Drug Interactions between Altocor and Diltiazem Hydrochloride CD

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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MONITOR: Like many CNS-active agents, alcohol can exhibit hypotensive effects. Coadministration with antihypertensive agents including diltiazem may result in additive effects on blood pressure and orthostasis.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered diltiazem in some patients. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In a study of ten healthy male volunteers, administration of a single 120 mg oral dose of immediate-release diltiazem in combination with 250 mL of grapefruit juice increased the diltiazem peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 22% and 20%, respectively, compared to administration with water. The time to reach Cmax (Tmax) and the terminal half-life were not affected, and no statistically significant differences in blood pressure and heart rate were observed during administration with grapefruit juice relative to water. In a different study, repeated administration of 200 mL of grapefruit juice at 0, 2, 4, 8 and 12 hours had no significant effect on the Cmax or AUC of a single 120 mg oral dose of diltiazem, but increased its half-life from 4.1 to 5.1 hours. The ratios for the N-demethyl and deacetyl metabolites to diltiazem were also not affected by grapefruit juice. However, because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients should be advised that alcohol may potentiate the hypotensive effects of diltiazem, especially during the initiation of therapy and following a dosage increase. Caution should be exercised when rising from a sitting or recumbent position, and patients should notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients who regularly consume grapefruit or grapefruit juice should be monitored for increased adverse effects of diltiazem such as such as headache, irregular heartbeat, edema, unexplained weight gain, and chest pain. Grapefruit and grapefruit juice should be avoided if an interaction is suspected.

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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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MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

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