May 31, 2016
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Mekinist

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Mekinist

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Review the Full Prescribing Information for dabrafenib for information on the serious risks of dabrafenib prior to initiation of MEKINIST with dabrafenib.

New Primary Malignancies

New primary malignancies, cutaneous and non-cutaneous, can occur when MEKINIST is administered with dabrafenib.

Cutaneous Malignancies

In Trial 2, the incidence of basal cell carcinoma in patients receiving MEKINIST and dabrafenib was 3.3% (7/209) compared with 6% (13/211) in patients receiving single-agent dabrafenib. The median time to first diagnosis of basal cell carcinoma was 5.1 months (range: 2.8 to 23.9 months) in the MEKINIST plus dabrafenib arm and was 4.4 months (range: 29 days to 16.5 months) in the dabrafenib arm. Among the 7 patients receiving MEKINIST with dabrafenib who developed basal cell carcinoma, 2 (29%) experienced more than one occurrence (range: 1 to 3).

Cutaneous squamous cell carcinomas (cuSCC) and keratoacanthoma occurred in 3% of patients receiving MEKINIST and dabrafenib and 10% of patients receiving single-agent dabrafenib. The median time to first diagnosis of cuSCC was 7.3 months (range: 1.8 to 16.8 months) in the MEKINIST plus dabrafenib arm and was 2 months (range: 9 days to 20.9 months) in the dabrafenib arm.

New primary melanoma occurred in 0.5% (1/209) of patients receiving MEKINIST and dabrafenib and in 1.9% (4/211) of patients receiving dabrafenib alone.

Perform dermatologic evaluations prior to initiation of MEKINIST when used with dabrafenib, every 2 months while on therapy, and for up to 6 months following discontinuation of the combination. No dose modifications of MEKINIST 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 Trial 2, non-cutaneous malignancies occurred in 1.4% (3/209) of patients receiving MEKINIST plus dabrafenib and in 2.8% (6/211) of patients receiving single-agent dabrafenib.

Monitor patients receiving MEKINIST and dabrafenib closely for signs or symptoms of non-cutaneous malignancies. No dose modification is required for MEKINIST in patients who develop non-cutaneous malignancies [see DOSAGE AND ADMINISTRATION].

Hemorrhage

Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur with MEKINIST.

In Trial 2, the incidence of hemorrhagic events in patients receiving MEKINIST and dabrafenib was 19% (40/209) compared with 15% (32/211) of patients receiving dabrafenib alone. Gastrointestinal hemorrhage occurred in 6% (12/209) of patients receiving MEKINIST in combination with dabrafenib compared with 2.8% (6/211) of patients receiving single-agent dabrafenib. In Trial 2, 1.4% (3/209) of patients receiving MEKINIST and dabrafenib developed fatal intracranial hemorrhage compared with none of the patients receiving single-agent dabrafenib alone.

Permanently discontinue MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold MEKINIST for Grade 3 hemorrhagic events; if improved, resume at the next lower dose level.

Venous Thromboembolism

Venous thromboembolism can occur with MEKINIST.

In Trial 2, deep venous thrombosis (DVT) and pulmonary embolism (PE) occurred in 2.8% (6/209) of patients receiving MEKINIST and dabrafenib compared with 0.9% (2/211) of patients receiving single-agent 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 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 [see DOSAGE AND ADMINISTRATION].

Cardiomyopathy

Cardiomyopathy, including cardiac failure, can occur with MEKINIST.

In clinical trials of MEKINIST, all patients were required to have an echocardiogram at baseline to document normal LVEF and repeat echocardiograms at Week 4, Week 12, and every 12 weeks thereafter.

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 receiving MEKINIST; no chemotherapy-treated patient in Trial 1 developed cardiomyopathy. The median time to onset of cardiomyopathy in patients receiving MEKINIST was 2.1 months (range: 16 days to 5.1 months); cardiomyopathy was identified within the first month of receiving MEKINIST in five of these 14 patients. Four percent of patients in Trial 1 required discontinuation (4/211) and/or dose reduction (7/211) of MEKINIST. Cardiomyopathy resolved in 10 of these 14 (71%) patients.

Across clinical trials of MEKINIST as a single agent (N = 329), 11% of patients developed evidence of cardiomyopathy [decrease in LVEF below institutional lower limits of normal (LLN) with an absolute decrease in LVEF ≥ 10% below baseline] and 5% demonstrated a decrease in LVEF below institutional LLN with an absolute decrease in LVEF of ≥ 20% below baseline.

In Trial 2, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF ≥ 10% below baseline) occurred in 6% (12/206) of patients receiving MEKINIST and dabrafenib and in 2.9% (6/207) of patients receiving single-agent dabrafenib. The median time to onset of cardiomyopathy in patients receiving MEKINIST and dabrafenib was 8.2 months (range: 28 days to 24.9 months); cardiomyopathy was identified within the first month of receiving MEKINIST and dabrafenib in 2 of these 12 patients. In patients receiving MEKINIST and dabrafenib, cardiomyopathy resulted in dose interruption (4.4%), dose reduction (2.4%), and permanent discontinuation (1.5%) of MEKINIST. Cardiomyopathy resolved in 10 of 12 patients receiving MEKINIST and dabrafenib.

Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of MEKINIST as a single agent or with dabrafenib, one month after initiation, and then at 2- to 3-month intervals while on treatment. Withhold 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 of > 20% from baseline that is below LLN that does not resolve within 4 weeks, permanently discontinue MEKINIST [see DOSAGE AND ADMINISTRATION].

Ocular Toxicities

Retinal Vein Occlusion (RVO)

Across all clinical trials with 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 [see DOSAGE AND ADMINISTRATION].

Retinal Pigment Epithelial Detachment (RPED)

Retinal pigment epithelial detachment (RPED) can occur with MEKINIST administration. Retinal detachments may be bilateral and multifocal, occurring in the central macular region of the retina or elsewhere in the retina. In Trial 1 and Trial 2, routine monitoring of patients to detect asymptomatic RPED was not conducted; therefore, the true incidence of this finding is unknown.

Perform ophthalmological evaluation periodically and at any time a patient reports visual disturbances. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST. Reduce the dose or discontinue MEKINIST if no improvement after 3 weeks [see DOSAGE AND ADMINISTRATION].

Interstitial Lung Disease

In clinical trials of single-agent MEKINIST (N = 329), ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2.4% (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 5.3 months (range: 2 to 5.7 months). In Trial 2, 1.0% (2/209) of patients receiving MEKINIST and dabrafenib developed pneumonitis compared with none of the patients receiving single-agent dabrafenib.

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 [see DOSAGE AND ADMINISTRATION].

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 administered with dabrafenib.

Fever (serious and non-serious) occurred in 57% (119/209) of patients receiving MEKINIST and dabrafenib and in 33% (69/211) of patients receiving dabrafenib alone. The median time to initial onset of fever was 1.2 months (range: 1 day to 23.5 months) with a median duration of fever of 3 days (range: 1 day to 1.7 months) on the MEKINIST plus dabrafenib arm compared with a median time to initial onset of fever of 20 days (range: 1 day to 22.9 months) and median duration of fever of 3 days (range: 1 day to 1.9 months) on the dabrafenib arm. Approximately one-half of the patients who received MEKINIST and dabrafenib and experienced pyrexia had three or more discrete episodes.

Across clinical trials of MEKINIST administered with dabrafenib, serious febrile reactions or fever of any severity complicated by severe rigors/chills hypotension, dehydration, renal failure, or syncope, occurred in 17% (93/559) of patients receiving MEKINIST and dabrafenib. Fever was complicated by severe chills/rigors in 0.4% (2/559), dehydration in 1.8% (10/559), renal failure in 0.5% (3/559), and syncope in 0.7% (4/559) of patients.

Withhold MEKINIST for fever higher than 104°F or for serious febrile reactions or fever accompanied by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Monitor serum creatinine and other evidence of renal function during and following severe pyrexia. Refer to Table 2 for recommended dose modifications for adverse reactions [see DOSAGE AND ADMINISTRATION]. Administer antipyretics as secondary prophylaxis when resuming MEKINIST if patient had a prior episode of severe febrile reaction or fever associated with complications. Administer corticosteroids (e.g., prednisone 10 mg daily) for at least 5 days for second or subsequent pyrexia if temperature does not return to baseline within 3 days of onset of pyrexia, or for pyrexia associated with complications such as dehydration, hypotension renal failure, or severe chills/rigors, and there is no evidence of active infection.

Serious Skin Toxicity

Serious skin toxicity can occur with MEKINIST.

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 receiving 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 initial onset of skin toxicity in patients treated with MEKINIST was 15 days (range: 1 day to 7.3 months) and median time to resolution of skin toxicity was 1.6 months (range: 1 day to 9.3 months). 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 overall incidence of any skin toxicity was 55% for patients receiving MEKINIST and dabrafenib compared with 55% for patients receiving single-agent dabrafenib. No serious or severe cases of skin toxicity occurred in patients treated with MEKINIST and dabrafenib. The median time to initial onset of skin toxicity for patients receiving MEKINIST with dabrafenib was 1.9 months (range: 1 day to 22.1 months) and median time to resolution of skin toxicity for patients receiving MEKINIST with dabrafenib was 1.2 months (range: 1 day to 24.4 months). Reductions in the dose of MEKINIST were required in 5% of patients receiving MEKINIST and dabrafenib and no patients required permanent discontinuation of MEKINIST for skin toxicity.

Across clinical trials of MEKINIST administered with dabrafenib (N = 559), serious skin toxicity occurred in 0.7% (4/559) of patients.

Withhold MEKINIST for intolerable or severe skin toxicity. Resume MEKINIST at reduced doses in patients with improvement or recovery from skin toxicity within 3 weeks [see DOSAGE AND ADMINISTRATION].

Hyperglycemia

Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycemic agent therapy can occur when MEKINIST is administered with dabrafenib.

In Trial 2, 27% (4/15) of patients with a history of diabetes who received MEKINIST and dabrafenib and 13% (2/16) of patients with a history of diabetes who received single-agent dabrafenib required more intensive hypoglycemic therapy. Grade 3 and Grade 4 hyperglycemia based on laboratory values occurred in 5% (11/208) and 0.5% (1/208) of patients receiving MEKINIST and dabrafenib, respectively, compared with 4.3% (9/209) for Grade 3 hyperglycemia and no patients with Grade 4 hyperglycemia for patients receiving single-agent dabrafenib.

Monitor serum glucose levels upon initiation and as clinically appropriate when MEKINIST is administered with dabrafenib in patients with pre-existing diabetes or hyperglycemia.

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, 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 MEKINIST is used during pregnancy, or if the patient becomes pregnant while taking MEKINIST, advise the patient of the potential risk to a fetus [see Use in Specific Populations].

Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after treatment. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Inform patients of the following:

Confirmation of BRAF V600E or V600K Mutation

Evidence of BRAF V600E or V600K mutation within the tumor specimen is necessary to identify patients for whom treatment with MEKINIST is indicated [see DOSAGE AND ADMINISTRATION].

New cutaneous and Non-cutaneous Malignancies

MEKINIST administered with dabrafenib can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see WARNINGS AND PRECAUTIONS].

Hemorrhage

MEKINIST administered with dabrafenib increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see WARNINGS AND PRECAUTIONS].

Venous Thrombosis

MEKINIST administered with dabrafenib increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see WARNINGS AND PRECAUTIONS].

Cardiomyopathy

MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see WARNINGS AND PRECAUTIONS].

Retinal Pigment Epithelial Detachment

MEKINIST can cause severe visual disturbances that can lead to blindness. Advise patients to contact their healthcare provider if they experience any changes in their vision [see WARNINGS AND PRECAUTIONS].

Interstitial Lung Disease

MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see WARNINGS AND PRECAUTIONS].

Serious Febrile Reactions

MEKINIST administered with dabrafenib can cause serious febrile reactions. Instruct patients to contact their healthcare provider if they develop fever while taking MEKINIST with dabrafenib [see WARNINGS AND PRECAUTIONS].

Serious Skin Toxicities

MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see WARNINGS AND PRECAUTIONS].

Hypertension

MEKINIST can cause hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness.

Diarrhea

MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment.

Embryo-fetal Toxicity

MEKINIST can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Females and Males of Reproductive Potential

Instruct females of reproductive potential to use highly effective contraception during treatment with MEKINIST and for 4 months after the last dose. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Lactation

Advise women not to breastfeed during treatment with MEKINIST and for 4 months after the last dose [see Use in Specific Populations].

Infertility

Advise males and females of reproductive potential of the potential risk for impaired fertility [see Use In Specific Populations].

Instructions for Taking MEKINIST

MEKINIST should be taken at least 1 hour before or at least 2 hours after a meal [see DOSAGE AND ADMINISTRATION].

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. [see Use in Specific Populations].

Use In Specific Populations

Pregnancy

Risk Summary

Based on its mechanism of action and findings from animal reproduction studies, MEKINIST can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. There is insufficient data in pregnant women exposed to MEKINIST to assess the risks. 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 [see Data]. If MEKINIST is used during pregnancy, or if the patient becomes pregnant while taking MEKINIST, advise the patient of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

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.

Lactation

Risk Summary

There are no data on the presence of trametinib in human milk, or the effects of trametinib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions in breastfed infants from MEKINIST, advise women not to breastfeed during treatment with MEKINIST and for 4 months following the last dose.

Females And Males Of Reproductive Potential

Based on its mechanism of action and findings from animal reproduction studies, MEKINIST can cause fetal harm when administered to pregnant women [see Use In Specific Populations].

Contraception

Females: Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after the last dose. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST.

Infertility

Females: Advise female patients of reproductive potential that MEKINIST may impair fertility. Increased follicular cysts and decreased corpora lutea were observed in female rats at dose exposures equivalent to 0.3 times the human exposure at the recommended dose [see Nonclinical Toxicology].

Pediatric Use

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

Juvenile Animal Data

In a repeat-dose toxicity study in juvenile rats, decreased bone length and corneal dystrophy were observed at doses resulting in exposures as low as 0.3 times the human exposure at the recommended adult dose based on AUC. Additionally, a delay in sexual maturation was noted at doses resulting in exposures as low as 1.6 times the human exposure at the recommended adult dose based on AUC.

Geriatric Use

Clinical trials of MEKINIST as a single agent did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

Of the 559 patients randomized to receive MEKINIST plus dabrafenib in clinical trials, 24% were aged 65 years and older and 6% patients aged 75 years and older. No overall differences in the effectiveness of MEKINIST plus dabrafenib were observed in elderly patients as compared to younger patients. The incidences of peripheral edema (26% vs. 12%) and anorexia (21% vs. 9%) increased in elderly patients as compared to younger patients.

Hepatic Impairment

No dedicated 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 [see CLINICAL PHARMACOLOGY].

The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment.

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]. The appropriate dose of MEKINIST has not been established in patients with severe renal impairment.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/22/2016

Warnings
Precautions

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