Drug Interactions between cobimetinib and troleandomycin

Grapefruit juice may increase the blood levels and effects of certain medications such as cobimetinib. You may want to limit your consumption of grapefruit and grapefruit juice during treatment with cobimetinib. However, if you have been regularly consuming grapefruit or grapefruit juice with cobimetinib, do not alter the amounts of these products in your diet without first talking to your doctor or other healthcare professional. Contact your doctor if your condition changes or you experience increased side effects. Orange juice is not expected to interact.

Troleandomycin is primarily excreted by the liver and may accumulate in patients with impaired hepatic function. In addition, the use of troleandomycin has been associated with an allergic type of cholestatic hepatitis, particularly in patients receiving the drug for more than 2 weeks or given repeated courses. Therapy with troleandomycin should be administered cautiously in patients with liver and/or biliary disease. Liver function tests should be monitored during prolonged or repeated courses of therapy, and the drug discontinued if abnormalities develop.

Clostridioides difficile-associated diarrhea (CDAD), formerly pseudomembranous colitis, has been reported with almost all antibacterial drugs and may range from mild diarrhea to fatal colitis. The most common culprits include clindamycin and lincomycin. Antibacterial therapy alters the normal flora of the colon, leading to overgrowth of C difficile, whose toxins A and B contribute to CDAD development. Morbidity and mortality are increased with hypertoxin-producing strains of C difficile; these infections can be resistant to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea after antibacterial use. Since CDAD has been reported to occur more than 2 months after antibacterial use, careful medical history is necessary. Therapy with broad-spectrum antibacterials and other agents with significant antibacterial activity should be administered cautiously in patients with history of gastrointestinal disease, particularly colitis; pseudomembranous colitis (generally characterized by severe, persistent diarrhea and severe abdominal cramps, and sometimes associated with the passage of blood and mucus), if it occurs, may be more severe in these patients and may be associated with flares in underlying disease activity. Antibacterial drugs not directed against C difficile may need to be stopped if CDAD is suspected or confirmed. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C difficile, and surgical evaluation should be started as clinically indicated.

Troleandomycin is primarily excreted by the liver and may accumulate in patients with impaired hepatic function. In addition, the use of troleandomycin has been associated with an allergic type of cholestatic hepatitis, particularly in patients receiving the drug for more than 2 weeks or given repeated courses. Therapy with troleandomycin should be administered cautiously in patients with liver and/or biliary disease. Liver function tests should be monitored during prolonged or repeated courses of therapy, and the drug discontinued if abnormalities develop.

Cardiomyopathy, defined as symptomatic and asymptomatic decline in left ventricular ejection fraction (LVEF), can occur with the use of cobimetinib. Evaluate LVEF prior to, 1 month after initiation, and every 3 months thereafter until discontinuation of cobimetinib. It is recommended to manage events of left ventricular dysfunction through treatment interruption, dose reduction, or discontinuation of therapy. If restarting cobimetinib after a dose reduction or interruption it is recommended to evaluate LVEF as clinically indicated. Care should be exercised when using cobimetinib as the safety of cobimetinib has not been established in patients with a baseline LVEF that is either below institutional lower limit of normal (LLN) or below 50%.

The use of certain multikinase inhibitors has been associated with pulmonary toxicity. Serious cases of interstitial lung disease (ILD), including fatal cases and interstitial pneumonitis or pulmonary fibrosis have been reported. Caution is recommended when using these agents in patients with a history of interstitial pneumonitis or pulmonary fibrosis or those patients presenting with acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, these agents should be permanently discontinued and appropriate measures should be instituted. Treatment should be immediately withheld in patients diagnosed with ILD/pneumonitis and permanently discontinued if no other potential causes of ILD/pneumonitis have been identified.

Hepatotoxicity can occur with the use of cobimetinib. It is recommended to monitor liver function tests before initiation of therapy, monthly during treatment, or more frequently as clinically indicated. Manage Grade 3 and 4 liver laboratory abnormalities with dose interruption, reduction, or discontinuation of therapy. Close monitoring is recommended.

The recommended dosage of olutasidenib has not been established in patients with severe hepatic impairment. Additionally, this drug can cause hepatotoxicity with elevated alanine transaminase (ALT), aspartate aminotransferase (AST), blood alkaline phosphatase and blood bilirubin being the most common findings. Use with caution and monitor patients frequently for signs and symptoms of hepatotoxicity and liver impairment during treatment.

Rhabdomyolysis can occur with the use of cobimetinib. It is recommended to obtain baseline serum creatine phosphokinase (CPK) and creatinine levels prior to initiating therapy with cobimetinib and periodically during treatment as clinically indicated. If CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or CPK elevation, dose interruption or discontinuation may be required. Care should be taken when using this agent in patients at risk for rhabdomyolysis.

The use of certain multikinase inhibitors has been associated with pulmonary toxicity. Serious cases of interstitial lung disease (ILD), including fatal cases and interstitial pneumonitis or pulmonary fibrosis have been reported. Caution is recommended when using these agents in patients with a history of interstitial pneumonitis or pulmonary fibrosis or those patients presenting with acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, these agents should be permanently discontinued and appropriate measures should be instituted. Treatment should be immediately withheld in patients diagnosed with ILD/pneumonitis and permanently discontinued if no other potential causes of ILD/pneumonitis have been identified.

The recommended dosage of olutasidenib has not been established in patients with severe renal impairment (CrCl 15 to 29 mL/min), kidney failure, and patients on dialysis. Caution is advised.

Ocular toxicities can occur with cobimetinib, including serous retinopathy. Consider ophthalmologic examinations including retinal evaluation before treatment and at regular intervals during, and any time a patient reports new or worsening visual disturbances. If serous retinopathy is diagnosed, interrupt treatment with cobimetinib until visual symptoms improve. Manage serous retinopathy with treatment interruption, dose reduction, or with treatment discontinuation. Close monitoring is recommended.