Drug Interactions between Juvisync and Proquin XR

GENERALLY AVOID: Coadministration with grapefruit juice may significantly increase the plasma concentrations of lovastatin and simvastatin and their active acid metabolites. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. When a single 60 mg dose of simvastatin was coadministered with 200 mL of double-strength grapefruit juice three times a day, simvastatin systemic exposure (AUC) increased by 16-fold and simvastatin acid AUC increased by 7-fold. Administration of a single 20 mg dose of simvastatin with 8 ounces of single-strength grapefruit juice increased the AUC of simvastatin and simvastatin acid by 1.9-fold and 1.3-fold, respectively. The interaction has also been reported with lovastatin, which has a similar metabolic profile to simvastatin. Clinically, high levels of HMG-CoA reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

ADJUST DOSING INTERVAL: Fibres such as oat bran and pectin may diminish the pharmacologic effects of HMG-CoA reductase inhibitors by interfering with their absorption from the gastrointestinal tract.

Coadministration with green tea may increase the plasma concentrations of simvastatin. The mechanism of interaction has not been established, but may involve inhibition of organic anion transporting polypeptide (OATP) 1B1- and/or 2B1-mediated hepatic uptake of simvastatin by catechins in green tea. The interaction was suspected in a 61-year-old man who experienced muscle intolerance during treatment with simvastatin while drinking an average of 3 cups of green tea daily. He also experienced similar muscle intolerance (leg cramps without creatine phosphokinase elevation) during treatments with atorvastatin and rosuvastatin while drinking green tea. Pharmacokinetic studies performed during his usual green tea intake demonstrated an approximately two-fold higher exposure to simvastatin lactone (the administered form of simvastatin) than that observed after stopping green tea intake for a month. He was also able to tolerate simvastatin after discontinuing green tea consumption. The authors of the report subsequently conducted two independent studies to assess the effect of different green tea preparations on simvastatin pharmacokinetics. One study was conducted in 12 Italian subjects and the other in 12 Japanese subjects. In the Italian study, administration of a single 20 mg dose of simvastatin following pretreatment with 200 mL of a hot green tea standardized infusion 3 times daily for 14 days (estimated daily intake of 335 mg total catechins and 173 mg epigallocatechin-3-gallate (EGCG), the most abundant and biologically active catechin in green tea) was found to have no significant effect on mean peak plasma concentration (Cmax) or systemic exposure (AUC) of simvastatin lactone and simvastatin acid relative to administration with water. However, green tea increased simvastatin lactone AUC (0-6h) by about two-fold in 3 of the study subjects. In the Japanese study, administration of a single 10 mg dose of simvastatin following pretreatment with 350 mL of a commercial green tea beverage twice daily for 14 days (estimated daily intake of 638 mg total catechins and 322 mg EGCG) did not affect mean simvastatin lactone Cmax or AUC to a statistically significant extent compared to administration with water, but increased mean simvastatin acid Cmax and AUC by 42% and 22%, respectively. Similar to the first study, green tea increased simvastatin lactone AUC (0-6h) by two- to three-fold in 4 of the study subjects. Although not studied, the interaction may also occur with lovastatin due to its similar metabolic profile to simvastatin.

MANAGEMENT: Patients receiving therapy with lovastatin, simvastatin, or red yeast rice (which contains lovastatin) should be advised to avoid the consumption of grapefruit and grapefruit juice. Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are metabolized by other enzymes and may be preferable alternatives in some individuals. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed. Also, patients should either refrain from the use of oat bran and pectin, or separate the administration times by at least 2 to 4 hours if concurrent use cannot be avoided. Caution may be advisable when coadministered with green tea or green tea extracts. Dosing reduction of the statin and/or limiting consumption of green tea and green tea products may be required if an interaction is suspected.

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ADJUST DOSING INTERVAL: Concurrent ingestion of dairy products (milk, yogurt) or calcium-fortified foods (i.e., cereal, orange juice) may decrease the activity of certain oral fluoroquinolone antibiotics. The mechanism is chelation of calcium and the quinolone, resulting in decreased bioavailability. In the case of orange juice, inhibition of intestinal transport mechanisms (P-glycoprotein or organic anion-transporting polypeptides) by flavones may also be involved. One study reported an average 41% decrease in maximum plasma concentrations and a 38% decrease in AUC when ciprofloxacin was given with calcium-fortified orange juice instead of water. Administration of ciprofloxacin tablets with enteral nutrition may reduce its bioavailability and maximum serum concentrations. Data have been conflicting and variable by the type of enteral nutrition product, location of the feeding tube, and patient characteristics. Decreased absorption is expected if ciprofloxacin is given by jejunostomy tube.

MANAGEMENT: Oral ciprofloxacin should not be taken with dairy products or calcium-fortified foods alone, but may be taken with meals that contain these products. When taken alone, dairy products or calcium-fortified foods should be ingested at least 2 hours before or after ciprofloxacin administration. When ciprofloxacin tablets are administered to patients receiving continuous enteral nutrition, some experts recommend that the tube feeding should be interrupted for at least 1 hour before and 2 hours after the dose of ciprofloxacin is given. Patients should be monitored for altered antimicrobial efficacy and switched to intravenous ciprofloxacin if necessary. If no enteral route besides a jejunostomy tube is available, it is also recommended to switch to intravenous ciprofloxacin. According to the manufacturer, ciprofloxacin oral suspension should not be administered via nasogastric or feeding tubes due to its physical characteristics.

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GENERALLY AVOID: Alcohol may cause hypoglycemia or hyperglycemia in patients with diabetes. Hypoglycemia most frequently occurs during acute consumption of alcohol. Even modest amounts can lower blood sugar significantly, especially when the alcohol is ingested on an empty stomach or following exercise. The mechanism involves inhibition of both gluconeogenesis as well as the counter-regulatory response to hypoglycemia. Episodes of hypoglycemia may last for 8 to 12 hours after ethanol ingestion. By contrast, chronic alcohol abuse can cause impaired glucose tolerance and hyperglycemia. Moderate alcohol consumption generally does not affect blood glucose levels in patients with well controlled diabetes. A disulfiram-like reaction (e.g., flushing, headache, and nausea) to alcohol has been reported frequently with the use of chlorpropamide and very rarely with other sulfonylureas.

MANAGEMENT: Patients with diabetes should avoid consuming alcohol if their blood glucose is not well controlled, or if they have hypertriglyceridemia, neuropathy, or pancreatitis. Patients with well controlled diabetes should limit their alcohol intake to one drink daily for women and two drinks daily for men (1 drink = 5 oz wine, 12 oz beer, or 1.5 oz distilled spirits) in conjunction with their normal meal plan. Alcohol should not be consumed on an empty stomach or following exercise.

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MONITOR: Concomitant use of statin medication with substantial quantities of alcohol may increase the risk of hepatic injury. Transient increases in serum transaminases have been reported with statin use and while these increases generally resolve or improve with continued therapy or a brief interruption in therapy, there have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Active liver disease or unexplained transaminase elevations are contraindications to statin use.

MANAGEMENT: Patients should be counseled to avoid substantial quantities of alcohol in combination with statin medications and clinicians should be aware of the increased risk for hepatotoxicity in these patients.

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ADJUST DOSING INTERVAL: Oral preparations that contain magnesium, aluminum, or calcium may significantly decrease the gastrointestinal absorption of quinolone antibiotics. Absorption may also be reduced by sucralfate, which contains aluminum, as well as other polyvalent cations such as iron and zinc. The mechanism is chelation of quinolones by polyvalent cations, forming a complex that is poorly absorbed from the gastrointestinal tract. The bioavailability of ciprofloxacin has been reported to decrease by as much as 90% when administered with antacids containing aluminum or magnesium hydroxide.

MANAGEMENT: When coadministration cannot be avoided, quinolone antibiotics should be dosed either 2 to 4 hours before or 4 to 6 hours after polyvalent cation-containing products to minimize the potential for interaction. When coadministered with Suprep Bowel Prep (magnesium/potassium/sodium sulfates), the manufacturer recommends administering fluoroquinolone antibiotics at least 2 hours before and not less than 6 hours after Suprep Bowel Prep to avoid chelation with magnesium. Please consult individual product labeling for specific recommendations.

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MONITOR: Coadministration with certain quinolones may increase the plasma concentrations and pharmacologic effects of caffeine due to inhibition of the CYP450 1A2 metabolism of caffeine. Quinolones that may inhibit CYP450 1A2 include ciprofloxacin, enoxacin, grepafloxacin, nalidixic acid, norfloxacin, pipemidic acid, and pefloxacin (not all commercially available). In healthy volunteers, enoxacin (100 to 400 mg twice daily) increased systemic exposure (AUC) of caffeine by 2- to 5-fold and reduced its clearance by approximately 80%. Pipemidic acid (400 to 800 mg twice daily) increased AUC of caffeine by 2- to 3-fold and reduced its clearance by approximately 60%. Ciprofloxacin (250 to 750 mg twice daily) increased AUC and elimination half-life of caffeine by 50% to over 100%, and reduced its clearance by 30% to 50%. Norfloxacin 400 mg twice daily increased caffeine AUC by 16%, while 800 mg twice daily increased caffeine AUC by 52% and reduced its clearance by 35%. Pefloxacin (400 mg twice daily) has been shown to reduce caffeine clearance by 47%.

MANAGEMENT: Patients using caffeine-containing products should be advised that increased adverse effects such as headache, tremor, restlessness, nervousness, insomnia, tachycardia, and blood pressure increases may occur during coadministration with quinolones that inhibit CYP450 1A2. Caffeine intake should be limited when taking high dosages of these quinolones. If an interaction is suspected, other quinolones such as gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, and ofloxacin may be considered, since they are generally believed to have little or no effect on CYP450 1A2 or have been shown not to interact with caffeine.

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