Drug Interaction Report

MONITOR CLOSELY: Coadministration of ozanimod with antineoplastic, immunosuppressive, or other immune-modulating therapies may increase the risk of unintended additive immunosuppressive effects. Ozanimod causes reversible sequestration of lymphocytes in lymphoid tissues. When administered daily in clinical trials for MS, ozanimod produces a mean reduction in peripheral blood lymphocyte count to 45% of baseline values, which may increase the risk of infections. Life-threatening and rare fatal infections have occurred in association with ozanimod. Decreased lymphocyte counts persist during chronic daily dosing and generally return to normal within 30 days after stopping the medication. Pharmacodynamic effects, such as decreased peripheral lymphocytes, may persist for up to 3 months after the last dose, and as a result, use of immunosuppressants during this time may also lead to additive immune effects. The safety and efficacy of ozanimod in combination with antineoplastic, immunosuppressive, or immune-modulating agents have not been evaluated.

MANAGEMENT: Concomitant use of ozanimod with antineoplastic, immunosuppressive, or immune-modulating agents should be avoided according to some authorities (UK); however, other authorities (AU, US) advise caution and close monitoring during coadministration and for up to 3 months after the last dose of ozanimod. When switching from drugs with prolonged immune effects to ozanimod, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation.

ADJUST DOSING INTERVAL: The oral bioavailability of mercaptopurine (6-MP) is highly variable and may be affected by administration with food or dairy products. The mechanism by which food may impact the absorption of 6-MP has not been fully established, but cow's milk specifically has been found to contain a high concentration of xanthine oxidase, the enzyme responsible for first-pass metabolism of 6-MP to the inactive metabolite 6-thiouric acid. Incubation with cow's milk at 37 C induced a 30% catabolism of 6-MP within 30 minutes in one investigation. However, food or dairy intake with 6-MP in study patients has yielded variable results. In a study conducted in 17 children with acute lymphoblastic leukemia (ALL), oral 6-MP 75 mg/m2 administered 15 minutes after a standardized breakfast including 250 mL of milk resulted in a prolonged Tmax and a lower Cmax and AUC compared with 6-MP administration in the fasting state (mean Tmax: 2.3 hours vs. 1.2 hours; mean Cmax: 0.63 uM vs. 0.98 uM; mean AUC: 105 uM vs. 143 uM, respectively). In a different study, oral 6-MP 31.2 to 81.1 mg/m2 administered to 7 subjects with ALL 15 minutes after a standard breakfast consisting of orange juice, cereal, and toast also trended towards longer Tmax and lower Cmax values compared to 6-MP administration after an overnight fast, although the differences were not statistically significant. Two subjects had blood samples that were all below the limit of detection (20 ng/mL) following administration in the fed state. Likewise, a study of 15 pediatric patients reported non-significant 20% to 22% decreases in the Cmax and AUC of 6-MP when administered after a standardized breakfast containing both milk and cheese compared to administration after fasting, but in contrast to the two earlier studies, Tmax was decreased from 1.8 to 1.1 hours. Another study of 10 children with ALL or non-Hodgkin's lymphoma given an average oral 6-MP dose of 63 mg/m2 revealed substantial interpatient variations in the effect of food intake on 6-MP plasma levels, with Cmax changes ranging from 67% decrease to 81% increase and AUC changes ranging from 53% decrease to 86% increase relative to administration following fasting. Collectively for the group, however, there was no statistically significant difference in mean Tmax, Cmax, or AUC between the fed and fasting states. In this study, patients were fed what they normally ate at home rather than a standardized breakfast, which may have contributed to the inconsistent results. The clinical significance of the data and observations from these studies has not been determined. An interaction with milk was suspected in a four-year-old male with ALL who experienced persistent elevations of peripheral blood counts during maintenance with 6-MP and methotrexate despite increasing doses of 6-MP up to 160% of the calculated dosage for his body surface area (75 mg/m2). Cessation of concomitant milk ingestion allowed for the 6-MP dosage to return to 75 mg/m2 and resulted in control of peripheral blood counts within a week. Other data do not support a clinically relevant interaction with food or dairy products. In a prospective study of 441 patients aged 2 to 20 years receiving 6-MP for ALL maintenance, investigators found no significant association between relapse risk and 6-MP ingestion habits including administration with food versus never with food and administration with milk/dairy versus never with milk/dairy. Among the 56.2% of patients who were considered adherent by the study, there was also no significant association between red cell thioguanine nucleotide (active metabolite) levels and taking 6-MP with food versus without or taking with milk/dairy versus without. However, taking 6-MP with milk/dairy was associated with a 1.9-fold increased risk for nonadherence. These results suggest that taking 6-MP with food or milk/dairy products may not influence clinical outcome but may hinder patient adherence. Poor 6-MP adherence has been associated with an increased risk of childhood ALL relapse.

MANAGEMENT: To minimize variability in absorption and systemic exposure, the timing of mercaptopurine administration should be standardized in relation to food intake (i.e., always with food or always on an empty stomach). Some authorities suggest avoiding concomitant administration with milk or dairy products, although the clinical relevance of their effects on mercaptopurine bioavailability has not been established. As a precaution, patients may consider taking mercaptopurine at least 1 hour before or 2 hours after milk or dairy ingestion if they are able to do so without compromising treatment adherence.

GENERALLY AVOID: Foods that contain large amounts of tyramine may precipitate a hypertensive crisis in patients treated with ozanimod. The proposed mechanism involves potentiation of the tyramine pressor effect due to inhibition of monoamine oxidase (MAO) by the major active metabolites of ozanimod, CC112273 and CC1084037. Monoamine oxidase in the gastrointestinal tract and liver, primarily type A (MAO-A), is the enzyme responsible for metabolizing exogenous amines such as tyramine and preventing them from being absorbed intact. Once absorbed, tyramine is metabolized to octopamine, a substance that is believed to displace norepinephrine from storage granules causing a rise in blood pressure. In vitro, CC112273 and CC1084037 inhibited MAO-B (IC50 values of 5.72 nM and 58 nM, respectively) with more than 1000-fold selectivity over MAO-A (IC50 values >10000 nM). Because of this selectivity, as well as the fact that free plasma concentrations of CC112273 and CC1084037 are less than 8% of the in vitro IC50 values for MAO-B inhibition, ozanimod is expected to have a much lower propensity to cause hypertensive crises than nonselective MAO inhibitors. However, rare cases of hypertensive crisis have occurred during clinical trials for the treatment of multiple sclerosis (MS) and ulcerative colitis (UC) and in postmarketing use. In controlled clinical trials, hypertension and blood pressure increases were reported more frequently in patients treated with ozanimod (up to 4.6% in MS patients receiving ozanimod 0.92 mg/day) than in patients treated with interferon beta-1a (MS) or placebo (UC).

Administration of ozanimod with either a high-fat, high-calorie meal (1000 calories; 50% fat) or a low-fat, low-calorie meal (300 calories; 10% fat) had no effects on ozanimod peak plasma concentration (Cmax) and systemic exposure (AUC) compared to administration under fasted conditions.

MANAGEMENT: Dietary restriction is not ordinarily required during ozanimod treatment with respect to most foods and beverages that contain tyramine, which usually include aged, fermented, cured, smoked, or pickled foods (e.g., air-dried and fermented meats or fish, aged cheeses, most soybean products, yeast extracts, red wine, beer, sauerkraut). However, certain foods like some of the aged cheeses (e.g., Boursault, Liederkrantz, Mycella, Stilton) and pickled herring may contain very high amounts of tyramine and could potentially cause a hypertensive reaction in patients taking ozanimod, even at recommended dosages, due to increased sensitivity to tyramine. Patients should be advised to avoid the intake of very high levels of tyramine (e.g., greater than 150 mg) and to promptly seek medical attention if they experience potential signs and symptoms of a hypertensive crisis such as severe headache, visual disturbances, confusion, stupor, seizures, chest pain, unexplained nausea or vomiting, and stroke-like symptoms. Blood pressure should be regularly monitored and managed accordingly. Because of the long elimination half-lives of the major active metabolites, these precautions may need to be observed for up to 3 months following the last ozanimod dose. Ozanimod can be administered with or without food.