Drug Interaction Report

GENERALLY AVOID: Coadministration with nonabsorbable cation-donating preparations such as antacids and laxatives may reduce the therapeutic effect of cation-exchange resins and increase the risk of systemic alkalosis. The proposed mechanism involves binding of the cation to the resin, which can interfere with the resin's potassium exchange capability and prevent the cation from neutralizing bicarbonate ions in the intestine. Concomitant use of sodium polystyrene sulfonate and antacids containing calcium, magnesium, and/or aluminum has been reported to cause metabolic alkalosis in patients with end-stage renal disease and advanced stages of chronic kidney disease. Theoretically, the interaction may also occur with other cation-exchange resins that possess nonspecific cation-binding capabilities such as calcium polystyrene sulfonate or patiromer. Other serious adverse effects have also been reported. One patient with chronic hypocalcemia of renal failure developed alkalosis and grand mal seizure when given sodium polystyrene sulfonate with magnesium hydroxide as a laxative. Intestinal obstruction due to concretions of aluminum hydroxide has occurred in combination with sodium polystyrene sulfonate and morphine.

MANAGEMENT: Nonabsorbable calcium, magnesium, or aluminum preparations such as antacids and laxatives should generally be avoided in patients receiving oral cation-exchange resins.

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring 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.

ADJUST DOSING INTERVAL: Administration with food may increase the absorption of calcium. However, foods high in oxalic acid (spinach or rhubarb), or phytic acid (bran and whole grains) may decrease calcium absorption.

MANAGEMENT: Calcium may be administered with food to increase absorption. Consider withholding calcium administration for at least 2 hours before or after consuming foods high in oxalic acid or phytic acid.

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.

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.

ADJUST DOSING INTERVAL: Patiromer can bind to some orally administered drugs, which may decrease their gastrointestinal absorption and reduce their effectiveness. According to the manufacturer, out of 28 drugs that were tested in in vitro binding studies, 14 did not show an interaction with patiromer (acetylsalicylic acid, allopurinol, amoxicillin, apixaban, atorvastatin, cephalexin, digoxin, glipizide, lisinopril, phenytoin, riboflavin, rivaroxaban, spironolactone, and valsartan). Twelve of the 14 drugs that did show an in vitro interaction were subsequently tested in in vivo studies with healthy volunteers, which revealed no changes in systemic exposure when coadministered with patiromer (amlodipine, cinacalcet, clopidogrel, furosemide, lithium, metoprolol, trimethoprim, verapamil, and warfarin). Patiromer was found to decrease systemic exposure of coadministered ciprofloxacin, levothyroxine, and metformin. However, no significant interaction occurred when patiromer and these drugs were dosed 3 hours apart.

MANAGEMENT: Patiromer should be administered with food at least 3 hours before or 3 hours after other oral medications. Alternatives to patiromer or the other medications should be considered if adequate dosing separation is not possible. Otherwise, clinical response and/or blood levels should be monitored where possible.