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

• Trametinib ® 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 .

• Trametinib , 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 . Improvement in disease-related symptoms or overall survival has not been demonstrated for Trametinib in combination with dabrafenib.

• Limitation of use: Trametinib 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 Trametinib based on presence of BRAF V600E or V600K mutation in tumor specimens [see Clinical Studies (14.1)].

Recommended Dosing

• The recommended dosage regimens of Trametinib 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 Trametinib as a single agent, or Trametinib in combination with dabrafenib, at least 1 hour before or 2 hours after a meal . Do not take a missed dose of Trametinib within 12 hours of the next dose of Trametinib . When administered in combination with dabrafenib, take the once daily dose of Trametinib 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 Trametinib . If used in combination with dabrafenib, permanently discontinue dabrafenib in patients who develop RAS mutation-positive non-cutaneous malignancies.

File:Trametinib 02.png

This image is provided by the National Library of Medicine.

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

• 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 Trametinib 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 Trametinib in combination with dabrafenib, with an incidence of 9% (5/55) in patients receiving Trametinib 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 Trametinib 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 Trametinib 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 Trametinib in combination with dabrafenib.

• Perform dermatologic evaluations prior to initiation of Trametinib 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 Trametinib 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 Trametinib 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 Trametinib 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 Trametinib is used in combination with dabrafenib.

• In Trial 2, treatment with Trametinib in combination with dabrafenib resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with Trametinib 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 Trametinib 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 Trametinib and dabrafenib.

• Permanently discontinue Trametinib , 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 Trametinib 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 Trametinib is used in combination with dabrafenib.

• In Trial 2, treatment with Trametinib 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 Trametinib 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 Trametinib 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 Trametinib and dabrafenib for life threatening PE. Withhold Trametinib for uncomplicated DVT and PE for up to 3 weeks; if improved, Trametinib 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 Trametinib 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 Trametinib ; no chemotherapy-treated patients in Trial 1 developed cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with Trametinib 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 Trametinib 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 Trametinib 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 Trametinib 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 Trametinib 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 Trametinib 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 Trametinib 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 Trametinib , 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 Trametinib in patients with documented RVO. If Trametinib 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 Trametinib 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 Trametinib developed RPED and no cases of RPED were identified in chemotherapy-treated patients. Across all clinical trials of Trametinib , 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 Trametinib , although Ocular Coherence Tomography (OCT) abnormalities persisted beyond a month in at least several cases.

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

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

Uveitis and Iritis:

• Uveitis and iritis can occur when Trametinib 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 Trametinib 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 Trametinib is used in combination with dabrafenib, do not modify the dose of Trametinib [see Dosage and Administration (2.3)].

Interstitial Lung Disease

• In clinical trials of Trametinib (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with Trametinib 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 Trametinib in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue Trametinib for patients diagnosed with treatment-related ILD or pneumonitis.If Trametinib is used in combination with dabrafenib, do not modify the dose of dabrafenib .

Serious Febrile Reactions

• Serious febrile reactions and fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure, can occur when Trametinib 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 Trametinib 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 Trametinib 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 Trametinib 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 Trametinib 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 Trametinib 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 Trametinib for fever higher than 104ºF. Withhold dabrafenib and Trametinib 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 Trametinib or dabrafenib.

Serious Skin Toxicity

• Serious skin toxicity can occur when Trametinib 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 Trametinib and 13% in chemotherapy-treated patients. Severe skin toxicity occurred in 12% of patients treated with Trametinib . Skin toxicity requiring hospitalization occurred in 6% of patients treated with Trametinib , 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 Trametinib 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 Trametinib were required in 12% and permanent discontinuation of Trametinib was required in 1% of patients with skin toxicity.

• In Trial 2, the incidence of any skin toxicity was similar for patients receiving Trametinib 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 Trametinib 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 Trametinib or dabrafenib for skin toxicity.

• Across clinical trials of Trametinib 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 Trametinib in combination with dabrafenib.

• Withhold Trametinib , and dabrafenib if used in combination, for intolerable or severe skin toxicity. Trametinib 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 Trametinib 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 Trametinib 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 Trametinib 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, Trametinib 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 a fetus .

• Advise female patients of reproductive potential to use highly effective contraception during treatment with Trametinib and for 4 months after treatment. Advise patients to use a highly effective non-hormonal method of contraception when Trametinib 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 Trametinib

• 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 Trametinib as a single agent and in combination with dabrafenib. Trametinib 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. Trametinib 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 Trametinib . The incidence of RPED and RVO are obtained from the 1,749 patients from all clinical trials with Trametinib .

• The safety of Trametinib 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 Trametinib 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 Trametinib and 66 (33%) were exposed to dabrafenib for greater than 6 to 12 months while 36 (18%) were exposed to Trametinib 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 Trametinib (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 Trametinib was 4.3 months. In Trial 1, 9% of patients receiving Trametinib experienced adverse reactions resulting in permanent discontinuation of trial medication. The most common adverse reactions resulting in permanent discontinuation of Trametinib 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 Trametinib . Rash and decreased LVEF were the most common reasons cited for dose reductions of Trametinib .

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This image is provided by the National Library of Medicine.

• 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 Trametinib 2 mg once daily in combination with dabrafenib 150 mg twice daily (N = 55), Trametinib 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 Trametinib (2-mg once-daily treatment group) and dabrafenib when used in combination, 10.6 months for both Trametinib (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 Trametinib 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 Trametinib 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 Trametinib and dabrafenib when used in combination.

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This image is provided by the National Library of Medicine.

• QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with Trametinib 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 Trametinib 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 Trametinib 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:

• Trametinib 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 Trametinib , 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 Trametinib 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 Trametinib 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 Trametinib 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

• No formal clinical trial has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild or moderate renal impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of Trametinib has not been established in patients with severe renal impairment.

Hepatic Impairment

• No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis
• The appropriate dose of Trametinib has not been established in patients with moderate or severe hepatic impairment.

Females of Reproductive Potential and Males

Contraception:

• Females: Trametinib 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 Trametinib . When Trametinib 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 Trametinib .

Infertility:

• Females: Trametinib may impair fertility in female patients .

• 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 Trametinib 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

• There were no reported cases of overdosage with Trametinib . The highest doses of Trametinib evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with Trametinib .

Pharmacology

File:Trametinib 00.png

This image is provided by the National Library of Medicine.

Mechanism of Action

• Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits BRAF V600 mutation-positive melanoma cell growth in vitro and in vivo.

• Trametinib and dabrafenib target two different tyrosine kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive melanoma cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive melanoma xenografts compared with either drug alone.

Structure

• Trametinib dimethyl sulfoxide is a kinase inhibitor. The chemical name is acetamide, N-[3-[3-cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl- 2,4,7-trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-, compound with 1,1’-sulfinylbis[methane] (1:1). It has a molecular formula C26H23FIN5O4•C2H6OS with a molecular mass of 693.53. Trametinib dimethyl sulfoxide has the following chemical structure:

File:Trametinib 01.png

This image is provided by the National Library of Medicine.

• Trametinib dimethyl sulfoxide is a white to almost white powder. It is practically insoluble in the pH range of 2 to 8 in aqueous media.

• Trametinib (trametinib) tablets are supplied as 0.5-mg, 1-mg, and 2-mg tablets for oral administration. Each 0.5-mg tablet contains 0.5635 mg trametinib dimethyl sulfoxide equivalent to 0.5 mg of trametinib non-solvated parent. Each 1-mg tablet contains 1.127 mg trametinib dimethyl sulfoxide equivalent to 1 mg of trametinib non-solvated parent. Each 2-mg tablet contains 2.254 mg trametinib dimethyl sulfoxide equivalent to 2 mg of trametinib non-solvated parent.

• The inactive ingredients of Trametinib tablets are: Tablet Core: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate (vegetable source), mannitol, microcrystalline cellulose, sodium lauryl sulfate. Coating: hypromellose, iron oxide red (2-mg tablets), iron oxide yellow (0.5-mg tablets), polyethylene glycol, polysorbate 80 (2-mg tablets), titanium dioxide.

Pharmacodynamics

• Administration of 1 mg and 2 mg trametinib to patients with BRAF V600 mutation-positive melanoma resulted in dose-dependent changes in tumor biomarkers including inhibition of phosphorylated ERK, inhibition of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis).

Pharmacokinetics

• The pharmacokinetics (PK) of trametinib were characterized following single- and repeat-oral administration in patients with solid tumors and BRAF V600 mutation-positive metastatic melanoma.

• Absorption: After oral administration, the median time to achieve peak plasma concentrations (Tmax) is 1.5 hours post-dose. The mean absolute bioavailability of a single 2-mg oral dose of trametinib tablet is 72%. The increase in Cmax was dose proportional after a single dose of 0.125 to 10 mg while the increase in AUC was greater than dose proportional. After repeat doses of 0.125 to 4 mg daily, both Cmax and AUC increase proportionally with dose. Inter-subject variability in AUC and Cmax at steady state is 22% and 28%, respectively.

• Administration of a single dose of trametinib with a high-fat, high-calorie meal decreased AUC by 24%, Cmax by 70%, and delayed Tmax by approximately 4 hours as compared with fasted conditions [see Dosage and Administration (2.2)].

• Distribution: Trametinib is 97.4% bound to human plasma proteins. The apparent volume of distribution (Vc/F) is 214 L.

• Metabolism: Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases.

• Following a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is represented as the parent compound. However, based on metabolite profiling after repeat dosing of trametinib, ≥75% of drug-related material in plasma is the parent compound.

• Elimination: The estimated elimination half-life based on the population PK model is 3.9 to 4.8 days. The apparent clearance is 4.9 L/h.

• Following oral administration of [14C]-trametinib, >80% of excreted radioactivity was recovered in the feces while <20% of excreted radioactivity was recovered in the urine with <0.1% of the excreted dose as parent.

Specific Populations:

• Based on a population pharmacokinetic analysis, age, gender, and body weight do not have a clinically important effect on the exposure of trametinib. There are insufficient data to evaluate potential differences in the exposure of trametinib by race or ethnicity.

• Hepatic Impairment: Based on a population pharmacokinetic analysis in 64 patients with mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1.0 to 1.5 x ULN and any AST), mild hepatic impairment has no clinically important effect on the systemic exposure of trametinib. The pharmacokinetics of trametinib have not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations (8.7)].

• Renal Impairment: As renal excretion of trametinib is low (<20%), renal impairment is unlikely to have a clinically important effect on the exposure of trametinib. Based on a population PK analysis in 223 patients with mild renal impairment (GFR 60 to 89 mL/min/1.73 m2) and 35 patients with moderate renal impairment (GFR 30 to 59 mL/min/1.73 m2), mild and moderate renal impairment have no clinically important effects on the systemic exposure of trametinib. The pharmacokinetics of trametinib have not been studied in patients with severe renal impairment [see Use in Specific Populations (8.8)].

• Pediatrics: No trials have been conducted to evaluate the pharmacokinetics of trametinib in pediatric patients.

Drug Interactions:

• Trametinib is not a substrate of CYP enzymes or efflux transporters human P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro.

• Based on in vitro studies, trametinib is not an inhibitor of CYP450 including CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, or of transporters including human organic anion transporting polypeptide (OATP1B1, OATP1B3), P-gp, and BCRP at a clinically relevant systemic concentration of 0.04 µM. Trametinib is an inhibitor of CYP2C8 in vitro.

• Trametinib is an inducer of CYP3A4 in vitro. Based on cross-study comparisons, oral administration of trametinib 2 mg once daily with everolimus (sensitive CYP3A4 substrate) 5 mg once daily, had no clinically important effect on the AUC and Cmax of everolimus.

• Coadministration of trametinib 2 mg daily with dabrafenib 150 mg twice daily resulted in a 23% increase in AUC of dabrafenib, a 33% increase in AUC of desmethyl-dabrafenib, and no change in AUC of trametinib or hydroxy-dabrafenib as compared with administration of either drug alone.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

• Carcinogenicity studies with trametinib have not been conducted. Trametinib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, and micronuclei in the bone marrow of rats.

• Trametinib may impair fertility in humans. In female rats given trametinib for up to 13 weeks, increased follicular cysts and decreased corpora lutea were observed at doses ≥0.016 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC). In rat and dog toxicity studies up to 13 weeks in duration, there were no treatment effects observed on male reproductive tissues

Clinical Studies

• BRAF V600E or V600K Mutation-Positive Unresectable or metastatic melanoma

• The safety and efficacy of Trametinib were evaluated in two clinical trials. Trial 1 was an international, multicenter, randomized (2:1), open-label, active-controlled trial in 322 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Trial 2 was a multicenter, randomized (1:1:1), open-label, dose-ranging trial designed to evaluate the clinical activity and safety of Trametinib (at two different doses) in combination with dabrafenib and to compare the safety with dabrafenib as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma.

• In Trial 1, patients were not permitted to have more than one prior chemotherapy regimen for advanced or metastatic disease; prior treatment with a BRAF inhibitor or MEK inhibitor was not permitted. The primary efficacy outcome measure was progression-free survival (PFS). Patients were randomized to receive Trametinib 2 mg orally once daily (N = 214) or chemotherapy (N = 108) consisting of either dacarbazine 1,000 mg/m2 intravenously every 3 weeks or paclitaxel 175 mg/m2intravenously every 3 weeks. Treatment continued until disease progression or unacceptable toxicity. Randomization was stratified according to prior use of chemotherapy for advanced or metastatic disease (yes versus no) and lactate dehydrogenase level (normal versus greater than upper limit of normal). Tumor tissue was evaluated for BRAF mutations at a central testing site using a clinical trial assay. Tumor samples from 289 patients (196 patients treated with Trametinib and 93 chemotherapy-treated patients) were also tested retrospectively using an FDA-approved companion diagnostic test, THxID™-BRAF assay.

• The median age for randomized patients was 54 years, 54% were male, >99% were white, and all patients had baseline ECOG performance status of 0 or 1. Most patients had metastatic disease (94%), were Stage M1c (64%), had elevated LDH (36%), no history of brain metastasis (97%), and received no prior chemotherapy for advanced or metastatic disease (66%). The distribution of BRAF V600 mutations was BRAF V600E (87%), V600K (12%), or both (<1%). The median durations of follow-up prior to initiation of alternative treatment were 4.9 months for patients treated with Trametinib and 3.1 months for patients treated with chemotherapy. Fifty-one (47%) patients crossed over from the chemotherapy arm at the time of disease progression to receive Trametinib .

• Trial 1 demonstrated a statistically significant increase in progression-free survival in the patients treated with Trametinib . Table 7 and Figure 1 summarize the PFS results.

File:Trametinib 05.png

This image is provided by the National Library of Medicine.

• In supportive analyses based on independent radiologic review committee (IRRC) assessment, the PFS results were consistent with those of the primary efficacy analysis.

• Trial 2 randomized (1:1:1) patients to Trametinib (at two different doses) in combination with dabrafenib compared with dabrafenib as a single agent in 162 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive Trametinib 2 mg orally once daily with dabrafenib 150 mg orally twice daily (n = 54), Trametinib 1 mg orally once daily with dabrafenib 150 mg orally twice daily (n = 54), or dabrafenib 150 mg orally twice daily (n = 54). Treatment continued until disease progression or unacceptable toxicity. Patients randomized to receive dabrafenib as a single agent were offered Trametinib 2 mg orally once daily with dabrafenib 150 mg orally twice daily at the time of investigator-assessed disease progression. The major efficacy outcome measure was investigator-assessed overall response rate (ORR). Additional efficacy outcome measures were investigator-assessed duration of response, independent radiology review committee (IRRC)-assessed ORR, and IRRC-assessed duration of response.

• The median age of patients in Trial 2 was 53 years, 57% were male, >99% were white, 66% of patients had a pretreatment ECOG performance status of 0, 67% had M1c disease, 54% had a normal LDH at baseline, and 8% had a history of brain metastases. Most patients (81%) had not received prior anti-cancer therapy for unresectable or metastatic disease. All patients had tumor containing BRAF V600E or V600K mutations as determined by local laboratory or centralized testing, 85% with BRAF V600E mutations and 15% with BRAF V600K mutations.

• The median duration of follow-up was 14 months. Efficacy outcomes for the arm receiving Trametinib 2 mg daily in combination with dabrafenib and the arm receiving dabrafenib as a single agent are summarized in Table 8.

File:Trametinib 06.png

This image is provided by the National Library of Medicine.

• The ORR results were similar in subgroups defined by BRAF mutation subtype, i.e., in the 85% of patients with V600E mutation-positive melanoma and in the 15% of patients with V600K mutation-positive melanoma. In exploratory subgroup analyses of the patients with retrospectively confirmed BRAF V600E or V600K mutation-positive melanoma using the THxID™-BRAF assay, the ORR results were also similar to the intent-to-treat analysis.

Lack of Clinical Activity in metastatic melanoma Following BRAF-Inhibitor Therapy

• The clinical activity of Trametinib as a single agent was evaluated in a single-arm, multicenter, international trial (Trial 3) in 40 patients with BRAF V600E or V600K mutation-positive, unresectable or metastatic melanoma who had received prior treatment with a BRAF inhibitor. All patients received Trametinib at a dose of 2 mg orally once daily until disease progression or unacceptable toxicity.

• The median age was 58 years, 63% were male, all were white, 98% had baseline ECOG PS of 0 or 1, and the distribution of BRAF V600 mutations was V600E (83%), V600K (10%), and the remaining patients had multiple V600 mutations (5%), or unknown mutational status (2%). No patient in Trial 3 achieved a confirmed partial or complete response as determined by the clinical investigators.

How Supplied

• 0.5-mg Tablets: Yellow, modified oval, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘TFC’ on the opposing face and are available in bottles of 30 (NDC 0173-0849-13).

• 1-mg Tablets: White, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘LHE’ on the opposing face and are available in bottles of 30 (NDC 0173-0858-13).

• 2-mg Tablets: Pink, round, biconvex, film-coated tablets with ‘GS’ debossed on one face and ‘HMJ’ on the opposing face and are available in bottles of 30 (NDC 0173-0848-13).

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

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

• MEKINIST ®

Look-Alike Drug Names

There is limited information regarding Trametinib Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

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

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