Drug Interactions between Crixivan and tazemetostat

GENERALLY AVOID: Consumption of grapefruit or grapefruit juice during tazemetostat therapy may significantly increase the plasma concentrations of tazemetostat. The proposed mechanism is inhibition of the CYP450 3A4-mediated metabolism of tazemetostat by certain compounds in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). According to the product labeling, coadministration of tazemetostat (400 mg twice daily) with the moderate CYP450 3A4 inhibitor fluconazole increased the tazemetostat steady state exposure (AUC 0 to 8 hours) by 3.1-fold and peak plasma concentration by 2.3-fold. 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. Clinically, this interaction may result in an increased risk of the frequency or severity of adverse reactions due to tazemetostat such as hemorrhage, pleural effusion, skin infection, dyspnea, pain, and respiratory distress.

MANAGEMENT: The manufacturer advises that patients treated with tazemetostat should avoid consumption of grapefruit or grapefruit juice.

ADJUST DOSING INTERVAL: According to the manufacturer, coadministration with a meal high in calories, fat, and protein reduces the absorption of indinavir. In ten patients given indinavir in this manner, the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of indinavir decreased by an average of 84% and 77%, respectively. In contrast, grapefruit juice may have only minor effects on the oral bioavailability of indinavir. The manufacturer's package labeling states that administration of a single 400 mg dose of indinavir with 8 oz. of grapefruit juice decreased indinavir AUC by an average of 26%. Likewise, a study consisting of 14 HIV-infected subjects found no uniform nor significant changes in steady-state indinavir AUC during administration with double-strength grapefruit juice compared to water. There was, however, a delay in absorption (Tmax) due to grapefruit juice that is unlikely to be of clinical significance.

MANAGEMENT: To ensure maximal oral absorption, indinavir should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, indinavir may be administered with other liquids such as skim milk, juice, coffee, or tea, or with a light meal (e.g., dry toast with jelly, juice, and coffee with skim milk and sugar; corn flakes, skim milk and sugar).

Crystalluria and nephrolithiasis may occur during treatment with indinavir. The cumulative frequency of nephrolithiasis is substantially higher in pediatric patients (29%) than in adult patients (12.4%; range 4.7% to 34.4% across individual trials) and increases with duration of exposure to indinavir; however, the risk over time remains relatively constant. The incidence is also higher when indinavir is used in combination with ritonavir than when used alone at 800 mg three times a day. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure and pyelonephritis with or without bacteremia. Therapy with indinavir should be administered cautiously in patients with a current or past history of nephrolithiasis. It is crucial that patients receive adequate hydration. Generally, at least 1.5 L (approximately 48 oz) of fluid per day is recommended for adults during indinavir therapy. Those who are dehydrated may be at increased risk and should be encouraged to consume additional amounts of liquid or given intravenous fluid if necessary. All patients receiving indinavir should be instructed to seek medical attention if they experience potential signs and symptoms of nephrolithiasis/urolithiasis such as flank pain, hematuria, dysuria, anuria, and urinary urgency. A brief interruption (e.g., 1 to 3 days) or discontinuation of therapy may be required.

Crystalluria and nephrolithiasis may occur during treatment with indinavir. The cumulative frequency of nephrolithiasis is substantially higher in pediatric patients (29%) than in adult patients (12.4%; range 4.7% to 34.4% across individual trials) and increases with duration of exposure to indinavir; however, the risk over time remains relatively constant. The incidence is also higher when indinavir is used in combination with ritonavir than when used alone at 800 mg three times a day. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure and pyelonephritis with or without bacteremia. Therapy with indinavir should be administered cautiously in patients with a current or past history of nephrolithiasis. It is crucial that patients receive adequate hydration. Generally, at least 1.5 L (approximately 48 oz) of fluid per day is recommended for adults during indinavir therapy. Those who are dehydrated may be at increased risk and should be encouraged to consume additional amounts of liquid or given intravenous fluid if necessary. All patients receiving indinavir should be instructed to seek medical attention if they experience potential signs and symptoms of nephrolithiasis/urolithiasis such as flank pain, hematuria, dysuria, anuria, and urinary urgency. A brief interruption (e.g., 1 to 3 days) or discontinuation of therapy may be required.

Crystalluria and nephrolithiasis may occur during treatment with indinavir. The cumulative frequency of nephrolithiasis is substantially higher in pediatric patients (29%) than in adult patients (12.4%; range 4.7% to 34.4% across individual trials) and increases with duration of exposure to indinavir; however, the risk over time remains relatively constant. The incidence is also higher when indinavir is used in combination with ritonavir than when used alone at 800 mg three times a day. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure and pyelonephritis with or without bacteremia. Therapy with indinavir should be administered cautiously in patients with a current or past history of nephrolithiasis. It is crucial that patients receive adequate hydration. Generally, at least 1.5 L (approximately 48 oz) of fluid per day is recommended for adults during indinavir therapy. Those who are dehydrated may be at increased risk and should be encouraged to consume additional amounts of liquid or given intravenous fluid if necessary. All patients receiving indinavir should be instructed to seek medical attention if they experience potential signs and symptoms of nephrolithiasis/urolithiasis such as flank pain, hematuria, dysuria, anuria, and urinary urgency. A brief interruption (e.g., 1 to 3 days) or discontinuation of therapy may be required.

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, hyperglycemia, and some cases of diabetic ketoacidosis have been reported during postmarketing surveillance in HIV-infected patients treated with protease inhibitors. Some patients required either initiation or dosage adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, hyperglycemia persisted despite discontinuation of protease inhibitor therapy. A causal relationship has not been established between protease inhibitor therapy and these events. Monitoring patients for hyperglycemia, new onset diabetes mellitus, or exacerbation of diabetes mellitus should be considered during protease inhibitor therapy.

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, hyperglycemia, and some cases of diabetic ketoacidosis have been reported during postmarketing surveillance in HIV-infected patients treated with protease inhibitors. Some patients required either initiation or dosage adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, hyperglycemia persisted despite discontinuation of protease inhibitor therapy. A causal relationship has not been established between protease inhibitor therapy and these events. Monitoring patients for hyperglycemia, new onset diabetes mellitus, or exacerbation of diabetes mellitus should be considered during protease inhibitor therapy.

Indinavir is primarily metabolized by the liver. Patients with liver disease may be at greater risk for adverse effects from indinavir due to decreased drug clearance. Therapy with indinavir should be administered cautiously in patients with liver disease. A dosage reduction to 600 mg three times a day is recommended for patients with mild to moderate hepatic insufficiency due to cirrhosis.

Tazemetostat has not been studied in patients with moderate or severe hepatic impairment. Care should be exercised when using this drug in these patients. No dose adjustment is needed for patients with mild hepatic impairment.