Drug Interactions between Natrol Sleep+Immune Health and rilonacept

MONITOR: Additive effects and possible toxicity (e.g., hypercalcemia, hypercalciuria, and/or hyperphosphatemia) may occur when patients using vitamin D and/or vitamin D analogs ingest a diet high in vitamin D, calcium, and/or phosphorus. The biologically active forms of vitamin D stimulate intestinal absorption of calcium and phosphorus. This may be helpful in patients with hypocalcemia and/or hypophosphatemia. However, sudden increases in calcium or phosphorus consumption due to dietary changes could precipitate hypercalcemia and/or hyperphosphatemia. Patients with certain disease states, such as impaired renal function, may be more susceptible to toxic side effects like ectopic calcification. On the other hand, if dietary calcium is inadequate for the body's needs, the active form of vitamin D will stimulate osteoclasts to pull calcium from the bones. This may be detrimental in a patient with reduced bone density.

MANAGEMENT: Given the narrow therapeutic index of vitamin D and vitamin D analogs, the amounts of calcium, phosphorus, and vitamin D present in the patient's diet may need to be taken into consideration. Specific dietary guidance should be discussed with the patient and regular lab work should be monitored as indicated. Calcium, phosphorus, and vitamin D levels should be kept within the desired ranges, which may differ depending on the patient's condition. Patients should also be counseled on the signs and symptoms of hypervitaminosis D, hypercalcemia, and/or hyperphosphatemia.

MONITOR: Oral caffeine may significantly increase the bioavailability of melatonin. The proposed mechanism is inhibition of CYP450 1A2 first-pass metabolism. After administration of melatonin 6 mg and caffeine 200 mg orally (approximately equivalent to 1 large cup of coffee) to 12 healthy subjects, the mean peak plasma concentration (Cmax) of melatonin increased by 137% and the area under the concentration-time curve (AUC) increased by 120%. The metabolic inhibition was greater in nonsmokers (n=6) than in smokers (n=6). The greatest effect was seen in subjects with the *1F/*1F genotype (n=7), whose melatonin Cmax increased by 202%. The half-life did not change significantly. The clinical significance of this interaction is unknown.

According to some authorities, alcohol may reduce the effect of melatonin on sleep. The mechanism of this interaction is not fully understood.

In addition, CYP450 1A2 inducers like cigarette smoking may reduce exogenous melatonin plasma levels. In a small clinical trial (n=8), habitual smokers had their melatonin plasma levels measured two times, each after a single oral dose of 25 mg of melatonin. They had smoked prior to the first measurement but had not smoked for 7 days prior to the second. Cigarette smoking significantly reduced melatonin plasma exposure (AUC) as compared to melatonin levels after 7 days of smoking abstinence (7.34 +/- 1.85 versus 21.07 +/- 7.28 nmol/L*h, respectively).

MANAGEMENT: Caution and monitoring are recommended if melatonin is used with inhibitors of CYP450 1A2 like caffeine or inducers of CYP450 1A2 like cigarette smoking. Consumption of alcohol should be avoided when taking melatonin.