Drug Interactions between Lithium Carbonate ER and venetoclax

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of venetoclax. Relative to fasting conditions, venetoclax systemic exposure (AUC) increased by approximately 3.4-fold when administered with a low-fat meal (approximately 512 kilocalories, 25% calories from fat) and by 5.1- to 5.3-fold when administered with a high-fat meal (approximately 753 kilocalories, 55% calories from fat).

GENERALLY AVOID: Grapefruit, grapefruit juice, Seville oranges, and starfruit may increase the plasma concentrations of venetoclax, which is primarily metabolized by the CYP450 3A4 isoenzyme. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported with potent CYP450 3A4 inhibitors. In a study of 11 previously treated non-Hodgkin lymphoma patients, when the potent CYP450 3A4 inhibitor, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor ketoconazole (400 mg daily for 7 days) was coadministered with venetoclax (50 mg single dose), venetoclax peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.3-fold and 6.4-fold, respectively. Physiologically based pharmacokinetic modeling estimates that the moderate CYP450 3A4 inhibitors diltiazem and erythromycin may increase the Cmax and AUC of venetoclax by between 1.4- to 2- fold and 2- to 4.9-fold, respectively, while the weak CYP450 3A4 inhibitors fluoxetine and fluvoxamine appear to have no significant effect on its Cmax or AUC. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased venetoclax exposure may potentiate the risk of tumor lysis syndrome, particularly at initiation of therapy and during the dosage ramp-up phase, as well as other adverse effects such as diarrhea, nausea, vomiting, neutropenia, anemia, and thrombocytopenia.

MANAGEMENT: Venetoclax should be administered with a meal and water at approximately the same time each day. Patients should avoid consumption of grapefruit products, Seville oranges, and starfruit during treatment with venetoclax.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

MONITOR: One study has suggested that caffeine withdrawal may significantly increase blood lithium levels. The mechanism may be involve reversal of a caffeine-induced increase in renal lithium excretion.

MANAGEMENT: When caffeine is eliminated from the diet of lithium-treated patients, caution should be exercised. When caffeine consumption is decreased, close observation for evidence of lithium toxicity and worsening of the psychiatric disorder is recommended. Patients should be advised to notify their physician if they experience symptoms of possible lithium toxicity such as drowsiness, dizziness, weakness, ataxia, tremor, vomiting, diarrhea, thirst, blurry vision, tinnitus, or increased urination.