). Concurrent cardiac conditions, medications that affect heart rate or ECG parameters, and need for monitoring heart rate or ECGs should be considered when prescribing COTELLIC as clinically indicated. Left Ventricular Dysfunction The safety of COTELLIC has not been established in patients with decreased LVEF.
In the Phase III study, all patients underwent evaluation of LVEF, either by echocardiography or multiple gated ejection acquisition scan, at regular intervals during treatment. Decrease in LVEF from baseline has been reported in patients receiving COTELLIC (see 8 ADVERSE REACTIONS).
Reductions in LVEF of Grade 2 or higher severity were reported in 11% of patients in the COTELLIC in combination with vemurafenib arm versus 5% of patients in the placebo in combination with vemurafenib arm. In the COTELLIC in combination with vemurafenib arm, median time to initial onset of decreased LVEF (all grades) was 4 months (range 1-26 months).
1-10) months. One patient in the Phase Ib study treated with COTELLIC in combination with vemurafenib at the therapeutic dose developed Grade 3 congestive cardiomyopathy. COTELLIC was permanently discontinued with documented improvement in LVEF from 25% to 36% approximately one month after the event.
PrCOTELLIC® (cobimetinib) Page 10 of 40 COTELLIC is not recommended in patients with decreased LVEF (< 50% or below the institutional lower limit of normal) at baseline. COTELLIC should be used with caution in patients with conditions that could impair left ventricular function (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).
Decrease in LVEF from baseline can be managed using treatment interruption, dose reduction or with treatment discontinuation (see 4 DOSAGE AND ADMINISTRATION). Hypertension In the Phase III study, hypertension was reported in 17% (including hypertensive crisis) of patients receiving COTELLIC in combination with vemurafenib and in 9% of patients receiving placebo in combination with vemurafenib.
Hypertension was observed at similar frequencies between patients with and without pre-existing hypertension. Grade ≥3 hypertension events were reported in 7% of patients treated with COTELLIC in combination with vemurafenib compared with 3% of patients who received placebo in combination with vemurafenib.
A greater proportion of patients in the COTELLIC in combination with vemurafenib arm compared to the placebo plus vemurafenib arm received treatment for hypertension (12% versus 5%, respectively) (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).
Driving and Operating Machinery No studies on the effects on the ability to drive and to use machines have been performed. Visual disturbances have been reported in some patients treated with COTELLIC during clinical trials (see 7 WARNINGS AND PRECAUTIONS, Ophthalmologic and 8 ADVERSE REACTIONS).
Patients should be advised not to drive or operate machines if they experience visual disturbances or any other adverse effects that may affect their ability. Hematologic Hemorrhage Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or organ, can occur during treatment with COTELLIC.
Severe hemorrhagic cases, including intracranial bleeding and gastrointestinal tract bleeding, have been reported in patients treated with COTELLIC in clinical trials and in the post marketing setting. In most cases, patients had additional risk factors for bleeding.
8%, respectively, were grade 3. Higher frequencies in the COTELLIC in combination with vemurafenib arm were also observed for cerebral hemorrhage (1% vs. 0%), gastrointestinal tract hemorrhage (4% vs. 2%), reproductive system hemorrhage (2% vs.
<1%), and hematuria (3% vs. 1%). Patients should be assessed for signs and symptoms of hemorrhagic events during treatment (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests). Hemorrhage can be managed using treatment interruption, dose reduction or with treatment discontinuation (see 4 DOSAGE AND ADMINISTRATION).
Caution should be used in patients with additional risk factors for bleeding and/or in patients that use concomitant medications that may increase the risk of bleeding (including antiplatelet or anticoagulant therapy). Hepatic PrCOTELLIC® (cobimetinib) Page 11 of 40 Hepatotoxicity can occur with COTELLIC.
Liver laboratory test abnormalities Grade ≥ 3 were reported more frequently in the Phase III study in patients who received COTELLIC in combination with vemurafenib than in patients who received placebo in combination with vemurafenib (24% vs.
15%, respectively) (see 8 ADVERSE REACTIONS). 4%) treated with COTELLIC in combination with vemurafenib versus none treated with placebo plus vemurafenib, developed concurrent elevations in alanine aminotransferase (ALT) >3 times the upper limit of normal (ULN) and bilirubin >2 X ULN without evidence of cholestasis (significantly elevated serum alkaline phosphatase (ALP)).
ALT and bilirubin values returned to normal with discontinuation of both drugs. Monitor liver laboratory tests before initiation of the combination treatment and monthly during treatment (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).
2 Recommended Dose and Dosage Adjustment). 2%) in the COTELLIC in combination with vemurafenib arm compared with no such events in the placebo plus vemurafenib arm; all events required hospitalization […]