Trametinib

Trametinib
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]

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Black Box Warning

ConditionName: See full prescribing information for complete Boxed Warning. ConditionName: Content

Overview

Trametinib is a {{{drugClass}}} that is FDA approved for the treatment of {{{indication}}}. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Metastatic melanoma

• MEKINIST® as a single agent is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test .

• MEKINIST, in combination with dabrafenib, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate [see Clinical Studies (14.1)]. Improvement in disease-related symptoms or overall survival has not been demonstrated for MEKINIST in combination with dabrafenib.

• Limitation of use: MEKINIST as a single agent is not indicated for treatment of patients who have received prior BRAF-inhibitor therapy

Patient Selection

• Select patients for treatment of unresectable or metastatic melanoma with MEKINIST based on presence of BRAF V600E or V600K mutation in tumor specimens [see Clinical Studies (14.1)]. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at: HTTP://WWW.FDA.GOV/COMPANIONDIAGNOSTICS.

Recommended Dosing

• The recommended dosage regimens of MEKINIST are:

• 2 mg orally taken once daily as a single agent
• 2 mg orally taken once daily in combination with dabrafenib 150 mg orally taken twice daily

• Continue treatment until disease progression or unacceptable toxicity occurs. Take MEKINIST as a single agent, or MEKINIST in combination with dabrafenib, at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)]. Do not take a missed dose of MEKINIST within 12 hours of the next dose of MEKINIST. When administered in combination with dabrafenib, take the once daily dose of MEKINIST at the same time each day with either the morning dose or the evening dose of dabrafenib.

Dose Modifications

• For New Primary Cutaneous Malignancies: No dose modifications are required.

• For New Primary Non-Cutaneous Malignancies: No dose modifications are required for MEKINIST. If used in combination with dabrafenib, permanently discontinue dabrafenib in patients who develop RAS mutation-positive non-cutaneous malignancies.

TABLE02

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Trametinib in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Trametinib in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Trametinib in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Trametinib in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Trametinib in pediatric patients.

Contraindications

• None.

Warnings

ConditionName: See full prescribing information for complete Boxed Warning. ConditionName: Content

• Review the Full Prescribing Information for dabrafenib prior to initiation of MEKINIST in combination with dabrafenib. The following serious adverse reactions of dabrafenib as a single agent, which may occur when MEKINIST is used in combination with dabrafenib, are not described in the Full Prescribing Information for MEKINIST:

• Tumor promotion in patients with BRAF wild-type melanoma
• Hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency

New Primary Malignancies

• New primary malignancies, cutaneous and non-cutaneous, can occur when MEKINIST is used in combination with dabrafenib and with dabrafenib as a single agent [refer to Full Prescribing Information for dabrafenib].

Cutaneous Malignancies:

• In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving MEKINIST in combination with dabrafenib, with an incidence of 9% (5/55) in patients receiving MEKINIST in combination with dabrafenib compared with 2% (1/53) in patients receiving dabrafenib as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving MEKINIST in combination with dabrafenib and was 197 days for the patient receiving dabrafenib as a single agent.

• Cutaneous squamous cell carcinomas (SCC), including keratoacanthoma, occurred in 7% of patients receiving MEKINIST in combination with dabrafenib and 19% of patients receiving dabrafenib as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving dabrafenib as a single agent.

• New primary melanoma occurred in 2% (1/53) of patients receiving dabrafenib and in none of the 55 patients receiving MEKINIST in combination with dabrafenib.

• Perform dermatologic evaluations prior to initiation of MEKINIST in combination with dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of the combination. No dose modifications of MEKINIST or dabrafenib are recommended in patients who develop new primary cutaneous malignancies.

Non-Cutaneous Malignancies:

• Based on its mechanism of action, dabrafenib may promote growth and development of malignancies with activation of RAS through mutation or other mechanisms [refer to the Full Prescribing Information for dabrafenib]. In patients receiving MEKINIST in combination with dabrafenib, four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. If used in combination with dabrafenib, no dose modification is required for MEKINIST in patients who develop non-cutaneous malignancies. Permanently discontinue dabrafenib in patients who develop RAS mutation-positive non-cutaneous malignancies.

Hemorrhage

• Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when MEKINIST is used in combination with dabrafenib.

• In Trial 2, treatment with MEKINIST in combination with dabrafenib resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with MEKINIST in combination with dabrafenib compared with 2% (1/53) of patients treated with dabrafenib as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with MEKINIST in combination with dabrafenib compared with none of the 53 patients treated with dabrafenib as a single agent. Intracranial hemorrhage was fatal in two (4%) patients receiving the combination of MEKINIST and dabrafenib.

• Permanently discontinue MEKINIST, and also permanently discontinue dabrafenib if administered in combination, for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold dabrafenib for Grade 3 hemorrhagic events; if improved resume at a lower dose level.

Venous Thromboembolism

• Venous thromboembolism can occur when MEKINIST is used in combination with dabrafenib.

• In Trial 2, treatment with MEKINIST in combination with dabrafenib resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with MEKINIST in combination with dabrafenib compared with none of the 53 patients treated with dabrafenib as a single agent. Pulmonary embolism was fatal in one (2%) patient receiving the combination of MEKINIST and dabrafenib.

• Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue MEKINIST and dabrafenib for life threatening PE. Withhold MEKINIST for uncomplicated DVT and PE for up to 3 weeks; if improved, MEKINIST may be resumed at a lower dose level. Do not modify the dose of dabrafenib [see Dosage and Administration (2.3)].

Cardiomyopathy

• Cardiomyopathy can occur when MEKINIST is administered as a single agent or when used in combination with dabrafenib.

• In Trial 1, cardiomyopathy (defined as cardiac failure, left ventricular dysfunction, or decreased left ventricular ejection fraction [LVEF]) occurred in 7% (14/211) of patients treated with MEKINIST; no chemotherapy-treated patients in Trial 1 developed cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with MEKINIST in combination with dabrafenib and in none of patients treated with dabrafenib as a single agent. The median time to onset of cardiomyopathy in patients treated with MEKINIST was 63 days (range: 16 to 156 days) for Trial 1 and 86 days (range: 27 to 253 days) for Trial 2.

• Cardiomyopathy was identified within the first month of treatment with MEKINIST in 5 of 14 patients in Trial 1 and in 2 of 5 patients in Trial 2. Development of cardiomyopathy resulted in dose reduction (7/211) and/or discontinuation (4/211) of study drug in Trial 1, and resulted in dose reduction (4/55) and/or dose interruption (1/55) in Trial 2. Cardiomyopathy resolved in 10 of 14 (71%) patients in Trial 1 and in all 5 patients in Trial 2.

• Across clinical trials of MEKINIST administered either as a single agent (N = 329), or in combination with dabrafenib (N = 202), 11% and 8% of patients, respectively, developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Five percent and 2% in single-agent and in combination trials, respectively, demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline.

• Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of MEKINIST as a single agent and in combination with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold treatment with MEKINIST for up to 4 weeks if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold dabrafenib. Resume dabrafenib at the same dose upon recovery of cardiac function [see Dosage and Administration (2.3)].

Ocular Toxicities

Retinal Vein Occlusion (RVO):

• Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma.

• Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with dabrafenib, do not modify dabrafenib dose [see Dosage and Administration (2.3)].

Retinal Pigment Epithelial Detachment (RPED):

• Retinal pigment epithelial detachment (RPED) can occur when MEKINIST is administered as a single agent or when used in combination with dabrafenib.

• In Trial 1 and Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment.

• In Trial 1, one patient (0.5%) receiving MEKINIST developed RPED and no cases of RPED were identified in chemotherapy-treated patients. Across all clinical trials of MEKINIST, the incidence of RPED was 0.8% (14/1,749). Retinal detachments were often bilateral and multifocal, occurring in the macular region of the retina. RPED led to reduction in visual acuity that resolved after a median of 11.5 days (range: 3 to 71 days) following the interruption of dosing with MEKINIST, although Ocular Coherence Tomography (OCT) abnormalities persisted beyond a month in at least several cases.

• In Trial 2, one patient (2%) receiving MEKINIST in combination with dabrafenib developed RPED.

• Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. If MEKINIST is used in combination with dabrafenib, do not modify the dose of dabrafenib

Uveitis and Iritis:

• Uveitis and iritis can occur when MEKINIST is used in combination with dabrafenib and with dabrafenib as a single agent [refer to Full Prescribing Information for dabrafenib].

• Uveitis occurred in 1% (2/202) of patients treated with MEKINIST in combination with dabrafenib.

• Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold dabrafenib for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If not improved, permanently discontinue dabrafenib. If MEKINIST is used in combination with dabrafenib, do not modify the dose of MEKINIST [see Dosage and Administration (2.3)].

Interstitial Lung Disease

• In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days).

• Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis.If MEKINIST is used in combination with dabrafenib, do not modify the dose of dabrafenib [see Dosage and Administration (2.3)].

Serious Febrile Reactions

• Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when MEKINIST is used in combination with dabrafenib and with dabrafenib as a single agent [refer to Full Prescribing Information for dabrafenib].

• The incidence and severity of pyrexia are increased when MEKINIST is used in combination with dabrafenib compared with dabrafenib as a single agent [see Adverse Reactions (6.1)].

• In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with MEKINIST in combination with dabrafenib and 26% (14/53) in patients treated with dabrafenib as a single agent. Serious febrile reactions and fever of any severity accompanied by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with MEKINIST in combination with dabrafenib compared with 2% (1/53) of patients treated with dabrafenib as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with MEKINIST in combination with dabrafenib, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with dabrafenib as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with dabrafenib as a single agent.

• Across clinical trials of MEKINIST administered in combination with dabrafenib (N = 202), the incidence of pyrexia was 57% (116/202).

• Withhold dabrafenib for fever of 101.3ºF or higher. Withhold MEKINIST for fever higher than 104ºF. Withhold dabrafenib and MEKINIST for any serious febrile reaction or fever accompanied by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions [see Dosage and Administration (2.3)]. Prophylaxis with antipyretics may be required when resuming MEKINIST or dabrafenib.

Serious Skin Toxicity

• Serious skin toxicity can occur when MEKINIST is administered as a single agent or when used in combination with dabrafenib. Serious skin toxicity can also occur with dabrafenib as a single agent[refer to Full Prescribing Information for dabrafenib].

• In Trial 1, the overall incidence of any skin toxicity, the most common of which were rash, dermatitis acneiform rash, palmar-plantar erythrodysesthesia syndrome, and erythema, was 87% in patients treated with MEKINIST and 13% in chemotherapy-treated patients. Severe skin toxicity occurred in 12% of patients treated with MEKINIST. Skin toxicity requiring hospitalization occurred in 6% of patients treated with MEKINIST, most commonly for secondary infections of the skin requiring intravenous antibiotics or severe skin toxicity without secondary infection. In comparison, no patients treated with chemotherapy required hospitalization for severe skin toxicity or infections of the skin. The median time to onset of skin toxicity in patients treated with MEKINIST was 15 days (range: 1 to 221 days) and median time to resolution of skin toxicity was 48 days (range: 1 to 282 days). Reductions in the dose of MEKINIST were required in 12% and permanent discontinuation of MEKINIST was required in 1% of patients with skin toxicity.

• In Trial 2, the incidence of any skin toxicity was similar for patients receiving MEKINIST in combination with dabrafenib (65% [36/55]) compared with patients receiving dabrafenib as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with MEKINIST in combination with dabrafenib was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of MEKINIST or dabrafenib for skin toxicity.

• Across clinical trials of MEKINIST administered in combination with dabrafenib (n = 202), severe skin toxicity and secondary infection of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with MEKINIST in combination with dabrafenib.

• Withhold MEKINIST, and dabrafenib if used in combination, for intolerable or severe skin toxicity. MEKINIST and dabrafenib may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks [see Dosage and Administration (2.3)].

Hyperglycemia

• Hyperglycemia can occur when MEKINIST is used in combination with dabrafenib and with dabrafenib as a single agent. Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycemic agent therapy occurred with dabrafenib as a single agent [refer to Full Prescribing Information for dabrafenib].

• In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with MEKINIST in combination with dabrafenib compared with 2% (1/53) in patients treated with dabrafenib as a single agent.

• Monitor serum glucose levels as clinically appropriate during treatment with MEKINIST in combination with dabrafenib in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia.

Embryofetal Toxicity

• Based on its mechanism of action, MEKINIST can cause fetal harm when administered to a pregnant woman. MEKINIST was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus .

• Advise female patients of reproductive potential to use highly effective contraception during treatment with MEKINIST and for 4 months after treatment. Advise patients to use a highly effective non-hormonal method of contraception when MEKINIST is administered in combination with dabrafenib, since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST

• The following adverse reactions are discussed in greater detail in another section of the label:

• New Primary Malignancies
• Hemorrhage
• Venous Thromboembolism
• Cardiomyopathy
• Ocular Toxicities
• Interstitial Lung Disease
• Serious Febrile Reactions
• Serious Skin Toxicity
• Hyperglycemia

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

• The data described in the Warnings and Precautions section and below reflect exposure to MEKINIST as a single agent and in combination with dabrafenib. MEKINIST as a single agent was evaluated in 329 patients including 107 (33%) exposed for greater than or equal to 6 months and 30 (9%) exposed for greater than or equal to one year. MEKINIST as a single agent was studied in open-label, single-arm trials (N = 118) or in an open-label, randomized, active-controlled trial (N = 211). The median age was 54 years, 60% were male, >99% were white, and all patients had metastatic melanoma. All patients received 2 mg once-daily doses of MEKINIST. The incidence of RPED and RVO are obtained from the 1,749 patients from all clinical trials with MEKINIST.

• The safety of MEKINIST in combination with dabrafenib was evaluated in Trial 2 and other trials consisting of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received MEKINIST 2 mg orally once daily in combination with dabrafenib 150 mg orally twice daily until disease progression or unacceptable toxicity. Among these 202 patients, 68 (34%) were exposed to MEKINIST and 66 (33%) were exposed to dabrafenib for greater than 6 to 12 months while 36 (18%) were exposed to MEKINIST and 40 (20%) were exposed to dabrafenib for greater than one year. The median age was 54 years, 57% were male and >99% were white.

• Table 3 presents adverse reactions identified from analyses of Trial 1, a randomized, open-label trial of patients with BRAF V600E or V600K mutation-positive melanoma receiving MEKINIST (N = 211) 2 mg orally once daily or chemotherapy (N = 99) (either dacarbazine 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks) [see Clinical Studies (14.1)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current evidence of Class II or greater congestive heart failure (New York Heart Association) were excluded from Trial 1. The median duration of treatment with MEKINIST was 4.3 months. In Trial 1, 9% of patients receiving MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication. The most common adverse reactions resulting in permanent discontinuation of MEKINIST were decreased left ventricular ejection fraction (LVEF), pneumonitis, renal failure, diarrhea, and rash. Adverse reactions led to dose reductions in 27% of patients treated with MEKINIST. Rash and decreased LVEF were the most common reasons cited for dose reductions of MEKINIST.

table03

• Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving MEKINIST 2 mg once daily in combination with dabrafenib 150 mg twice daily (N = 55), MEKINIST 1 mg once daily in combination with dabrafenib 150 mg twice daily (N = 54), and dabrafenib as a single agent 150 mg twice daily (N = 53) [see Clinical Studies (14.1)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history of RVO, or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both MEKINIST (2-mg once-daily treatment group) and dabrafenib when used in combination, 10.6 months for both MEKINIST (1-mg once-daily treatment group) and dabrafenib when used in combination, and 6.1 months for dabrafenib as a single agent.

• In Trial 2, 13% of patients receiving MEKINIST in combination with dabrafenib at the recommended dose experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with MEKINIST in combination with dabrafenib. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions, and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of MEKINIST and dabrafenib when used in combination.

table04

• QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with MEKINIST in combination with dabrafenib and in 2% (1/53) of patients treated with dabrafenib as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with MEKINIST in combination with dabrafenib and 2% (1/53) of patients treated with dabrafenib as a single agent.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Trametinib Clinical Trials Experience in the drug label.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Trametinib in the drug label.

Drug Interactions

• No formal clinical trials have been conducted to evaluate human cytochrome P450 (CYP) enzyme-mediated drug interactions with trametinib .

Dabrafenib

• Coadministration of MEKINIST 2 mg once daily and dabrafenib 150 mg twice daily resulted in no clinically relevant pharmacokinetic drug interactions .

• Refer to the Full Prescribing Information for dabrafenib for further details on the drug interaction potential of dabrafenib. Avoid concurrent administration of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 with dabrafenib. If concomitant use of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers. Concomitant use of dabrafenib with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these agents. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category D

Risk Summary:

• MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Animal Data:

• In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss.

• In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in post-implantation loss, including total loss of pregnancy, compared with control animals.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trametinib in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Trametinib during labor and delivery.

Nursing Mothers

• It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from MEKINIST, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use

• The safety and effectiveness of MEKINIST as a single agent or in combination with dabrafenib have not been established in pediatric patients.

• Adequate juvenile animal studies using trametinib have not been completed. In a repeat-dose toxicity study in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose of dabrafenib based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC.

Geriatic Use

• Clinical trials of MEKINIST as a single agent did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In Trial 1, 49 patients (23%) were 65 years of age and older, and 9 patients (4%) were 75 years of age and older.

• Across all clinical trials of MEKINIST administered in combination with dabrafenib, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older.

Gender

There is no FDA guidance on the use of Trametinib with respect to specific gender populations.

Race

There is no FDA guidance on the use of Trametinib with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Trametinib in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Trametinib in patients with hepatic impairment.

Females of Reproductive Potential and Males

Contraception:

Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with dabrafenib, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)].

Infertility:

Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)].

Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with dabrafenib.

Immunocompromised Patients

There is no FDA guidance one the use of Trametinib in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Trametinib in the drug label.

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Trametinib in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Trametinib in the drug label.

Pharmacology

There is limited information regarding Trametinib Pharmacology in the drug label.

Mechanism of Action

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Trametinib in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Trametinib in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Trametinib in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Trametinib in the drug label.

How Supplied

Storage

There is limited information regarding Trametinib Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Trametinib in the drug label.

Precautions with Alcohol

• Alcohol-Trametinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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