Mekinist Special Precautions

When Mekinist is used together with dabrafenib read the full prescribing information for dabrafenib precautions section.
LVEF Reduction/Left Ventricular Dysfunction: Mekinist has been reported to decrease LVEF (see Adverse Reactions). In clinical trials, the median time to onset of the first occurrence of left ventricular dysfunction, cardiac failure and LVEF decrease in patients treated with Mekinist as monotherapy or in combination with dabrafenib was between two to five months. Mekinist should be used with caution in patients with conditions that could impair left ventricular function. LVEF should be evaluated in all patients prior to initiation of treatment with Mekinist with a recommendation of periodic follow-up within eight weeks of initiating therapy, as clinically appropriate. LVEF should continue to be evaluated during treatment with Mekinist as clinically appropriate (see Dosage & Administration).
Hemorrhage: Hemorrhagic events, including major hemorrhagic events have occurred in patients taking Mekinist as monotherapy and in combination with dabrafenib (see Adverse Reactions). Out of the 559 unresectable or metastatic melanoma patients treated with Mekinist in combination with dabrafenib, there were six fatal intracranial hemorrhagic cases (1%). Three cases were from study MEK115306 (COMBI-d) and three cases were from study MEK116513 (COMBI-v). No fatal hemorrhagic events occurred in the Phase III study in the adjuvant treatment of melanoma. Two out of 93 patients (2%) receiving Mekinist in combination with dabrafenib in a Phase II NSCLC trial had fatal hemorrhagic events. If patients develop symptoms of hemorrhage, they should immediately seek medical care.
Visual impairment: Disorders associated with visual disturbances, including chorioretinopathy or retinal pigment epithelial detachment (RPED) and Retinal Vein Occlusion (RVO) have been observed with Mekinist. Symptoms such as blurred vision, decreased acuity, and other visual phenomena have been reported in the clinical trials with Mekinist (see Adverse Reactions). Mekinist is not recommended in patients with a history of RVO. A thorough ophthalmological evaluation should be performed at baseline and during treatment with Mekinist, if clinically warranted. If patients report visual disturbances at any time while on Mekinist therapy, additional ophthalmological evaluation should be undertaken. If a retinal abnormality is noted, treatment with Mekinist should be interrupted immediately and referral to a retinal specialist should be considered. If RPED is diagnosed, the dose modification schedule (intolerable) in Table 14 should be followed (see Dosage & Administration). In patients who experience RVO, treatment with Mekinist should be permanently discontinued.
Skin toxicity: Rash: In clinical studies, rash has been observed in about 60% of patients receiving Mekinist as monotherapy and 20 to 30% receiving Mekinist in combination with dabrafenib (see Adverse Reactions). The majority of these cases were Grade 1 or 2 and did not require any dose interruptions or dose reductions.
Severe cutaneous adverse reactions: Cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with Mekinist in combination with Dabrafenib. Before initiating treatment, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of SCARs appear, Mekinist and Dabrafenib should be withdrawn.
Venous thromboembolism (VTE): VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE) can occur on Mekinist monotherapy and when Mekinist is used in combination with dabrafenib. Patients should be advised to immediately seek medical care if they develop symptoms of VTE (see Adverse Reactions).
Pyrexia: Pyrexia was reported in the clinical trials with Mekinist. The incidence and severity of pyrexia are increased when Mekinist is used in combination with dabrafenib (see Adverse Reactions). In patients with unresectable or metastatic melanoma who received the combination dose of Mekinist 2 mg once daily and Dabrafenib 150 mg twice daily developed pyrexia, approximately half of the first occurrences of pyrexia happened within the first month of therapy. About one-third of the patients receiving combination therapy who experienced pyrexia had three or more events. Pyrexia may be accompanied by severe rigors, dehydration, and hypotension, which in some cases can lead to acute renal insufficiency. Serum creatinine and other evidence of renal function should be monitored during and following severe events of pyrexia. Serious non-infectious febrile events have been observed. These events responded well to dose interruption and/or dose reduction and supportive care in clinical trials.
A cross-study comparison in 1,810 patients treated with combination therapy demonstrated a reduction in the incidence of high-grade pyrexia and other pyrexia-related adverse outcomes when both Mekinist and Dabrafenib were interrupted, compared to when only Dabrafenib was interrupted. Therefore, interruption of both Mekinist and Dabrafenib is recommended if patient's temperature is ≥38°C (100.4°F), and in case of recurrence, therapy can also be interrupted at the first symptom of pyrexia (see Dosage & Administration and Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Colitis and gastrointestinal perforation: Colitis and gastrointestinal perforation, including fatal outcome, have been reported in patients taking Mekinist as monotherapy and in combination with dabrafenib (Adverse Reactions). Treatment with Mekinist monotherapy or in combination with dabrafenib should be used with caution in patients with risk factors for gastrointestinal perforation, including a history of diverticulitis, metastases to the gastrointestinal tract and concomitant use of medications with a recognized risk of gastrointestinal perforation.
If patients develop symptoms of colitis and gastrointestinal perforation, they should immediately seek medical care.
Hemophagocytic lymphohistiocytosis (HLH): In post-marketing experience, HLH has been observed with Mekinist in combination with Dabrafenib. If HLH is suspected, treatment should be interrupted. If HLH is confirmed, treatment should be discontinued and appropriate management of HLH should be initiated.
Tumour Lysis Syndrome (TLS): Cases of TLS, including fatal cases, have been reported in patients treated with Mekinist in combination with Tafinlar (see Adverse Reactions). Risk factors for TLS include rapidly growing tumors, a high tumor burden, renal dysfunction, and dehydration. Patients with risk factors for TLS should be closely monitored, prophylaxis should be considered (e.g., intravenous hydration and treatment of high uric acid levels prior to initiating treatment) and treated as clinically indicated.