Drug Interaction Report

MONITOR: A disulfiram-like reaction has been reported in two patients who consumed alcohol while taking sulfamethoxazole-trimethoprim DS every 12 hours, although a causal relationship has not been established. The mechanism of interaction is unknown. Both ritonavir oral solution and lopinavir-ritonavir oral solution contain a substantial amount of alcohol (greater than 40% by volume), which, theoretically, can produce a disulfiram-like reaction when coadministered with sulfamethoxazole-trimethoprim. Pharmacokinetically, coadministration of ritonavir (500 mg every 12 hours) and sulfamethoxazole-trimethoprim (single 800mg-160 mg dose) has resulted in a 20% decrease in the area under the plasma concentration-time curve (AUC) of sulfamethoxazole and a 20% increase in the AUC of trimethoprim. The plasma level of ritonavir was not affected. These alterations are unlikely to be of clinical significance, thus dosage adjustments should not be necessary.

MANAGEMENT: Until further information is available, it may be advisable to avoid using ritonavir oral solution and lopinavir-ritonavir oral solution with sulfamethoxazole-trimethoprim. Patients who are prescribed the combination should be alerted to the potential of a disulfiram reaction, which may include symptoms such as flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, weakness, vertigo, blurred vision, and confusion.

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of ombitasvir, paritaprevir, ritonavir, and dasabuvir. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a moderate-fat meal (approximately 600 Kcal; 20% to 30% calories from fat) increased the mean systemic exposure (AUC) by 82%, 211%, 49%, and 30%, respectively. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a high-fat meal (approximately 900 Kcal; with 60% calories from fat) increased the mean AUC by 76%, 180%, 44%, and 22%, respectively.

MANAGEMENT: Ombitasvir/paritaprevir/ritonavir plus dasabuvir should always be administered with a meal. The fat or calorie content does not matter.