FELODIPINE ER (felodipine)

There are 2 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Felodipine; Nisoldipine/Itraconazole; Ketoconazole; Levoketoconazole SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Itraconazole(1), ketoconazole(2), and levoketoconazole(3) may inhibit the metabolism of felodipine by CYP3A4. Nisoldipine has a low absolute bioavailability of approximately 5% due to intestinal and hepatic first-pass metabolism by CYP3A4.(4) FDA designates nisoldipine as a CYP3A4 sensitive substrate, i.e. a drug whose plasma area-under-curve (AUC) has been shown to increase 5-fold or more in the presence of a strong inhibitor of CYP3A4.(5) Both itraconazole(1,5-6) and ketoconazole(2,5-6) are strong inhibitors of CYP3A4. In addition, itraconazole has been shown to have negative inotropic effects, which may be additive with those of nisoldipine.(1) CLINICAL EFFECTS: The concurrent administration of itraconazole or ketoconazole may result in a 6 to 8 fold increase in felodipine AUC(1) or a 10 to 24-fold increase in nisoldipine AUC(1) leading to adverse effects such as severe hypotension or peripheral edema. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent use of itraconazole(1,7,8), ketoconazole(2,9), or levoketoconazole(3) with felodipine or nisoldipine is contraindicated. The US manufacturer of itraconazole states that concurrent administration with felodipine or nisoldipine is contraindicated during and two weeks after itraconazole treatment.(1) While all dihydropyridine calcium channel blockers are metabolized and could be affected by CYP3A4 inhibitors, nisoldipine and felodipine are particularly sensitive to CYP3A4 inhibition.(6) If ketoconazole or itraconazole therapy is required, it would be prudent to change to a low dose of a different dihydropyridine with careful monitoring for adverse effects. DISCUSSION: A double-blind, randomized, two-phase crossover study in nine subjects examined the effects of itraconazole on felodipine. The area-under-curve (AUC) and half-life of felodipine increased by 6-fold and 2-fold, respectively, during concurrent itraconazole. In seven of the nine subjects, the maximum concentration (Cmax) of felodipine when administered with placebo was lower than the 32-hour concentration of felodipine when administered with itraconazole. Concurrent use also resulted in significantly greater effects on both blood pressure and heart rate.(10) There are two case reports of patients developing edema following the addition of itraconazole to felodipine therapy. In the second report, the patient was rechallenged with concurrent itraconazole and again developed edema.(11) Concurrent use of itraconazole produces clinically significant increases in nisoldipine levels that cannot be managed by dosage adjustment.(1) A randomized cross-over trial in seven subjects examined the effects of ketoconazole (200 mg daily for 4 days) on nisoldipine (5 mg daily). The concurrent use of ketoconazole increased the nisoldipine AUC and Cmax by 24-fold and 11-fold, respectively. Increases in the M9 nisoldipine metabolite were similar.(12) A study in 14 healthy volunteers with concurrent administration of levoketoconazole (400 mg once daily) with felodipine increased the felodipine AUC and Cmax by 1007.3% and 937.1%.(3)	ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KETOCONAZOLE, RECORLEV, SPORANOX, TOLSURA
Selected CYP3A4 Substrates/Mifepristone SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Mifepristone is an inhibitor of CYP3A4 and may increase levels and effects of drugs metabolized by this enzyme.(1) CLINICAL EFFECTS: Lovastatin, simvastatin and CYP3A4 substrates with a narrow therapeutic window such as alprazolam, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, and tacrolimus or CYP3A4 substrates with a high first pass effect such as oral midazolam, sildenafil, and triazolam are particularly susceptible to significant toxicity.(1,2) PREDISPOSING FACTORS: Due to the need for continuous therapy and mifepristone's long half-life of 85 hours(1) which leads to accumulation, patients with endogenous Cushing's syndrome may be at an increased risk for toxicity. With pimozide, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3) PATIENT MANAGEMENT: The US manufacturer of mifepristone for hypercortisolism due to endogenous Cushing's syndrome states use with lovastatin, simvastatin, CYP3A4 substrates with a narrow therapeutic range, or CYP3A4 substrates with a high first pass effect is contraindicated.(1) DISCUSSION: Administration of mifepristone 1200 mg daily for 10 days followed by a single dose of simvastatin 80 mg led to an increase of simvastatin and simvastatin acid (active metabolite) area-under-curve (AUC) of 10.4-fold and 15.7-fold, respectively.	KORLYM, MIFEPREX, MIFEPRISTONE

Drug contraindication overview.

No enhanced Contraindications information available for this drug.

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None