time.
-If vomiting occurs after a dose, do not take an additional dose and take the next dose at the regular time.
Oral Solid Formulations
-Swallow whole; do not open, crush, or break tablets.
-Do not use in patients who weigh less than 26 kg or in children not able to swallow trametinib tablets whole.
Oral Liquid Formulations
-Refer caregivers to the Instructions for Use provided with the medication on how to correctly prepare and give a dose of the oral suspension.
Reconstitution:
-Tap the trametinib for oral solution bottle until the powder flows freely.
-Add 90 mL of distilled or purified water to the powder in the bottle for a final concentration of 0.05 mg/mL.
-Invert or gently shake the bottle with re-attached cap for up to 5 minutes until the powder is fully dissolved and the solution is clear.
-Separate the dosing adapter from the oral syringe; insert the dosing adapter into the bottle neck after reconstitution.
-Storage: Store the oral solution in the original bottle below 25 degrees C (77 degrees F) for up to 35 days; do not freeze.
Administration:
-Administer the appropriate dose orally using an oral dosing syringe; the reconstituted solution may also be given via a feeding tube.
-If the solution is given via a feeding tube, use a 4-French gauge or larger tube.
Cardiomyopathy (e.g., congestive heart failure and left ventricular dysfunction (LVD)) defined as a decrease in left ventricular ejection fraction (LVEF) by 10% or more from baseline and LVEF below the institutional lower limit of normal (LLN) has been reported with trametinib and dabrafenib combination therapy. Obtain an echocardiogram or multigated acquisition (MUGA) scan prior to starting combination therapy, 1 month after starting dabrafenib, and then every 2 to 3 months during treatment. Interruption of therapy, a dose reduction, and/or permanent discontinuation may be necessary in patients who develop LVD. Cardiomyopathy was reported in 6% of adult patients who received trametinib and dabrafenib combination therapy in clinical trials (n = 1,087); cardiomyopathy resolved in most (90%) cases. Decreased ejection fraction occurred in 8% or less of patients with BRAF V600 mutation-positive tumors who received dabrafenib and trametinib therapy in clinical trials. Cardiomyopathy occurred in 9% of pediatric patients who received trametinib and dabrafenib in 2 clinical trials (n = 166).
Lymphedema including peripheral edema and edema has been reported in up to 32% of patients with BRAF V600 mutation-positive tumors who received single-agent trametinib in clinical trials; grade 3 or 4 lymphedema occurred in 1% of patients. In a pooled analysis (n = 559), peripheral edema was reported in 21% of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received dabrafenib and trametinib in 2 randomized trials; 0.7% of patients experienced grade 3 or 4 peripheral edema. Edema including peripheral edema occurred in 28% of patients with BRAF V600E mutation-positive metastatic non-small cell lung cancer who received dabrafenib and trametinib in an open-label trial (n = 93). The incidence of adverse reactions was similar in patients with anaplastic thyroid cancer (n = 16) who received dabrafenib and trametinib in a multi-cohort, nonrandomized trial.
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, visual impairment, neovascularization, and glaucoma. Retinal detachment may be bilateral and multifocal and occur in the macular region of the retina. RVO (2%), blurred vision (10% or less), and xerophthalmia (10% or less) were reported in patients who received trametinib as monotherapy in clinical trials (n =329). Because routine monitoring of patients for asymptomatic RPED was not performed, the incidence of this finding is unknown. Blurred vision occurred in 6% of patients with BRAF V600 mutation-positive advanced melanoma who received adjuvant therapy with dabrafenib and trametinib (n = 435) in a randomized trial. RPED events occurred in less than 1% of pediatric patients who received dabrafenib and trametinib in 2 clinical trials (n = 166).
Interstitial lung disease (ILD) or pneumonitis was reported in 2% of patients who received trametinib as monotherapy in clinical trials (n = 329). ILD or pneumonitis occurred in 1% of patients who received trametinib and dabrafenib combination therapy in clinical trials (n = 1,087). Hold trametinib therapy in patients who develop new or worsening pulmonary symptoms. Permanently discontinue therapy in patients with confirmed, treatment-related ILD or pneumonitis. Cough (29% or less) and dyspnea (20%; grade 3 or 4, 5%) were reported in adult patients with BRAF V600 mutation-positive tumors who received trametinib and dabrafenib combination therapy in clinical trials. Additionally, cough occurred in 44% of pediatric patients with BRAF V600 mutation-positive refractory or recurrent solid tumors who received combination therapy in a clinical trial (n = 48). Oropharyngeal pain was reported in 11% of pediatric patients (median age, 10 years; range, 1 to 17 years) with low-grade glioma who received trametinib and dabrafenib (n = 73) in a clinical trial.
Dermatologic toxicity has been reported with trametinib therapy. Interruption of therapy, a dose reduction, or permanent therapy discontinuation may be necessary in patients who develop skin toxicity. Rash occurred with single-agent trametinib (57%; grade 3 or 4, 8%), acneiform rash/dermatitis (19% grade 3 or 4, less than 1%), xerosis (11%), and pruritus (10%; grade 3 or 4, 2%) were reported in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received single-agent trametinib (n = 211) in a randomized trial. Rash (28% to 40%; grade 3 or 4, 3.2% or less), xerosis/dry skin (31% or less; grade 3 or 4, 1.1% or less), and panniculitis (less than 10%) were reported in adult patients who received trametinib and dabrafenib in clinical trials. Rash (54%), dry skin/xerosis (31%), and acneiform rash/dermatitis (23%) were reported in pediatric patients who received dabrafenib and trametinib in 2 clinical trials (n = 166). Alopecia occurred in 3% of pediatric patients (median age, 10 years; range, 1 to 17 years) with low-grade glioma who received dabrafenib and trametinib (n = 73) a clinical trial. The term rash included maculopapular rash, erythematous rash, pruritic rash, nodular rash, vesicular rash, pustular rash, bullous rash/dermatitis, exfoliative dermatitis, eczema, erythema multiforme, palmar-plantar erythrodysesthesia (hand and foot syndrome).
Colitis and GI perforation each have been reported in less than 1% of adult patients who received trametinib as a single agent or in combination with dabrafenib in clinical trials. Some cases of colitis and GI perforation were fatal. Monitor patients for signs and symptoms of colitis and GI perforation. Other gastrointestinal adverse events including abdominal pain (18% or less; grade 3 or 4, 1% or less), anorexia (29% or less), diarrhea (43% or less; grade 3 or 4, 1.3% or less), nausea (45% or less; grade 3 or 4, less than 1%), stomatitis/oral ulceration (15% or less; grade 3 or 4, 2% or less), xerostomia (less than 10%), and vomiting (33% or less; grade 3 or 4, 3.2% or less) have been reported in adult patients with BRAF V600 mutation-positive tumors who received trametinib as a single agent or in combination with dabrafenib in clinical trials. Vomiting (38%), diarrhea (30%), nausea (26%), abdominal pain (24%), and constipation (23% or less) occurred in pediatric patients who received trametinib and dabrafenib in 2 clinical trials (n = 166). Stomatitis was reported in 10% of pediatric patients (median age, 10 years; range, 1 to 17 years) with low-grade glioma who received dabrafenib and trametinib (n = 73) a clinical trial. The term stomatitis included cheilitis, mouth ulceration, aphthous ulcer, and glossitis. Additionally, anorexia was reported in 21% of geriatric patients aged 65 years and older who received trametinib plus dabrafenib compared with 9% of younger patients in this analysis.
Cardiac adverse events including hypertension (15% to 26%) and bradycardia (10% or less) 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. Monitor blood pressure in patients who develop symptoms of hypertension. In pooled results from 2 clinical trials (n = 329), bradycardia occurred in 10% or less of melanoma patients who received single-agent trametinib. Hypertension occurred in 15% of patients who received single-agent trametinib (n = 211) in a randomized, comparative trial; grade 3 and 4 hypertension was reported in 12% of these patients. In pooled results from 2 randomized trials (n = 559), hypertension (26%; grade 3 or 4, 11%) and bradycardia (10% or less) were reported in patients with previously untreated melanoma who received trametinib in combination with dabrafenib. The incidence of adverse reactions was similar in patients with anaplastic thyroid cancer (n = 16) who received dabrafenib and trametinib in a multi-cohort, nonrandomized trial.
Serious bleeding events have been reported with dabrafenib and trametinib combination therapy. Monitor patients who receive trametinib for signs or symptoms of bleeding. Interruption of therapy, a dose reduction, or permanent therapy discontinuation may be necessary in patients who develop grade 3 or 4 bleeding. Bleeding, defined as symptomatic bleeding in a critical area or organ, occurred in 17% of adult patients who received trametinib and dabrafenib combination therapy in clinical trials (n = 1,087); GI bleeding (3%), intracranial bleeding (0.6%), and fatal hemorrhage including cerebral hemorrhage and brainstem hemorrhage (0.5%) were reported. Bleeding was reported in 13% (grade 3 or 4, less than 1%) of adult patients with RAF V600E or V600K mutation-positive unresectable or metastatic melanoma who received single-agent trametinib (n = 211) in a randomized trial. Bleeding (25%) including epistaxis (16%), GI bleeding (1.2%), intracranial bleeding/cerebral hemorrhage (0.6%), uterine bleeding (0.6%), and post-procedural bleeding (0.6%) occurred in pediatric patients who received trametinib and dabrafenib in 2 clinical trials (n = 166). In clinical studies, bleeding included hemoptysis, hematoma, epistaxis, petechiae, gingival bleeding, purpura, hematuria, subarachnoid bleeding, GI bleeding, rectal hemorrhage, melena, urinary bladder hemorrhage, contusion, hematochezia, injection site hemorrhage, pulmonary hemorrhage, vaginal bleeding, bleeding from hemorrhoids, retroperitoneal bleeding, and conjunctival/ocular hemorrhage.
Infection has been reported with trametinib therapy. Monitor patients for signs of infection particularly secondary infections of the skin. Cellulitis (10% or less), folliculitis (10% or less), and paronychia (10%) were reported in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received single-agent trametinib in clinical trials. Additionally, paronychia occurred in 23% of pediatric patients with BRAF V600 mutation-positive refractory or recurrent solid tumors (n = 48) and respiratory tract infection occurred in 15% of pediatric patients with low-grade glioma who received dabrafenib and trametinib (n = 73) in clinical trials.
Rhabdomyolysis was reported in 10% or less of melanoma patients who received single-agent trametinib in pooled results from 2 clinical trials (n = 329) and in less than 10% of patients with previously untreated melanoma who received trametinib in combination with dabrafenib in pooled results from 2 randomized trials (n = 559). Rhabdomyolysis occurred in less than 1% of patients with BRAF V600 mutation-positive advanced melanoma who received adjuvant therapy with dabrafenib and trametinib (n = 435) in a randomized, placebo-controlled clinical trial. The incidence of adverse reactions was similar in patients with anaplastic thyroid cancer (n = 16) who received dabrafenib and trametinib in a multi-cohort, nonrandomized trial.
Headache (39% or less; grade 3 or higher, 1.5% or less), dysgeusia (10% or less), and dizziness (11% or less; grade 3 or higher, 0.2% or less) were reported in adult patients with BRAF V600 mutation-positive tumors who received trametinib as monotherapy or in combination with dabrafenib in clinical trials. Headache was reported in 40% of pediatric patients who received trametinib and dabrafenib in 2 clinical trials (n = 166). Dizziness including vertigo (15%) and peripheral neuropathy (7%) occurred in pediatric patients (median age, 10 years; range, 1 to 17 years) with low-grade glioma who received trametinib and dabrafenib (n = 73) a clinical trial. The term peripheral neuropathy included paresthesias, neuralgia, and hypoesthesia.
Elevated hepatic enzymes including increased AST (57% to 61%; grade 3 or 4, 2% to 6%), ALT (32% to 48%; grade 3 or 4, 3% to 6%), and alkaline phosphatase (24% to 64%; grade 3 or 4, 2.7% or less) levels have been reported in adult patients with BRAF V600 mutation-positive tumors who received trametinib as a single agent or in combination with dabrafenib in clinical trials. In pediatric patients who received trametinib and dabrafenib in clinical trials, increased AST (55%; grade 3 or 4, 4.2%), ALT (40%; grade 3 or 4, 6%), and alkaline phosphatase (28%; grade 3 or 4, 6%) levels and increased total bilirubin/hyperbilirubinemia (21%; grade 3 or 4, 2.1%) occurred in patients with BRAF V600 mutation-positive refractory or recurrent solid tumors (n = 48) and increased AST (37%; grade 3 or higher, 1.4%), ALT (29%; grade 3 or higher, 3%), and alkaline phosphatase (55%) levels occurred in patients with low-grade glioma (n = 73).
Anemia (25% to 46%; grade 3 or 4, 10% or less), leukopenia (48% or less; grade 3 or 4, 8% or less), lymphopenia (26% to 42%; grade 3 or 4, 5% to 14%), neutropenia (44% to 47%; grade 3 or 4, 6% to 8%), and thrombocytopenia (21% or less; grade 3 or 4, 0.7% or less) have been reported in adult patients with BRAF V600 mutation-positive tumors who received trametinib as a single agent or in combination with dabrafenib in clinical trials. Decreased neutrophil count was reported in 44% to 49% (grade 3 or 4, 20%) of pediatric patients who received trametinib and dabrafenib 2 clinical trials (n = 166). In pediatric patients who received dabrafenib and trametinib in clinical trials, decreased hemoglobin level occurred in 60% (grade 3 or 4, 6%) of patients with BRAF V600 mutation-positive refractory or recurrent solid tumors (n = 48) and decreased leukocyte count (59%), decreased hemoglobin level (46%), decreased platelet count (30%), increased lymphocyte count/lymphocytosis (24%), and decreased lymphocyte count (16%; grade 3 or higher, 1.4%) occurred in patients with low-grade glioma (n = 73).
Serious febrile reactions and fever have been reported in patients who received trametinib and dabrafenib combination therapy in clinical trials. Interruption of therapy, a dose reduction, or permanent therapy discontinuation may be necessary for patients who develop a fever or a febrile reaction (or complications including renal failure or hypotension); 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. Fever (58%) and serious febrile reactions (fever of any severity complicated by hypotension, rigors or chills, dehydration or renal failure) (5%) occurred in adult patients who received trametinib and dabrafenib combination therapy in clinical trials (n = 1,087); fever was complicated by hypotension (4%), dehydration (3%), syncope (2%), renal failure (unspecified) (1%), and severe chills/rigors (less than 1%). Fever was reported in 66% of pediatric patients who received trametinib and dabrafenib in 2 clinical trials (n = 166). Chills (23% to 37%; grade 3 or 4, 0.5% to 1.1%) have also been reported in patients treated with trametinib and dabrafenib in clinical trials. In a pyrexia management study, melanoma patients treated with dabrafenib plus trametinib had therapy with both drugs interrupted when the patients' temperature was 100.4 degrees F or higher; grade 3 or 4 fever occurred in 4.3% of patients, hospitalizations due to fever in 5.1%, fever with complications in 2.2%, and treatment discontinuation due to fever in 2.5%.
Hypophosphatemia (42% or less; grade 3 or 4, 7% or less), hyponatremia (57% or less; grade 3 or 4, 17% or less), and decreased magnesium level/hypomagnesemia (24% or less) were reported in adult patients with BRAF V600 mutation-positive tumors who received trametinib and dabrafenib combination therapy in clinical trials. In pediatric patients who received trametinib and dabrafenib in clinical trials, hypocalcemia (40%; grade 3 or 4, 2.1%), decreased phosphate level (38%), decreased magnesium level/hypomagnesemia (33%; grade 3 or 4, 2.1%), and hypokalemia (21%; grade 3 or 4, 2.1%) occurred in patients with BRAF V600 mutation-positive refractory or recurrent solid tumors (n = 48) and decreased magnesium level (34%; grade 3 or higher, 4.1%), decreased calcium level (14%; grade 3 or higher, 4.1%), decreased potassium level (8%; grade 3 or higher, 1.4%), decreased phosphate level (7%; grade 3 or higher, 2.7%), and decreased sodium level (5%; grade 3 or higher, 1.4%) occurred in patients with low-grade glioma (n = 73).
New primary malignancy including new skin malignancy (e.g., cutaneous squamous cell carcinoma (cuSCC), keratoacanthomas, and basal cell carcinoma (BCC)) has been reported in patients who received trametinib and dabrafenib combination therapy. When trametinib is used as part of combination therapy, perform a dermatologic evaluation before initiation, every 2 months on therapy, and for up to 6 months after therapy discontinuation. No trametinib dose adjustment is necessary in patients who develop new primary cutaneous or non-cutaneous malignancies during combination therapy. cuSCC including keratoacanthomas (2%), BCC (3%), and new primary melanoma (less than 1%) occurred in adult patients who received trametinib and dabrafenib combination therapy in clinical trials (n = 1,087). A new primary melanoma occurred in less than 1% of pediatric patients who received trametinib and dabrafenib in 2 clinical trials (n = 166). Noncutaneous malignancies were reported in 1% of patients who received combination therapy in clinical trials. Noncutaneous malignancies may also occur due to dabrafenib-mediated RAS mutation activation or other mechanisms. Monitor patients receiving combination therapy for signs or symptoms of noncutaneous malignancy.
Venous thromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in 2% of adult patients who received trametinib and dabrafenib combination therapy in clinical trials (n = 1,087). Additionally, embolic events occurred in less than 1% of pediatric patients who received trametinib and dabrafenib in 2 clinical trials (n = 166). 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 VTE.
Hyperglycemia has occurred with trametinib and dabrafenib combination therapy. In patients with pre-existing diabetes or hyperglycemia, monitor serum glucose levels at baseline and periodically during therapy; advise patients to report symptoms of severe hyperglycemia. Hyperglycemia was reported in 60% to 71% (grade 3 or 4, 3% to 9%) of adult patients with BRAF V600 mutation-positive tumors who received combination therapy with trametinib and dabrafenib in clinical trials; more intensive hypoglycemic therapy was required in 15% (grade 3 or 4, 2%) of patients with a history of diabetes. Grade 3 or 4 hyperglycemia events occurred in less than 1% of pediatric patients who received trametinib and dabrafenib in 2 clinical trials (n = 166). Hyperglycemia occurred in 65% (grade 3 or 4, 2.2%) of pediatric patients with BRAF mutation-positive refractory or recurrent solid tumors who received combination therapy in a clinical trial (n = 48).
No significant QT prolongation, such as mean QTc interval increase of more than 20 milliseconds (msec), was detected in a study that evaluated 32 patients who received placebo on day 1 and trametinib 2 mg tablets once daily on days 2 to 14 followed by trametinib 3 mg tablets on day 15. In pooled results from clinical trials (n = 264), QTc prolongation greater than 500 msec and a QTc interval increase greater than 60 msec from baseline occurred in 0.8% and 3.8% of patients, respectively, following combination therapy with trametinib plus dabrafenib. Additionally, PR prolongation occurred in this study, specifically an increased PR interval from baseline of 20 msec (90%CI, 13 to 27.4 msec) compared with placebo.
Fatigue was reported in 50% to 59% (grade 3 or higher, 5% or less) of adult patients with BRAF V600 mutation-positive tumors who received trametinib and dabrafenib in clinical trials. Fatigue was reported in 31% of pediatric patients who received trametinib and dabrafenib 2 clinical trials (n = 166). The term fatigue included asthenia and malaise.
Musculoskeletal adverse events including arthralgia (28% or less; grade 3 or 4, 1% or less) and myalgia (24% or less; grade 3 or 4, less than 1%) were reported in adults patients with BRAF mutation-positive tumors who trametinib and dabrafenib combination therapy in clinical trials. Musculoskeletal pain occurred in 36% of pediatric patients who received dabrafenib and trametinib in 2 clinical trials (n = 166). Jaw pain was reported in 1.4% of pediatric patients (median age, 10 years; range, 1 to 17 years) with low-grade glioma who received dabrafenib and trametinib (n = 73) in a clinical trial. The term musculoskeletal pain included back pain, myalgia, extremity pain, arthralgia, bone pain, non-cardiac chest pain, neck pain, and musculoskeletal stiffness.
Sarcoidosis was reported in less than 10% of patients with previously untreated melanoma who received trametinib in combination with dabrafenib in pooled results from 2 randomized trials (n = 559). Additionally, sarcoidosis occurred in less than 1% of patients with BRAF V600 mutation-positive advanced melanoma who received adjuvant therapy with dabrafenib and trametinib (n = 435) in a randomized, placebo-controlled clinical trial.
Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in postmarketing surveillance in patients who received trametinib and dabrafenib therapy; some cases were life-threatening or fatal. Monitor patients for new or worsening skin reactions. Interruption of therapy, a dose reduction, or permanent therapy discontinuation may be necessary in patients who develop intolerable or severe skin toxicity; discontinue therapy in patients who develop SCARs. Serious skin toxicities occurred in less than 1% of adult patients (n = 1,087) and 1.8% of pediatric patients (n = 166) who received trametinib and dabrafenib combination therapy in clinical trials.
Anxiety was reported in 1.4% of pediatric patients (median age, 10 years; range, 1 to 17 years) with low-grade glioma who received trametinib and dabrafenib (n = 73) in a clinical trial.
Weight gain was reported in 15% (grade 3 or higher, 7%) of pediatric patients (median age, 10 years; range, 1 to 17 years) with low-grade glioma who received trametinib and dabrafenib (n = 73) in a clinical trial.
Hypoalbuminemia was reported in 48% or less (grade 3 or 4, 2% or less) of adult patients with BRAF V600 mutation-positive tumors who received trametinib as a single agent or in combination with dabrafenib in clinical trials. Hypoalbuminemia occurred in 48% (grade 3 or 4, 2.1%) of pediatric patients with BRAF mutation-positive refractory or recurrent solid tumors who received combination therapy in a clinical trial (n = 48).
In pediatric patients who received trametinib and dabrafenib in clinical trials, hypernatremia occurred in 27% of patients with BRAF V600 mutation-positive refractory or recurrent solid tumors (n = 48) and increased magnesium level/hypermagnesemia (32%) and increased potassium level/hyperkalemia (15%; grade 3 or higher, 4.2%) occurred in patients with low-grade glioma (n = 73).
Hemophagocytic lymphohistiocytosis (HLH) was reported in postmarketing surveillance in patients who received trametinib and dabrafenib therapy. Hold therapy if HLH is suspected; discontinue therapy and start appropriate management if HLH is confirmed.
Photosensitivity was reported in less than 10% of patients with previously untreated melanoma who received trametinib in combination with dabrafenib in pooled results from 2 randomized trials (n = 559).
Atrioventricular block occurred in less than 10% of patients who received single-agent trametinib and 2.9% or less of patients who received trametinib plus dabrafenib in clinical trials. Bundle-branch block was reported in less than 10% of patients who received trametinib as monotherapy or in combination with dabrafenib in clinical trials. Complete AV block was also reported in postmarketing surveillance of trametinib
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.
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.
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.
Serious rash (e.g., Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS)) has been reported with trametinib and dabrafenib combination therapy; some cases were fatal. Monitor patients for new or worsening skin reactions and secondary infections. Interruption of therapy, a dose reduction, and/or permanent discontinuation may be necessary in patients who develop intolerable or severe skin toxicity.
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 events (e.g., intracranial bleeding and GI bleeding) have been reported in patients who received trametinib as monotherapy or in combination with dabrafenib in clinical trials; some events were fatal. Monitor patients who receive trametinib for signs or symptoms of bleeding. Interruption of therapy, a dose reduction, or permanent therapy discontinuation may be necessary in patients who develop grade 3 or 4 bleeding.
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.
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.
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.
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).
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 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 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.
Patients should discontinue breast-feeding during trametinib therapy and for 4 months after the last dose because of the potential for serious adverse reactions in the breastfed child. It is not known if trametinib is secreted in human milk or if it affects the breastfed child or milk production.
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.
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 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. 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).
-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. 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. 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. 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.
-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. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.
-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. Interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.
For the treatment of BRAF V600E-mutation positive solid tumors:
NOTE: Trametinib is not indicated for treatment of patients with colorectal cancer due to known intrinsic resistance to BRAF inhibition.
-for the treatment of unresectable or metastatic BRAF V600E-mutation positive solid tumors that have progressed after prior treatment and have no satisfactory alternative treatment options, in combination with dabrafenib:
NOTE: Patients should be selected based on the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment. An FDA-approved test for this mutation in solid tumors other than melanoma and NSCLC is not currently available.
Oral dosage (tablets):
NOTE: The recommended dosage of trametinib tablets has not been established in patients who weigh less than 26 kg.
Adults: 2 mg PO once daily in combination with dabrafenib (150 mg PO twice daily) until disease progression. Interruption of therapy, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with selected BRAF V600E mutation-positive tumors (n = 137) were treated with trametinib in 2 single-arm, open-label, clinical trials (BRF117019 and NCI-MATCH) were treated with trametinib plus dabrafenib. Response rates varied widely depending on indication including biliary tract cancer (n = 48; 46%); high grade gliomas (n = 48; 33%) including glioblastoma (n = 32; 25%), anaplastic pleomorphic xanthoastrocytoma (n = 6; 67%), anaplastic astrocytoma (n = 5; 20%), and astroblastoma (n = 2; 100%); low grade gliomas (n = 14; 50%); low grade serous ovarian cancer (n = 5; 80%); and others.
Children and Adolescents 1 to 17 years weighing 26 kg or more: Dosage is based on weight as follows: 26 to 37 kg, give 1 mg PO once daily; 38 to 50 kg, give 1.5 mg PO once daily; and 51 kg or more, give 2 mg PO once daily. Administer in combination with dabrafenib until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Interruption of therapy, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop toxicity. In 2 cohorts of a multicenter, multicohort, open-label clinical trial (Study X2101), pediatric patients with refractory or recurrent BRAF V600E mutation-positive solid tumors were treated with dabrafenib (n = 48), including 34 patients with low-grade glioma and 2 patients with high grade glioma. The objective response rate was 25%, with a duration of at least 6 months for 78% of patients and at least 24 months for 44% of patients.
Oral dosage (oral solution):
Adults: 2 mg PO once daily in combination with dabrafenib (150 mg PO twice daily) until disease progression. Interruption of therapy, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Patients with selected BRAF V600E mutation-positive tumors (n = 137) were treated with trametinib in 2 single-arm, open-label, clinical trials (BRF117019 and NCI-MATCH) were treated with trametinib plus dabrafenib. Response rates varied widely depending on indication including biliary tract cancer (n = 48; 46%); high grade gliomas (n = 48; 33%) including glioblastoma (n = 32; 25%), anaplastic pleomorphic xanthoastrocytoma (n = 6; 67%), anaplastic astrocytoma (n = 5; 20%), and astroblastoma (n = 2; 100%); low grade gliomas (n = 14; 50%); low grade serous ovarian cancer (n = 5; 80%); and others.
Children and Adolescents 1 to 17 years: Dosage is based on weight as follows: 8 kg, give 0.3 mg (6 mL) once daily; 14 to 17 kg, give 0.55 mg (11 mL) once daily; 18 to 21 kg, give 0.7 mg (14 mL) once daily; 22 to 25 kg, give 0.85 mg (17 mL) once daily; 26 to 29 kg, give 0.9 mg (18 mL) once daily; 30 to 33 kg, give 1 mg (20 mL) once daily; 34 to 37 kg, give 1.15 mg (23 mL) once daily; 38 to 41 kg, give 1.25 mg (25 mL) once daily; 42 to 45 kg, give 1.4 mg (28 mL) once daily; 46 to 50 kg, give 1.6 mg (32 mL) once daily; and 51 kg or more, give 2 mg (40 mL) once daily. Administer in combination with dabrafenib until disease progression. Interruption of therapy, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In 2 cohorts of a multicenter, multicohort, open-label clinical trial (Study X2101), pediatric patients with refractory or recurrent BRAF V600E mutation-positive solid tumors were treated with dabrafenib (n = 48), including 34 patients with low-grade glioma and 2 patients with high grade glioma. The objective response rate was 25%, with a duration of at least 6 months for 78% of patients and at least 24 months for 44% of patients.
For the treatment of BRAF V600E mutation-positive malignant glioma:
NOTE: Trametinib is designated as an orphan drug by the FDA for this indication.
-for the treatment of BRAF V600E mutation-positive low-grade gliomas (LGG) in patients who require systemic therapy, in combination with dabrafenib:
NOTE: Patients should be selected based on the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment. An FDA-approved test for this mutation in LGG is not currently available.
Oral dosage (tablets):
NOTE: A recommended dosage of trametinib tablets has not been established in pediatric patients who weigh less than 26 kg.
Children and Adolescents: Dosage is based on weight as follows: 26 to 37 kg, give 1 mg PO once daily; 38 to 50 kg, give 1.5 mg PO once daily; and 51 kg or more, give 2 mg PO once daily. Administer in combination with dabrafenib until disease progression. Interruption of therapy, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop toxicity. The primary endpoint of overall response rate (evaluated by an independent review committee) was significantly improved (47% vs. 11%; risk ratio = 4.31; 95% CI, 1.7 to 11.2; p-value less than 0.001) in pediatric patients aged 1 to less than 18 years with BRAF V600E mutation-positive LGG who received dabrafenib plus trametinib (n = 73) compared with carboplatin plus vincristine (n = 37) as first systemic therapy in a randomized (2:1), phase 2 (TADPOLE) trial. The complete response rate was 3% in each treatment arm. The median duration of response was 20.3 months in the dabrafenib plus trametinib arm and not estimable in the carboplatin plus vincristine arm. At a median follow-up time of 18.9 (range, 7.9 to 35.4) months, the median progression-free survival time was significantly improved in patients who received dabrafenib plus trametinib compared with carboplatin plus vincristine (20.1 months vs. 7.4 months; hazard ratio = 0.31; 95% CI, 0.17 to 0.55).
Oral dosage (oral solution):
Children and Adolescents: Dosage is based on weight as follows: 8 kg, give 0.3 mg (6 mL) once daily; 9 to 10 kg, give 0.35 mg (7 mL) once daily; 11 kg, give 0.4 mg (8 mL) once daily; 12 to 13 kg, give 0.45 mg (9 mL) once daily; 14 to 17 kg, give 0.55 mg (11 mL) once daily; 18 to 21 kg, give 0.7 mg (14 mL) once daily; 22 to 25 kg, give 0.85 mg (17 mL) once daily; 26 to 29 kg, give 0.9 mg (18 mL) once daily; 30 to 33 kg, give 1 mg (20 mL) once daily; 34 to 37 kg, give 1.15 mg (23 mL) once daily; 38 to 41 kg, give 1.25 mg (25 mL) once daily; 42 to 45 kg, give 1.4 mg (28 mL) once daily; 46 to 50 kg, give 1.6 mg (32 mL) once daily; and 51 kg or more, give 2 mg (40 mL) once daily. Administer in combination with dabrafenib until disease progression. Interruption of therapy, a dosage reduction, or discontinuation of therapy may be necessary in patients who develop toxicity. The primary endpoint of overall response rate (evaluated by an independent review committee) was significantly improved (47% vs. 11%; risk ratio = 4.31; 95% CI, 1.7 to 11.2; p-value less than 0.001) in pediatric patients aged 1 to less than 18 years with BRAF V600E mutation-positive LGG who received dabrafenib plus trametinib (n = 73) compared with carboplatin plus vincristine (n = 37) as first systemic therapy in a randomized (2:1), phase 2 (TADPOLE) trial. The complete response rate was 3% in each treatment arm. The median duration of response was 20.3 months in the dabrafenib plus trametinib arm and not estimable in the carboplatin plus vincristine arm. At a median follow-up time of 18.9 (range, 7.9 to 35.4) months, the median progression-free survival time was significantly improved in patients who received dabrafenib plus trametinib compared with carboplatin plus vincristine (20.1 months vs. 7.4 months; hazard ratio = 0.31; 95% CI, 0.17, 0.55).
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity:
Recommended Dosage Reductions
Tablets
Starting dose of 1 mg once daily: 0.5 mg once daily.
Starting dose of 1.5 mg once daily: first, 1 mg once daily; second, 0.5 mg once daily*.
Starting dose of 2 mg once daily: first, 1.5 mg once daily; second, 1 mg once daily*.
*Permanently discontinue therapy if unable to tolerate a maximum of 2 dose reductions.
Oral Solution
Starting dose of 0.3 mg (6 mL) once daily: first, 5 mL once daily; second, 3 mL once daily.
Starting dose of 0.35 mg (7 mL) once daily: first, 5 mL once daily; second, 4 mL once daily.
Starting dose of 0.4 mg (8 mL) once daily: first, 6 mL once daily; second, 4 mL once daily.
Starting dose of 0.45 mg (9 mL) once daily: first, 7 mL once daily; second, 5 mL once daily.
Starting dose of 0.55 mg (11 mL) once daily: first, 8 mL once daily; second, 6 mL once daily.
Starting dose of 0.7 mg (14 mL) once daily: first, 11 mL once daily; second, 7 mL once daily.
Starting dose of 0.85 mg (17 mL) once daily: first, 13 mL once daily; second, 9 mL once daily.
Starting dose of 0.9 mg (18 mL) once daily: first, 14 mL once daily; second, 9 mL once daily.
Starting dose of 1 mg (20 mL) once daily: first, 15 mL once daily; second, 10 mL once daily.
Starting dose of 1.15 mg (23 mL) once daily: first, 17 mL once daily; second, 12 mL once daily.
Starting dose of 1.25 mg (25 mL) once daily: first, 19 mL once daily; second, 13 mL once daily.
Starting dose of 1.4 mg (28 mL) once daily: first, 21 mL once daily; second, 14 mL once daily.
Starting dose of 1.6 mg (32 mL) once daily: first, 24 mL once daily; second, 16 mL once daily.
Starting dose of 2 mg (40 mL) once daily: first, 30 mL once daily; second, 20 mL once daily.
*Permanently discontinue therapy if unable to tolerate a maximum of 2 dose reductions.
Bleeding
Grade 3 bleeding event: Hold trametinib until toxicity improves, then resume therapy at a reduced dose level. If toxicity does not improve, permanently discontinue trametinib.
Grade 4 bleeding event: Permanently discontinue trametinib.
Cardiac Toxicity
Asymptomatic cardiac toxicity and an absolute decrease in LVEF of 10% or greater from baseline and is below institutional lower limits of normal (LLN) from pretreatment value: Hold trametinib for up to 4 weeks. If the LVEF is improved within 4 weeks, resume therapy at a reduced dose level. If the LVEF does not improve to normal within 4 weeks, permanently discontinue trametinib.
Symptomatic congestive heart failure or an absolute decrease in LVEF of greater than 20% from baseline and is below institutional LLN: Permanently discontinue trametinib.
Skin Toxicity
Intolerable grade 2 or any grade 3 or 4 toxicity: Hold trametinib for up to 3 weeks. If the rash is improved within 3 weeks, resume therapy at a reduced dose level. If the rash does not improve within 3 weeks, permanently discontinue trametinib.
Severe cutaneous adverse reactions (SCARs): Permanently discontinue trametinib.
Febrile Reactions
Temperature of 100.4 to 104 degrees F (or first symptoms in case of recurrence): Hold trametinib if used as monotherapy and both dabrafenib and trametinib if used in combination until fever resolves for at least 24 hours; therapy may be resumed at the same dose or at a reduced dose level.
Temperature greater than 104 degrees F or fever complicated by rigors, hypotension, dehydration, or renal failure: Hold therapy until febrile reactions resolve for at least 24 hours, then resume trametinib at a reduced dose level or permanently discontinue therapy.
Pulmonary Toxicity
Interstitial lung disease / pneumonitis: Permanently discontinue trametinib.
Malignancy
New Primary Cutaneous or Non-Cutaneous Malignancy: Dose adjustment not required.
Ocular Toxicity
Retinal pigment epithelial detachment (RPED): Hold trametinib for up to 3 weeks. If the RPED improves within 3 weeks, resume therapy at the same or a reduced dose level. If the RPED does not improve within 3 weeks, discontinue or resume trametinib at a lower dose. Do not dose below trametinib 1 mg/day.
Retinal vein occlusion: Permanently discontinue trametinib.
Uveitis: Dose adjustment not required.
Thromboembolism
Uncomplicated deep vein thrombosis (DVT) or pulmonary embolism (PE): Hold trametinib for up to 3 weeks. If the thromboembolism improves to grade 1 or less within 3 weeks, resume therapy at a reduced dose level. If the thromboembolism does not improve to at least grade 1 within 3 weeks, permanently discontinue trametinib.
Life-threatening PE: Permanently discontinue trametinib.
Other Toxicity
Intolerable grade 2 or any grade 3 toxicity: Hold trametinib therapy. If the toxicity improves to grade 1 or less, resume therapy at a reduced dose level. If the toxicity does not improve to at least grade 1, permanently discontinue therapy.
Grade 4 toxicity, first occurrence: Hold trametinib therapy. When toxicity resolves to grade 1 or less, resume therapy at a reduced dose level or permanently discontinue trametinib.
Recurrent grade 4 toxicity: Permanently discontinue trametinib.
Maximum Dosage Limits:
-Adults
2 mg PO once daily.
-Geriatric
2 mg PO once daily.
-Adolescents
Tablets:
Less than 26 kg: Safety and efficacy have not been established.
26 kg to 37 kg: 1 mg PO once daily.
38 kg to 50 kg: 1.5 mg PO once daily.
51 kg or more: 2 mg PO once daily.
Oral Solution:
26 to 29 kg: 0.9 mg once daily.
30 to 33 kg: 1 mg once daily.
34 to 37 kg: 1.15 mg once daily.
38 to 41 kg: 1.25 mg once daily.
42 to 45 kg: 1.4 mg once daily.
46 to 50 kg: 1.6 mg once daily.
51 kg or more: 2 mg once daily.
-Children
Tablets:
Less than 26 kg: Safety and efficacy have not been established.
26 kg to 37 kg: 1 mg PO once daily.
38 kg to 50 kg: 1.5 mg PO once daily.
51 kg or more: 2 mg PO once daily.
Oral Solution:
8 kg: 0.3 mg once daily.
9 to 10 kg: 0.35 mg once daily.
11 kg: 0.4 mg once daily.
12 to 13 kg: 0.45 mg once daily.
14 to 17 kg: 0.55 mg once daily.
18 to 21 kg: 0.7 mg once daily.
22 to 25 kg: 0.85 mg once daily.
26 to 29 kg: 0.9 mg once daily.
30 to 33 kg: 1 mg once daily.
34 to 37 kg: 1.15 mg once daily.
38 to 41 kg: 1.25 mg once daily.
42 to 45 kg: 1.4 mg once daily.
46 to 50 kg: 1.6 mg once daily.
51 kg or more: 2 mg once daily.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
-Mild hepatic impairment (bilirubin at the upper limit of normal (ULN) or less and AST greater than ULN; OR bilirubin 1.1 to 1.5 times ULN and any AST): No dose adjustment necessary.
-Moderate to severe hepatic impairment (bilirubin 1.6 to 10 times ULN and any AST): A recommended dose of trametinib has not been established. Consider the risks versus benefits of treatment.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Chloroquine: (Moderate) Concurrent use of chloroquine and trametinib is not recommended as there is an increased risk of retinal toxicity.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
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.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
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.
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.
Induction of EGFR-mediated MAPK pathway reactivation has been identified as a mechanism of intrinsic resistance to BRAF inhibitors in the setting of BRAF-mutant colorectal cancer.
Trametinib is administered orally. It is highly bound to plasma proteins (97.4%) and has an apparent volume of distribution of 214 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/hour. 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 (less than 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: None
In vitro, trametinib is a substrate of P-glycoprotein (P-gp) and bile salt export pump (BSEP) and an inhibitor of CYP2C8.
-Route-Specific Pharmacokinetics
Oral Route
The mean absolute oral bioavailability is 72% for trametinib tablets and 81% for trametinib oral solution. 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 tablets exhibit 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.
Effects of food: Administering trametinib tablets 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. For both tablets and oral solution, take the trametinib dose at least 1 hour before or at least 2 hours after a meal.
-Special Populations
Hepatic Impairment
Hepatic impairment had no clinically significant impact on trametinib exposure or apparent drug clearance compared with patients with normal hepatic function.
Renal Impairment
Renal impairment (eGFR 15 to 89 mL/minute/1.73 m2) did not have a clinically important effect on the exposure of trametinib.
Pediatrics
Following weight-based trametinib dosing (range, 6 to 156 kg), the pharmacokinetic values of trametinib in pediatric patients aged 1 to 17 years with glioma or other solid tumors (n = 244) were within the range of those observed in adults.
Geriatric
Age (range, 18 to 93 years) had no clinically significant impact on trametinib exposure in a population pharmacokinetic analysis.
Gender Differences
Gender had no clinically significant impact on trametinib exposure in a population pharmacokinetic analysis.
Obesity
Body weight (range, 36 to 170 kg) had no clinically significant impact on trametinib exposure in a population pharmacokinetic analysis.