TRAMETINIB DIMETHYL SULFOXIDE Drug Interactions: What You Need to Know

INTERACTIONS MEKINIST is indicated for use in combination with dabrafenib. Refer to the dabrafenib prescribing information for additional risk information that applies to combination use treatment.

None. None. ( 4 )

AND PRECAUTIONS New Primary Malignancies, Cutaneous and Non-Cutaneous : Can occur when MEKINIST is used with dabrafenib. Monitor patients for new malignancies prior to, or while on therapy, and following discontinuation of treatment. ( 5.1 ) Hemorrhage : Major hemorrhagic events can occur. Monitor for signs and symptoms of bleeding. ( 5.2 ) Colitis and Gastrointestinal Perforation : Colitis and gastrointestinal perforation can occur in patients receiving MEKINIST. ( 5.3 )

Venous Thromboembolic

Events : Deep vein thrombosis (DVT) and pulmonary embolism (PE) can occur in patients receiving MEKINIST. ( 5.4 , 2.4 ) Cardiomyopathy : Assess left ventricular ejection fraction (LVEF) before treatment, after one month of treatment, then every 2 to 3 months thereafter. ( 5.5 , 2.4 )

Ocular

Toxicities : Perform ophthalmological evaluation for any visual disturbances.

For Retinal Vein

Occlusion (RVO), permanently discontinue MEKINIST. ( 5.6 , 2.4 )

Interstitial Lung

Disease (ILD)/Pneumonitis : Withhold MEKINIST for new or progressive unexplained pulmonary symptoms. Permanently discontinue MEKINIST for treatment-related ILD or pneumonitis. ( 5.7 , 2.4 )

Serious Febrile

Reactions : Can occur when MEKINIST is used with dabrafenib. ( 5.8 , 2.4 )

Serious Skin

Toxicities : Monitor for skin toxicities and for secondary infections. Permanently discontinue MEKINIST for intolerable Grade 2 or for Grade 3 or 4 rash not improving within 3 weeks despite interruption of MEKINIST. Permanently discontinue for severe cutaneous adverse reactions (SCARs). ( 5.9 , 2.4 ) Hyperglycemia : Monitor serum glucose levels in patients with preexisting diabetes or hyperglycemia. ( 5.10 )

Hemophagocytic

Lymphohistiocytosis (HLH) : Interrupt treatment for suspected HLH. Discontinue treatment if HLH is confirmed. ( 5.12 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.13 , 8.1 , 8.3 )

5.1 New Primary Malignancies Cutaneous Malignancies MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> , cutaneous squamous cell carcinomas (cuSCCs) and keratoacanthomas occurred in 2% of patients. Basal cell carcinoma and new primary melanoma occurred in 3% and &lt; 1% of patients, respectively.

Mekinist

Administered with Dabrafenib (Pediatric) : In the pooled safety population, new primary melanoma occurred in < 1% of patients. 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. 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 prescribing information for dabrafenib. In the pooled safety population of MEKINIST administered with dabrafenib, non-cutaneous malignancies occurred in 1% of patients. 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.

5.2 Hemorrhage Hemorrhages, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur with MEKINIST. Fatal cases have been reported.

Mekinist

Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , hemorrhagic events occurred in 17% of patients; gastrointestinal hemorrhage occurred in 3% of patients; intracranial hemorrhage occurred in 0.6% of patients; fatal hemorrhage occurred in 0.5% of patients. The fatal events were cerebral hemorrhage and brainstem hemorrhage.

Mekinist

Administered with Dabrafenib (Pediatric) : In the pooled safety population, hemorrhagic events occurred in 25% of patients; the most common type of bleeding was epistaxis (16%). Serious events of bleeding occurred in 3.6% of patients and included gastrointestinal hemorrhage (1.2%), cerebral hemorrhage (0.6%), uterine hemorrhage (0.6%), post-procedural hemorrhage (0.6%), and epistaxis (0.6%). 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 MEKINIST at the next lower dose level.

5.3 Colitis and Gastrointestinal Perforation Colitis and gastrointestinal perforation, including fatal outcomes, have been reported in patients taking: MEKINIST Monotherapy and Administered with Dabrafenib (Adult) : In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> , colitis occurred in &lt; 1% of patients and gastrointestinal perforation occurred in &lt; 1% of patients.

Mekinist

Administered with Dabrafenib (Pediatric) : In the pooled safety population, colitis events occurred in < 1% of patients. Monitor patients closely for colitis and gastrointestinal perforations.

5.4 Venous Thromboembolic Events MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> , deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 2% of patients.

Mekinist

Administered with Dabrafenib (Pediatric) : In the pooled safety population, embolism events occurred in < 1% of patients. 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 (2.4)] .

5.5 Cardiomyopathy Cardiomyopathy, including cardiac failure, can occur with MEKINIST.

Mekinist

Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥ 10% from baseline and below the institutional lower limit of normal (LLN), occurred in 6% of patients. Development of cardiomyopathy resulted in dose interruption or discontinuation of MEKINIST in 3% and < 1% of patients, respectively. Cardiomyopathy resolved in 45 of 50 patients who received MEKINIST administered with dabrafenib.

Mekinist

Administered with Dabrafenib (Pediatric) : In the pooled safety population, cardiomyopathy, defined as a decrease in LVEF ≥ 10% from baseline and below the institutional LLN, occurred in 9% of patients. 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. For an asymptomatic absolute decrease in LVEF of 10% or greater from baseline that is below the institutional LLN, withhold MEKINIST for up to 4 weeks. If improved to normal LVEF value, resume MEKINIST at a lower dose. If no improvement to normal LVEF value within 4 weeks, permanently discontinue MEKINIST. For symptomatic cardiomyopathy or an absolute decrease in LVEF of greater than 20% from baseline that is below the institutional LLN, permanently discontinue MEKINIST [see Dosage and Administration (2.4)] .

5.6 Ocular Toxicities Retinal Vein Occlusion In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> of MEKINIST monotherapy, the incidence of retinal vein occlusion (RVO) was 0.6%. In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> of MEKINIST administered with dabrafenib, there were no cases of RVO. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.4)]</span> .

Retinal Pigment Epithelial Detachment

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

Mekinist

Administered with Dabrafenib (Pediatric) : In the pooled safety population, RPED events occurred in < 1% of patients. 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 at same or reduced dose. If no improvement after 3 weeks, resume MEKINIST at reduced dose or permanently discontinue MEKINIST [see Dosage and Administration (2.4)] .

5.7 Interstitial Lung Disease/Pneumonitis In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> of MEKINIST monotherapy, interstitial lung disease or pneumonitis occurred in 2% of patients. In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> of MEKINIST administered with dabrafenib, ILD or pneumonitis occurred in 1% of patients. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.4)]</span> .

5.8 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.

Mekinist

Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , fever occurred in 58% of patients. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills, dehydration or renal failure occurred in 5% of patients. Fever was complicated by hypotension in 4%, dehydration in 3%, syncope in 2%, renal failure in 1%, and severe chills/rigors in < 1% of patients.

Mekinist

Administered with Dabrafenib (Pediatric) : In the pooled safety population [see Adverse Reactions (6.1)] , pyrexia occurred in 66% of patients. Withhold MEKINIST when used as monotherapy, and both MEKINIST and dabrafenib when used in combination, if the patient’s temperature is ≥ 100.4°F. In case of recurrence, therapy can also be interrupted at the first symptom of pyrexia [see Adverse Reactions (6.1)] . Fever may be complicated by hypotension, rigors or chills, dehydration, or renal failure. Evaluate for signs and symptoms of infection and monitor serum creatinine and other evidence of renal function during and following severe pyrexia. If appropriate, MEKINIST, or both MEKINIST and dabrafenib when used in combination, may be restarted if the patient has recovered from the febrile reaction for at least 24 hours, either at same or lower dose [see Dosage and Administration (2.4)] . 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.

5.9 Serious Skin Toxicities Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with MEKINIST administered with dabrafenib <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> .

Mekinist

Administered with Dabrafenib (Adult) : In the pooled safety population [see Adverse Reactions (6.1)] , other serious skin toxicity occurred in < 1% of patients.

Mekinist

Administered with Dabrafenib (Pediatric) : In the pooled safety population, serious adverse events of skin and subcutaneous tissue disorders occurred in 1.8% of patients. Monitor for new or worsening serious skin reactions. Permanently discontinue MEKINIST for SCARs [see Dosage and Administration (2.4)] . For other skin toxicities, withhold MEKINIST for intolerable or severe skin toxicity. Resume MEKINIST at a lower dose in patients with improvement or recovery from skin toxicity within 3 weeks. Permanently discontinue MEKINIST if skin toxicity has not improved in 3 weeks [see Dosage and Administration (2.4)] .

5.10 Hyperglycemia MEKINIST Administered with Dabrafenib (Adult) : In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> , 15% of patients with a history of diabetes who had received MEKINIST with dabrafenib required more intensive hypoglycemic therapy.

Grade

3 and Grade 4 hyperglycemia occurred in 2% of patients.

Mekinist

Administered with Dabrafenib (Pediatric) : In the pooled safety population, Grade 3 and Grade 4 hyperglycemia events occurred in < 1% of patients. Monitor serum glucose levels upon initiation and as clinically appropriate when MEKINIST is administered with dabrafenib in patients with preexisting diabetes or hyperglycemia. Initiate or optimize anti-hyperglycemic medications as clinically indicated.

5.11 Risks Associated with Combination Treatment MEKINIST is indicated for use in combination with dabrafenib. Review the prescribing information for dabrafenib for information on the serious risks of dabrafenib prior to initiation of MEKINIST with dabrafenib.

5.12 Hemophagocytic Lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH) has been observed in the post-marketing setting when MEKINIST was administered with dabrafenib. If HLH is suspected, interrupt treatment. If HLH is confirmed, discontinue treatment and initiate appropriate management of HLH.

5.13 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 adult clinical dose. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with MEKINIST and for 4 months after treatment <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1, 8.3)]</span> .