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Interactions with Diltiazem

Contents
Verapamil (oral), Clarithromycin, Diazepam, Alprazolam, Bromocriptine, Chlordiazepoxide, Clonazepam, Clorazepate, Dihydroergotamine, Disopyramide, Ergotamine, Ethosuximide, Felodipine, Flurazepam, Isradipine, Medroxyprogesterone, Nicardipine, Quinine, Tamoxifen, Terfenadine, Trazodone, Estradiol oral, Estradiol transdermal, Conjugated estrogens, Esterified estrogens, Estropipate, Chlorotrianisene, Bepridil, Astemizole, Sertraline, Halazepam, Estazolam, Quazepam, Cyclobenzaprine, Troleandomycin, Loratadine, Granisetron, Albendazole, Lansoprazole, Indinavir, Dapsone, Diazepam rectal, Doxorubicin, Etoposide (oral), Ifosfamide, Medroxyprogesterone (injectable), Nimodipine, Vinblastine, Vincristine, Estradiol topical (for use on skin), Estradiol vaginal (systemic), Estradiol injection, Progesterone, Progesterone vaginal, Norethindrone, Levonorgestrel, Levonorgestrel emergency contraceptive, Testosterone injection, Testosterone topical (patches and gel), Testosterone buccal system, Finasteride, Vinorelbine, Nisoldipine (oral), Doxorubicin liposomal, Docetaxel, Mirtazapine, Estradiol (topical), Estradiol vaginal (local), Tiagabine, Dihydroergotamine nasal, Montelukast, Conjugated estrogens (vaginal), Zaleplon

If you are currently being treated with any of the following medications, you should not use Diltiazem without reading these interactions.

Atazanavir (oral)

ADJUST DOSE: Coadministration with atazanavir may significantly increase the plasma concentrations of diltiazem. The mechanism is atazanavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of diltiazem. In addition, both atazanavir and diltiazem can prolong the PR interval of the electrocardiogram and may have additive effects when used in combination. In a pharmacokinetic study, coadministration of atazanavir (400 mg once a day) and diltiazem (180 mg once a day) resulted in a 2-fold increase in diltiazem plasma concentration, and an additive effect on the PR interval was observed. Excessive prolongation of the PR interval may result in conduction disturbances and atrioventricular block.

MANAGEMENT: When used in combination with atazanavir, a reduction of diltiazem dosage by one-half should be considered and ECG monitoring is recommended. Pharmacologic response to diltiazem should be monitored more closely following addition or withdrawal of atazanavir, and the diltiazem dosage adjusted as necessary.

Tolterodine

ADJUST DOSE: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of tolterodine, which is partially metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of tolterodine should be considered. Although tolterodine is primarily metabolized by CYP450 2D6, there is some evidence that CYP450 3A4 may play a minor role, thus any alteration in its activity levels could conceivably affect the metabolism of tolterodine. The clinical significance of this interaction is yet unknown but may be greater in patients who are CYP450 2D6-deficient, or so-called poor metabolizers of CYP450 2D6 (approximately 7% of Caucasians and less than 2% of Asians and individuals of African descent).

MANAGEMENT: The manufacturer recommends a maximum tolterodine dosage of 1 mg twice daily in patients receiving concomitant CYP450 3A4 inhibitors. Close clinical and laboratory monitoring is advised whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to notify their physician if they experience an irregular heartbeat, severe blurry vision, difficulty urinating, dry mouth, headache, drowsiness, dizziness, or GI upset.

Cilostazol

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4 and/or 2C19 may increase the plasma concentrations of cilostazol and or its pharmacologically active metabolites, which are substrates of these isoenzymes. The possibility of prolonged and/or increased pharmacologic effects of cilostazol should be considered. In pharmacokinetic studies, pretreatment with a 400 mg priming dose of ketoconazole (a potent CYP450 3A4 inhibitor) one day prior to coadministration of single doses of ketoconazole 400 mg and cilostazol 100 mg resulted in a 94% increase in cilostazol peak plasma concentration (Cmax) and a 117% increase in cilostazol systemic exposure (AUC). Coadministration of the less potent inhibitor erythromycin (500 mg every 8 hours) with a single 100 mg dose of cilostazol resulted in a 47% and 73% increase in cilostazol Cmax and AUC, respectively, while AUC of 4-trans-hydroxy-cilostazol (an active metabolite with 1/5 the pharmacologic activity) increased by 141% as a result of the inhibition of cilostazol metabolism via CYP450 3A4. Coadministration with 180 mg of diltiazem, a moderate CYP450 3A4 inhibitor, decreased cilostazol clearance by 30% and increased its Cmax by 30% and AUC by 40%. In contrast, cilostazol metabolism was not significantly affected when coadministered with omeprazole, a potent CYP450 2C19 inhibitor, but the systemic exposure to 3,4-dehydro-cilostazol (the most active metabolite of cilostazol) was increased by 69%.

MANAGEMENT: The manufacturer recommends a 50% dosage reduction of cilostazol (i.e., 50 mg twice a day) in patients receiving the CYP450 3A4 inhibitors ketoconazole, itraconazole, erythromycin, and diltiazem, or the 2C19 inhibitor omeprazole. Other potent inhibitors include clarithromycin, telithromycin, troleandomycin, fluconazole, miconazole, voriconazole, delavirdine, nefazodone, and protease inhibitors. Close clinical and laboratory monitoring is advised whenever a potent CYP450 3A4 and/or 2C19 inhibitor is added to or withdrawn from cilostazol therapy. Patients should be advised to contact their physician if they experience adverse effects of cilostazol such as headache, dizziness, nausea, diarrhea, or irregular heartbeat.

Eplerenone

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of eplerenone, which is primarily metabolized by the isoenzyme. In pharmacokinetic studies, administration of eplerenone (100 mg single dose) with the potent inhibitor ketoconazole (200 mg twice a day) resulted in a 1.7-fold increase in eplerenone peak plasma concentration (Cmax) and a 5.4-fold increase in systemic exposure (AUC), while administration with other 3A4 inhibitors (erythromycin 500 mg twice daily; verapamil 240 mg once daily; saquinavir 1200 mg three times daily; fluconazole 200 mg once daily) resulted in increases in eplerenone Cmax ranging from 1.4- to 1.6-fold and AUC from 2.0 to 2.9-fold.

MANAGEMENT: Eplerenone should not be used with potent inhibitors of CYP450 3A4 (e.g., itraconazole, ketoconazole, nefazodone, delavirdine, ketolide and certain macrolide antibiotics, most protease inhibitors) and should be used cautiously with other inhibitors of the isoenzyme. The initial dosage of eplerenone should be reduced to 25 mg once daily during concomitant therapy with moderate inhibitors and titrated slowly based on therapeutic response.

Sildenafil (oral)

ADJUST DOSE: The coadministration of diltiazem may increase the plasma concentrations of sildenafil. The mechanism is inhibition of CYP450 3A4 metabolism. While the extent of the interaction may vary, the possibility of prolonged and/or increased pharmacologic effects of sildenafil and of exaggerated or prolonged responses to nitrates should be considered. There may be a significant prolongation of the post-dose period during which use of nitrates is potentially hazardous. A 72-year-old male on a stable regimen which included diltiazem and metoprolol developed asymptomatic hypotension (central arterial pressure decreased from 160/90 to 90/60) after taking sublingual nitroglycerin during angiography. It was determined that he had taken an unprescribed 50 mg dose of sildenafil 48 hours before the procedure. Additive hypotensive effects by metoprolol and diltiazem may also have contributed to the nitrate-induced hypotension.

MANAGEMENT: Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. The manufacturer recommends that an initial sildenafil dosage of 25 mg be considered in patients treated concomitantly with a potent CYP450 3A4 inhibitor. It is unknown when nitrates could be safely administered after a sildenafil dose and in the presence of a CYP450 3A4 inhibitor. Patients should be advised to promptly notify their physician if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

Tizanidine

ADJUST DOSE: Tizanidine may potentiate the hypotensive effect of some medications secondary to its alpha-2 adrenergic activity. Pharmacologic studies have found tizanidine to possess between 1/10 to 1/50 of the potency of clonidine, a structurally similar agent, in lowering blood pressure. In a single-dose study where blood pressure was monitored closely after dosing, two-thirds of patients treated with an 8 mg dose had a 20% reduction in either the diastolic or systolic blood pressure. The reduction was seen within 1 hour after dosing, peaked 2 to 3 hours after dosing, and was associated at times with bradycardia, orthostatic hypotension, lightheadedness, dizziness, and rarely, syncope. The hypotensive effect of tizanidine is dose-related and has been measured following single doses of 2 mg or more. In clinical trials, the addition of tizanidine to antihypertensive therapy was associated with a 20% to 30% increase in the incidence of clinically significant decreases in systolic or diastolic blood pressure compared with placebo plus antihypertensive therapy and tizanidine alone. The incidence of orthostatic hypotension was also increased.

MANAGEMENT: Lower initial dosages and cautious dosage titration should be considered when tizanidine is initiated in patients receiving antihypertensive therapy or if antihypertensive therapy is initiated in patients receiving tizanidine. Although single doses of less than 8 mg of tizanidine have not been shown effective for spasticity in controlled clinical studies, it may be prudent to initiate treatment with 4 mg doses and gradually increase in 2 to 4 mg increments until optimum effect is achieved. The dose can be repeated at 6 to 8 hour intervals as needed, up to a maximum of three doses in 24 hours and a total daily dosage of 36 mg. However, experience with single doses exceeding 8 mg and daily doses exceeding 24 mg is limited. Close monitoring for development of hypotension is recommended. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

Insulin regular, Insulin isophane, Insulin zinc, Insulin zinc extended, Insulin lispro, Insulin glargine, Insulin aspart, Insulin glulisine, Insulin detemir, Insulin inhalation

A single case report suggests that diltiazem may decrease the hypoglycemic effect of insulin. The mechanism of interaction is unknown. Diltiazem 180 mg/day reportedly had no effect on glucose levels in normal subjects. In addition, diltiazem 240 to 360 mg/day had no significant effects on glucose control in 23 hypertensive patients with Type II diabetes. While no special precautions appear to be necessary, patients may consider monitoring blood glucose more closely during the first few days or weeks of diltiazem therapy until glucose control is assured.

Fluoxetine

A small series of cases has suggested that fluoxetine may potentiate the effects of calcium channel blockers. Specific adverse effects that have been reported include edema, headaches, nausea, and flushing. Caution is recommended if these drugs must be used together.

Donepezil (oral)

Coadministration with inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations of donepezil, which is primarily metabolized by these isoenzymes. In a 7-day crossover study in 18 healthy volunteers, the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily) increased the mean peak plasma concentration (Cmax) and systemic exposure (AUC) of donepezil (5 mg once daily) by approximately 36% each. The clinical relevance of these increases is unknown.

Retapamulin topical

Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of retapamulin, which is primarily metabolized by the isoenzyme. In healthy adult males, coadministration of the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally twice a day) increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of retapamulin by 81% following topical application of retapamulin ointment 1% on abraded skin. However, dosage adjustments are not necessary due to the low systemic exposure to retapamulin following topical application.

Moricizine

Concomitant administration of diltiazem and moricizine has been reported to increase serum concentrations of moricizine and to decrease serum concentrations of diltiazem. The mechanism of action and clinical significance are unknown. If these drugs are used together, close monitoring for altered effects is strongly recommended when either drug is initiated, stopped, or a dosage adjustment made.

Pimozide (oral)

CONTRAINDICATED: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of pimozide, which is partially metabolized by the isoenzyme. The use of pimozide has been associated with dose-related prolongation of the QT interval, thus elevated plasma levels of the drug may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes as well as cardiac arrest and sudden death.

MANAGEMENT: The manufacturer considers the use of pimozide with potent CYP450 3A4 inhibitors like protease inhibitors, macrolide antibiotics, azole antifungals, and nefazodone to be contraindicated. With respect to less potent CYP450 3A4 inhibitors, the manufacturer recommends that they also not be used with pimozide.

Ranolazine

CONTRAINDICATED: Coadministration with potent and moderately potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of ranolazine, which is primarily metabolized by the isoenzyme. Because ranolazine prolongs QT interval in a dose-dependent manner, high plasma levels of ranolazine may increase the risk of ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, and torsade de pointes. In pharmacokinetic studies, plasma levels of ranolazine (1000 mg twice a day) were increased 3.2-fold by the potent CYP450 3A4 inhibitor, ketoconazole (200 mg twice a day), and 1.8- to 2.3-fold by the moderately potent inhibitor diltiazem (180 to 360 mg/day). Plasma levels of ranolazine (750 mg twice a day) were increased about 2-fold by the CYP450 3A4 and P-glycoprotein inhibitor, verapamil (120 mg three times a day).

MANAGEMENT: Ranolazine should not be used in combination with potent or moderately potent CYP450 3A4 inhibitors, including but not limited to diltiazem, verapamil, nefazodone, delavirdine, azole antifungal agents, protease inhibitors, and ketolide and certain macrolide antibiotics.

Salsalate, Magnesium salicylate, Diflunisal

Diltiazem may enhance the antiplatelet effect of salicylates. The mechanism is unknown. If occult bleeding occurs, consider discontinuing or adjusting the dosage of one or both agents.

Pramipexole (oral)

Drugs that are secreted by the renal tubules via the cationic transport system may decrease the oral clearance of pramipexole by approximately 20%. The mechanism of action is competitive inhibition of tubular secretion of pramipexole. This interaction is not likely to be of clinical importance, although it may be prudent to monitor the patient for increased adverse effects due to pramipexole.

Cisapride (oral)

GENERALLY AVOID: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of cisapride, which is primarily metabolized by the isoenzyme. High plasma levels of cisapride have been associated with prolongation of the QT interval on the ECG; ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsade de pointes; cardiac arrest; and sudden death.

MANAGEMENT: Given the potential for serious and life-threatening adverse cardiac events associated with increased plasma levels of cisapride, the concomitant use with potent CYP450 3A4 inhibitors (e.g., azole antifungal agents, protease inhibitors, certain macrolide antibiotics, nefazodone) is considered contraindicated. Use with other agents known to inhibit CYP450 3A4 should generally be avoided if possible.

Rifampin, Carbamazepine (oral), Griseofulvin, Pentobarbital, Phenobarbital, Primidone, Secobarbital, Sulfinpyrazone, Mephobarbital, Rifabutin, Felbamate, Nevirapine, Somatropin, Aminoglutethimide, Troglitazone (oral), Rifapentine, Efavirenz, Modafinil, St. John's wort, Bexarotene, Oxcarbazepine, Bosentan

GENERALLY AVOID: Coadministration with inducers of CYP450 3A4 may significantly decrease the plasma concentrations of diltiazem, which is primarily metabolized by the isoenzyme. In one study, coadministration with the inducer efavirenz (600 mg daily for 14 days) decreased the peak plasma concentration (Cmax), trough plasma concentration (Cmin) and systemic exposure (AUC) of diltiazem (240 mg daily for 21 days) by a mean of 60%, 63% and 69%, respectively, in 13 subjects. Rifampin, another CYP450 3A4 inducer, has been reported to lower diltiazem plasma concentrations to undetectable levels.

MANAGEMENT: Use of diltiazem with rifampin or any known CYP450 3A4 inducer should be avoided when possible, and alternative therapy considered. Diltiazem dose adjustment should be guided by clinical response if concomitant use with a CYP450 3A4 inducer is necessary.

Erythromycin

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of erythromycin, which is primarily metabolized by the isoenzyme. The use of erythromycin has been associated with dose-related prolongation of the QT interval, thus elevated plasma levels of the drug may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes. In a population-based retrospective study of 1476 cases of confirmed sudden death from cardiac causes, concurrent use of erythromycin and a CYP450 3A4 inhibitor (mostly verapamil or diltiazem) was associated with a marked increase in the risk of sudden death from cardiac causes as compared to nonuse of CYP450 3A4 inhibitors, erythromycin, or amoxicillin; concurrent use of amoxicillin and CYP450 3A4 inhibitors; use of CYP450 3A4 inhibitors without erythromycin or amoxicillin; and concurrent use of erythromycin and calcium channel blockers that do not significantly inhibit CYP450 3A4 (e.g., nifedipine). In fact, the risk was five times as high as that for nonuse of CYP450 3A4 inhibitors, erythromycin, or amoxicillin.

MANAGEMENT: The concurrent use of erythromycin and potent inhibitors of CYP450 3A4 (e.g., itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, ketolide and certain macrolide antibiotics) should be avoided.

Apomorphine

MONITOR: Antihypertensive agents and vasodilators may increase the hypotensive effect of apomorphine due to additive effects. Apomorphine alone has been associated with orthostatic hypotension, hypotension, syncope. and dose dependent decreases in systolic blood pressure. In clinical trials, an increased incidence of myocardial infarction, serious pneumonia, serious falls, and bone and joint injuries were reported in patients receiving concomitant therapy. The cause is unknown, but may be due to increased hypotension.

MANAGEMENT: Caution and close monitoring for altered efficacy and safety are recommended if patients receive apomorphine with an antihypertensive agent or vasodilator. Patients should be made aware of the possible side effects (e.g., dizziness, lightheadedness, orthostasis) and be cautioned about driving, operating machinery, or performing other hazardous tasks, and to arise slowly from a sitting or lying position. They should also be advised to notify their physician if they experience dizziness or fainting.

Dutasteride

MONITOR: Based on in vitro data, the coadministration with drugs that are inhibitors of the CYP450 3A4 enzymatic pathway may increase the plasma concentrations of dutasteride, which is metabolized by this isoenzyme. No clinical drug interaction studies have been conducted. However, a population pharmacokinetic analysis found decreased clearance of dutasteride when it is coadministered with the CYP450 3A4 inhibitors, verapamil and diltiazem (37% and 44%, respectively). In contrast, no decrease in dutasteride clearance was seen during coadministration with amlodipine, a calcium channel blocker that is not a CYP450 3A4 inhibitor.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of dutasteride should be considered during chronic, concomitant therapy with CYP450 3A4 inhibitors, particularly potent inhibitors such as ketoconazole, itraconazole, ritonavir, nefazodone and erythromycin.

Grepafloxacin

MONITOR: Based on in vitro inhibition data, coadministration with grepafloxacin may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by grepafloxacin.

MANAGEMENT: Caution is advised if grepafloxacin must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever grepafloxacin is added to or withdrawn from therapy.

Calcium carbonate, Multivitamins and minerals, Prenatal multivitamins, Calcium acetate, Calcium gluconate, Calcium lactate, Calcium phosphate, tribasic (tricalcium phosphate), Calcium glubionate, Calcium citrate

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.

Rotigotine (transdermal)

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.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. 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.

Acebutolol, Metoprolol, Pindolol, Timolol, Metipranolol ophthalmic, Carteolol, Bisoprolol, Levobunolol ophthalmic, Carvedilol, Timolol ophthalmic, Betaxolol ophthalmic, Carteolol ophthalmic, Betaxolol, Esmolol, Penbutolol, Sotalol, Sotalol AF, Levobetaxolol ophthalmic

MONITOR CLOSELY: Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occur when calcium channel blockers, especially verapamil and diltiazem, are used concomitantly with beta blockers. While this combination may be useful and effective in some situations, potentially serious cardiovascular adverse effects such as congestive heart failure, severe hypotension, and/or exacerbation of angina may occur. Ventricular asystole, sinus arrest, and heart block have also been reported. The risk is increased with high dosages, IV administration, left ventricular dysfunction, or AV conduction abnormalities. Beta blocker ophthalmic solutions may also interact, as they are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Bradycardia (36 bpm) with wandering atrial pacemaker occurred in a patient taking oral verapamil and timolol ophthalmic drops. The proposed mechanisms include additive slowing in AV conduction, reduced cardiac contractility secondary to beta-blockade, and decreased peripheral vascular resistance secondary to calcium channel blockade. Verapamil and diltiazem may also decrease the clearance of some beta blockers.

MANAGEMENT: Close clinical monitoring of patient hemodynamic response and tolerance is recommended if these agents are used together, and the dosage of one or both agents adjusted as necessary. Patients should be advised to promptly report any symptoms including fatigue, headache, fainting, swelling of the extremities, weight gain, shortness of breath, chest pain, increased or decreased heartbeat, or irregular heartbeat.

Halofantrine

MONITOR CLOSELY: Coadministration with CYP450 3A4 inhibitors may increase the plasma concentrations of halofantrine, resulting in an increased risk of QT interval prolongation and ventricular arrhythmias. The mechanism is inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of halofantrine. Halofantrine has been associated with QT interval prolongation, ventricular arrhythmias, and sudden death, even at recommended dosages.

MANAGEMENT: Caution and close monitoring is recommended if halofantrine is prescribed with CYP450 3A4 inhibitors, especially potent inhibitors such as itraconazole, ketoconazole, nefazodone, delavirdine, ketolide and certain macrolide antibiotics, and most protease inhibitors. The manufacturer recommends performing an ECG before initiating halofantrine therapy and cardiac monitoring during and for 8 to 12 hours after completion of therapy.

Fentanyl topical, Fentanyl (buccal), Fentanyl citrate (oral transmucosal)

MONITOR CLOSELY: Coadministration with potent and moderate inhibitors of CYP450 3A4 may increase the plasma concentrations of fentanyl, which is primarily metabolized by the isoenzyme. Increased fentanyl concentrations could conceivably increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

MANAGEMENT: Patients receiving fentanyl in combination with potent or moderate CYP450 3A4 inhibitors (e.g., azole antifungal agents, protease inhibitors, ketolide and certain macrolide antibiotics, aprepitant, diltiazem, dalfopristin-quinupristin, delavirdine, imatinib, nefazodone, verapamil) should be carefully monitored, and dosage adjustments made accordingly if necessary. Patients and/or their caregivers should be advised to seek medical attention if potential signs and symptoms of toxicity occur such as dizziness, confusion, fainting, extreme sedation, bradycardia, slow or difficult breathing, and shortness of breath. Patients treated with transdermal formulations of fentanyl should be cautioned that drug interactions and drug effects may be observed for a prolonged period beyond removal of the patch, as significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed.

Flecainide

MONITOR CLOSELY: Limited data indicate that verapamil and flecainide may have additive cardiodepressant effects. In pharmacokinetic studies with healthy volunteers, there were minor effects on drug plasma concentrations and QRS intervals were prolonged. However, cases of cardiogenic shock, asystole, and death have been reported in patients receiving flecainide and verapamil. Diltiazem may interact with flecainide in a similar manner, although no data are available.

MANAGEMENT: The patient should be monitored closely when either drug is added to the regimen or when dose increases are made.

Epoprostenol

MONITOR: Coadministration of epoprostenol may increase the effects of hypotensive agents. While epoprostenol and antihypertensive agents have been used together in many clinical trials, caution is recommended if they must be administered concurrently.

MANAGEMENT: Hemodynamic responses should be monitored during coadministration, especially during the first few weeks of therapy. Patients should be advised to notify their physician if they experience dizziness or syncope.

Temsirolimus

MONITOR: Coadministration of temsirolimus with inhibitors of CYP450 3A4 may increase the plasma concentrations of sirolimus, a major active metabolite of temsirolimus and known substrate of CYP450 3A4. According to the product labeling, administration of temsirolimus in combination with the potent CYP450 3A4 inhibitor ketoconazole resulted in a 2.2-fold and 3.1-fold increase in sirolimus peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of temsirolimus alone. No significant effect on the pharmacokinetics of temsirolimus was reported.

MANAGEMENT: Caution is advised if temsirolimus is prescribed in combination with CYP450 3A4 inhibitors. Pharmacologic response to temsirolimus should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the temsirolimus dosage adjusted as necessary. Patients should be advised to contact their physician if they experience increased adverse effects of temsirolimus such as hyperglycemia (e.g., excessive thirst; increased volume and/or frequency of urination), infections, fever, dyspnea, abdominal pain, diarrhea, and bloody stools.

Amprenavir, Fosamprenavir

MONITOR: Coadministration with amprenavir or its prodrug, fosamprenavir, may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by amprenavir.

MANAGEMENT: Caution is advised if amprenavir must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever amprenavir is added to or withdrawn from therapy.

Fluconazole, Ketoconazole, Clotrimazole, Voriconazole, Posaconazole

MONITOR: Coadministration with an azole antifungal agent may increase the plasma concentrations of certain calcium channel blockers (CCBs) including the dihydropyridines (amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nimodipine, nisoldipine), diltiazem, and verapamil. The mechanism is decreased clearance and/or first-pass metabolism of these CCBs due to inhibition of CYP450 3A4 enzymatic activity by azole antifungal agents. Significant increases of several fold in felodipine and nifedipine plasma concentrations have been observed during coadministration with itraconazole, and there have been case reports of leg and ankle edema associated with various itraconazole-dihydropyridine combinations. Similarly, in a pharmacokinetic study, the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of nisoldipine increased 11-fold and 24-fold, respectively, following pretreatment and during concomitant administration with ketoconazole. Other azole antifungal agents are expected to interact similarly with CCBs, although probably to a lesser extent.

MANAGEMENT: During concomitant therapy with azole antifungal agents, patients should be closely monitored for excessive CCB effects, including hypotension and lower extremity edema. Dosage reduction of the CCB may be necessary.

Conivaptan

MONITOR: Coadministration with conivaptan may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by conivaptan. In pharmacokinetic studies with drugs that are primarily metabolized by CYP450 3A4 such as midazolam, simvastatin, and amlodipine, conivaptan has increased systemic exposure (AUC) by 2- to 3-fold.

MANAGEMENT: Caution is advised if conivaptan must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever conivaptan is added to or withdrawn from therapy, or the combination avoided altogether. If a clinical decision is made to discontinue concomitant medications at recommended doses, clinicians should allow an appropriate amount of time following the end of conivaptan administration before resuming these medications.

Verapamil (oral), Clarithromycin, Diazepam, Alprazolam, Bromocriptine, Chlordiazepoxide, Clonazepam, Clorazepate, Dihydroergotamine, Disopyramide, Ergotamine, Ethosuximide, Felodipine, Flurazepam, Isradipine, Medroxyprogesterone, Nicardipine, Quinine, Tamoxifen, Terfenadine, Trazodone, Estradiol oral, Estradiol transdermal, Conjugated estrogens, Esterified estrogens, Estropipate, Chlorotrianisene, Bepridil, Astemizole, Sertraline, Halazepam, Estazolam, Quazepam, Cyclobenzaprine, Troleandomycin, Loratadine, Granisetron, Albendazole, Lansoprazole, Indinavir, Dapsone, Diazepam rectal, Doxorubicin, Etoposide (oral), Ifosfamide, Medroxyprogesterone (injectable), Nimodipine, Vinblastine, Vincristine, Estradiol topical (for use on skin), Estradiol vaginal (systemic), Estradiol injection, Progesterone, Progesterone vaginal, Norethindrone, Levonorgestrel, Levonorgestrel emergency contraceptive, Testosterone injection, Testosterone topical (patches and gel), Testosterone buccal system, Finasteride, Vinorelbine, Nisoldipine (oral), Doxorubicin liposomal, Docetaxel, Mirtazapine, Estradiol (topical), Estradiol vaginal (local), Tiagabine, Dihydroergotamine nasal, Montelukast, Conjugated estrogens (vaginal), Zaleplon

MONITOR: Coadministration with diltiazem may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by diltiazem.

MANAGEMENT: Caution is advised if diltiazem must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever diltiazem is added to or withdrawn from therapy.

Valdecoxib

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2C9 and/or 3A4 may increase the plasma concentrations of valdecoxib, which is metabolized by these isoenzymes. According to the product labeling for valdecoxib, multi-dose administration of fluconazole (CYP450 2C9/3A4 inhibitor) and ketoconazole (CYP450 3A4 inhibitor) increased the area under the plasma concentration-time curve (AUC) of a single 20 mg dose of valdecoxib by 62% and 38%, respectively. Parecoxib, a prodrug of valdecoxib, may be similarly affected.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of valdecoxib or parecoxib, including serious adverse effects such as gastrointestinal ulceration and bleeding, should be considered during concomitant therapy with CYP450 2C9 or 3A4 inhibitors, particularly combination (2C9/3A4) inhibitors such as fluconazole, fluvoxamine, imatinib, and zafirlukast. Dose reductions of the COX-2 inhibitor may be required.

Aprepitant

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of aprepitant, which is primarily metabolized by the isoenzyme. According to the manufacturer, coadministration of the potent CYP450 3A4 inhibitor ketoconazole (400 mg/day for 10 days) and a single 125 mg dose of aprepitant on day 5 resulted in a 5-fold increase in the area under the plasma concentration-time curve (AUC) and a 3-fold increase in the mean terminal half-life of aprepitant. In patients with mild to moderate hypertension, coadministration of the moderate inhibitor diltiazem (120 mg three times a day for 5 days) and aprepitant (approximately 230 mg once a day) resulted in a 2-fold increase in the AUC of aprepitant and a 1.7-fold increase in that of diltiazem. No clinically significant changes in ECG, heart rate, or blood pressure were observed beyond those induced by diltiazem alone.

MANAGEMENT: Caution is advised if aprepitant is used with CYP450 3A4 inhibitors, particularly potent ones like protease inhibitors, macrolide antibiotics, itraconazole, ketoconazole, and nefazodone. Pharmacologic response to aprepitant should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. In addition, many CYP450 3A4 inhibitors are also substrates of the isoenzyme, thus pharmacologic response to these agents should also be monitored during coadministration with aprepitant.

Dofetilide

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of dofetilide, a small amount of which is metabolized by CYP450 3A4. The use of dofetilide alone has been associated with dose-related prolongation of the QT interval and torsade de pointes. Although clinical data are limited, this interaction may result in potentiation of the proarrhythmic effect of dofetilide and consequently an increased risk of ventricular arrhythmias.

MANAGEMENT: Close clinical and laboratory monitoring is recommended whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the dosage of dofetilide adjusted accordingly if necessary. Patients should be advised to promptly contact their physician if they experience dizziness, syncope, fast or irregular heartbeats, or palpitations.

Galantamine

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of galantamine, which is partially metabolized by the isoenzyme. In multiple dose pharmacokinetic studies, a potent CYP450 3A4 inhibitor such as ketoconazole has been shown to increase the systemic exposure (AUC) of galantamine by 30%. Erythromycin and cimetidine, which are less potent inhibitors, have been shown to increase galantamine AUC by 10% and 16%, respectively.

MANAGEMENT: Pharmacologic response to galantamine should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the galantamine dosage adjusted as necessary. Patients should be advised to notify their physician if they experience excessive cholinergic symptoms such as severe nausea, vomiting, GI cramping, salivation, lacrimation, sweating, dizziness, or syncope.

Methadone

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of methadone, which is metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of methadone, such as central nervous system and respiratory depression, should be considered. In addition, high doses of methadone have been associated with QT interval prolongation and torsade de pointes.

MANAGEMENT: Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should also be advised to immediately seek medical attention if they experience palpitations, dizziness, lightheadedness, fainting, or seizures.

Repaglinide (oral)

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of repaglinide, which is metabolized by the isoenzyme in the intestine and liver. In nine healthy volunteers, pretreatment with the CYP450 3A4 inhibitor clarithromycin (250 mg orally twice a day for 4 days) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of repaglinide (0.25 mg single oral dose) by 66% and 41%, respectively, compared to placebo. Increases in repaglinide Cmax and AUC values were observed in every subject. Clarithromycin also increased the mean elimination half-life of repaglinide by 21% (from 1.4 to 1.7 hours), as well as the mean incremental AUC from 0 to 3 hours of serum insulin by 51% and the maximum increase in the serum insulin concentration by 61%. No statistically significant differences were found in the blood glucose concentrations between the clarithromycin and placebo phases, and no subject developed symptomatic hypoglycemia as a result of the interaction. However, the lack of clinical adverse effects may be explained, at least partially, by frequent carbohydrate intake during the study and the use of a subtherapeutic dose of repaglinide.

MANAGEMENT: Because the antidiabetic effect of repaglinide is dose- and concentration-dependent, pharmacologic response to repaglinide should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to regularly monitor their blood sugar and counseled on how to recognize and treat hypoglycemia, which may include symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, and palpitations. The repaglinide dosage may require adjustment if an interaction is suspected.

Tadalafil

MONITOR: Coadministration with drugs that are inhibitors of CYP450 3A4 may increase the plasma concentrations of tadalafil, which is primarily metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of tadalafil should be considered.

MANAGEMENT: Caution is advised if tadalafil is prescribed with CYP450 3A4 inhibitors. Dosage adjustments may be appropriate for tadalafil whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy based on efficacy and side effects. Tadalafil labeling recommends that the dosage not exceed 10 mg once every 72 hours in patients treated concomitantly with a potent CYP450 3A4 inhibitor, such as erythromycin, itraconazole, ketoconazole, protease inhibitors, and nefazodone. Patients should be advised to promptly notify their physician if they experience potential symptoms of PDE5 inhibitor toxicity such as pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

Buprenorphine (oral), Buprenorphine (injection)

MONITOR: Coadministration with drugs that are inhibitors of the CYP450 3A4 isoenzyme may increase the plasma concentrations and pharmacologic effects of buprenorphine, which is metabolized in the liver by CYP450 3A4. The risk of central nervous system and respiratory depression may be increased.

MANAGEMENT: Pharmacologic response to buprenorphine and vital signs should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the buprenorphine dosage adjusted as necessary. If clinically significant respiratory depression occurs, buprenorphine should be withdrawn.

Darifenacin

MONITOR: Coadministration with inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations of darifenacin, which is a substrate of these isoenzymes. According to the product labeling, coadministration of darifenacin (30 mg once daily) with the mixed CYP450 inhibitor cimetidine resulted in a 42% increase in the mean darifenacin steady-state peak plasma concentration (Cmax) and a 34% increase in the systemic exposure (AUC) compared to administration of darifenacin alone. The potent CYP450 2D6 inhibitor paroxetine (20 mg) increased steady-state AUC of darifenacin (30 mg once daily) by 33%. Erythromycin, a CYP450 3A4 inhibitor, increased the mean steady-state Cmax and AUC of darifenacin (30 mg once daily) by 128% and 95%, respectively. Fluconazole, another 3A4 inhibitor, increased these values by 88% and 84%, respectively.

MANAGEMENT: Pharmacologic response to darifenacin should be monitored more closely whenever a CYP450 2D6 and/or 3A4 inhibitor is added to or withdrawn from therapy, and the darifenacin dosage adjusted if necessary. Patients should be advised to contact their physician if they experience undue adverse effects of darifenacin such as severe abdominal pain or constipation for 3 or more days.

Aliskiren

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and pharmacologic effects of aliskiren, which is primarily metabolized by the isoenzyme. According to the product labeling, plasma levels of aliskiren were increased approximately 80% by the potent CYP450 3A4 inhibitor ketoconazole at a dosage of 200 mg twice daily. A 400 mg once daily dose of ketoconazole was not studied but would be expected to further increase aliskiren blood levels.

MANAGEMENT: Pharmacologic response to aliskiren should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the aliskiren dosage adjusted if necessary. Patients should be advised to notify their physician if they experience excessive adverse effects of aliskiren such as dizziness, lightheadedness, diarrhea, abdominal pain, and gastroesophageal reflux.

Dasatinib

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and pharmacologic effects of dasatinib, which is primarily metabolized by the isoenzyme. In a drug interaction study of 18 patients with solid tumors, coadministration of dasatinib (20 mg once a day) with the potent inhibitor ketoconazole (200 mg twice a day) increased the dasatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 4- and 5-fold, respectively, compared to administration without ketoconazole. Data are not available for dasatinib in combination with other CYP450 3A4 inhibitors. Theoretically, a reverse interaction may also occur, since many CYP450 3A4 inhibitors are also substrates of the isoenzyme and dasatinib is an inhibitor.

MANAGEMENT: Caution is advised if dasatinib is used in combination with moderate CYP450 3A4 inhibitors. Close monitoring for toxicity (e.g., myelosuppression, bleeding complications, fluid retention) is recommended, and the dasatinib dosage adjusted as necessary. Patients should also be monitored for altered efficacy and safety of the concomitant administered drug.

Budesonide inhalation, Budesonide (oral)

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and systemic effects of budesonide, which is metabolized by the isoenzyme. According to budesonide labeling, potent inhibitors can increase the plasma levels of budesonide several fold. For example, an eight-fold increase in the systemic exposure (AUC) has been observed during coadministration of oral budesonide with ketoconazole. In a prospective study of a cystic fibrosis center patient population, 11 of 25 patients receiving high-dose itraconazole (400 to 600 mg/day) and budesonide inhalation therapy (800 to 1600 mcg/day) were found to have adrenal insufficiency (one developed Cushing's syndrome), compared to none in a group of 12 patients treated with itraconazole alone and none in a group of 30 cystic fibrosis patients retrospectively included as controls, 24 of whom had been treated with high-dose inhaled budesonide for several years. Adrenal function improved but did not normalize in 10 of the 11 patients during a follow-up of two to ten months after discontinuation of itraconazole and institution of hydrocortisone replacement therapy.

MANAGEMENT: The possibility of increased systemic pharmacologic effects of budesonide should be considered during concomitant therapy with CYP450 3A4 inhibitors, particularly potent ones like itraconazole, ketoconazole, voriconazole, nefazodone, protease inhibitors, and ketolide and macrolide antibiotics. Adrenal function should be monitored regularly during chronic use of these agents, and reduction of budesonide dosage may be necessary. Systemic glucocorticoid effects of budesonide during prolonged administration may include symptoms of hypercorticism (e.g., acne, easy bruising, moon face, edema, hirsutism, buffalo hump, skin striae, glucose intolerance, irregular menstruations); adrenal suppression (which reduces patient's ability to respond to stress situations); immunosuppression; and osteoporosis.

Gefitinib

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of gefitinib, which is primarily metabolized by the isoenzyme. According to the product labeling, administration of gefitinib (250 mg single dose) with the potent inhibitor itraconazole (200 mg once a day for 12 days) increased the mean gefitinib systemic exposure (AUC) by 88% in healthy male volunteers. This increase may be clinically significant, as adverse events of gefitinib are related to dose and exposure.

MANAGEMENT: Caution is advised if gefitinib is administered with CYP450 3A4 inhibitors, particularly potent ones like itraconazole, ketoconazole, nefazodone, delavirdine, ketolide and certain macrolide antibiotics, and most protease inhibitors. Pharmacologic response to gefitinib should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the dosage adjusted as necessary. Patients should be advised to contact their doctor if they experience possible symptoms of gefitinib toxicity such as severe diarrhea, nausea, dyspnea, cough, and fever.

Lapatinib

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of lapatinib, which is primarily metabolized by the isoenzyme. In healthy subjects, administration of lapatinib in combination with the potent inhibitor ketoconazole (200 mg twice daily for 7 days) resulted in lapatinib systemic exposure (AUC) and half-life that were approximately 3.6- and 1.7-fold, respectively, of the control values.

MANAGEMENT: Caution is advised if lapatinib is prescribed in combination with CYP450 3A4 inhibitors. Pharmacologic response to lapatinib should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the lapatinib dosage adjusted as necessary. Patients should be advised to contact their physician if they experience increased adverse effects of lapatinib such as diarrhea, nausea, vomiting, dyspepsia, and fatigue.

Solifenacin

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of solifenacin, which has been shown to be a substrate of the isoenzyme in vitro. According to product labeling, coadministration of solifenacin (10 mg) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of solifenacin by 1.5- and 2.7-fold, respectively, compared to administration of solifenacin alone.

MANAGEMENT: Pharmacologic response to solifenacin should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the solifenacin dosage adjusted if necessary. Patients should be advised to contact their physician if they experience undue adverse effects of solifenacin such as severe abdominal pain or constipation for 3 or more days.

Eletriptan

MONITOR: Coadministration with inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of eletriptan, which is primarily metabolized by the isoenzyme. According to the product labeling, eletriptan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by nearly 3-fold and 6-fold, respectively, during coadministration with the potent inhibitor ketoconazole (400 mg). Likewise, erythromycin (1000 mg) increased eletriptan Cmax by 2-fold and AUC by nearly 4-fold. The half-life of eletriptan increased from about 5 hours to 8 hours with ketoconazole and 7 hours with erythromycin. Verapamil (480 mg), a moderate CYP450 3A4 inhibitor, increased eletriptan Cmax by 2.2-fold and AUC by 2.7-fold, while fluconazole (100 mg), a relatively weak inhibitor, increased eletriptan Cmax by 1.4-fold and AUC by 2-fold. Clinically, this interaction may result in increased risk of vasospastic reactions associated with the use of 5-HT1 receptor agonists, such as coronary artery vasospasm, peripheral vascular ischemia, and colonic ischemia.

MANAGEMENT: Eletriptan should not be used within at least 72 hours of treatment with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, nefazodone, delavirdine, most protease inhibitors, and ketolide and certain macrolide antibiotics. The manufacturer makes no specific recommendations for use with less potent inhibitors, but caution is appropriate. Patients should have vital signs monitored regularly and advised to notify their physician if they experience signs and symptoms of vasospasm such as numbness, tingling, or cyanosis in the extremities; muscle pains; weakness; or chest pain or tightness. Alternatively, other 5-HT1 receptor agonists that are not metabolized by CYP450 3A4 may be considered, such as frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan.

Nefazodone

MONITOR: Coadministration with nefazodone may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by nefazodone.

MANAGEMENT: Caution is advised if nefazodone must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. A lower initial dosage, as well as clinical and laboratory monitoring, may be appropriate for some drugs.

Nelfinavir

MONITOR: Coadministration with nelfinavir may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by nelfinavir.

MANAGEMENT: Caution is advised if nelfinavir must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever nelfinavir is added to or withdrawn from therapy.

Ritonavir

MONITOR: Coadministration with ritonavir may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by ritonavir. The area under the plasma concentration-time curve (AUC) of some coadministered drugs has been reported to increase by 3-fold or more.

MANAGEMENT: Caution is advised if ritonavir must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ritonavir is added to or withdrawn from therapy.

Saquinavir

MONITOR: Coadministration with saquinavir may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by saquinavir.

MANAGEMENT: Caution is advised if saquinavir must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever saquinavir is added to or withdrawn from therapy.

Telithromycin

MONITOR: Coadministration with telithromycin may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by telithromycin.

MANAGEMENT: Caution is advised if telithromycin must be used concurrently with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever telithromycin is added to or withdrawn from therapy.

Lovastatin, Simvastatin, Atorvastatin, Cerivastatin, Red yeast rice

MONITOR: Coadministration with the calcium channel blocker (CCB) diltiazem or verapamil may increase the plasma concentrations of some HMG-CoA reductase inhibitors and/or their pharmacologically active metabolites. The mechanism is CCB inhibition of intestinal and hepatic CYP450 3A4, the isoenzyme responsible for the metabolic clearance of HMG-CoA reductase inhibitors like atorvastatin, lovastatin acid, and simvastatin acid. 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.

MANAGEMENT: Caution is recommended if atorvastatin, lovastatin, simvastatin, or red yeast rice (which contains lovastatin) is prescribed with diltiazem or verapamil. Patients should be advised to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. The HMG-CoA reductase inhibitor should be discontinued if creatine kinase is markedly elevated (greater than 10 times the upper limit of normal) or if myopathy is suspected or diagnosed. Fluvastatin, pravastatin, and rosuvastatin are probably safer alternatives in patients receiving diltiazem or verapamil, since they are not metabolized by CYP450 3A4.

Tipranavir

MONITOR: Coadministration with tipranavir in combination with ritonavir may alter the pharmacokinetics of calcium channel blockers that are dual substrates of CYP450 3A4 and P-glycoprotein. The potential changes cannot be predicted due to the conflicting effects of tipranavir and ritonavir on CYP450 3A4 and P-glycoprotein. Specifically, ritonavir is a potent inhibitor of CYP450 3A4 and tend to reduce clearance of substrate drugs, while tipranavir is a potent inducer of P-glycoprotein intestinal efflux transporters and tend to increase clearance of substrate drugs.

MANAGEMENT: Caution is advised if calcium channel blockers such as diltiazem, felodipine, nicardipine, nisoldipine, and verapamil are coadministered with tipranavir/ritonavir. Patients should be monitored for potentially altered pharmacologic response to calcium channel blocker therapy following initiation or discontinuation of tipranavir/ritonavir.

Alfuzosin

MONITOR: Concomitant administration of diltiazem may increase the plasma concentration of alfuzosin. The mechanism is inhibition of CYP450 3A4 metabolism by diltiazem. Multiple doses of diltiazem 240 mg with alfuzosin 2.5 mg three times daily increased alfuzosin maximum plasma concentrations (Cmax) by 1.5-fold and the area under the concentration-time curve (AUC) 1.3-fold. In addition, the diltiazem Cmax increased 1.4-fold; the mechanism has not been reported. No changes in blood pressure were reported in this study; however, the manufacturer cautions that additive hypotension may occur when alfuzosin is given in combination with antihypertensive agents.

MANAGEMENT: Hemodynamic responses should be monitored during coadministration, especially during the first few weeks of therapy. Patients should be advised to avoid situations where injury could result if syncope occurs (e.g., driving) and to notify their physician if they experience dizziness or syncope.

Fluvoxamine

MONITOR: Concurrent administration of fluvoxamine and diltiazem may cause bradycardia.

MANAGEMENT: The manufacturer recommends caution if these drugs must be used together.

Delavirdine

MONITOR: Concurrent administration with delavirdine may significantly increase the plasma concentrations of dihydropyridine calcium channel blockers. The mechanism is inhibition of CYP450 3A4 metabolism by delavirdine.

MANAGEMENT: Clinical monitoring of patient response and tolerance is recommended and calcium channel blocker dosage adjustments may be indicated. Patients should be advised to notify their doctor if they experience headache, dizziness, orthostasis, syncope, slow heartbeat, or edema.

Cetirizine

MONITOR: Concurrent use of cetirizine or levocetirizine with alcohol or other central nervous system (CNS) depressants may result in additive impairment of mental alertness and performance. Several studies have shown no effect of racemic cetirizine on cognitive function, motor performance, or sleep latency as indicated by objective measurements. However, there have been reports of somnolence, fatigue, and asthenia in some patients treated with cetirizine or levocetirizine in clinical trials.

MANAGEMENT: Concomitant use of cetirizine or levocetirizine with alcohol or other CNS depressants should generally be avoided if possible. In the event that they are used together, 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.

Prednisolone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisone, Cortisone, Triamcinolone (oral and injectable), Triamcinolone inhalation, Betamethasone, Fludrocortisone, Triamcinolone acetonide injection

MONITOR: Corticosteroids may antagonize the effects of antihypertensive medications by causing sodium and fluid retention. These effects may be more common with the natural corticosteroids (cortisone, hydrocortisone) which have greater mineralocorticoid activity. In addition, some calcium channel blockers (e.g., diltiazem and verapamil) may increase corticosteroid plasma levels and effects by inhibiting their CYP450 3A4 metabolism.

MANAGEMENT: If concomitant therapy is necessary, it is advisable to monitor the patient's blood pressure, electrolyte levels, weight, and for the development of edema and congestive heart failure. The dosages of antihypertensive medications may require adjustment.

Triazolam

MONITOR: Diltiazem and verapamil both have been reported to increase peak plasma concentration and to prolong the elimination half-life of midazolam. The mechanism probably is related to an increase in the bioavailability and a decrease in the plasma clearance of midazolam. Diltiazem, verapamil, midazolam, and triazolam all appear to be metabolized by the CYP450 (3A4) enzyme.

MANAGEMENT: If diltiazem or verapamil must be used with midazolam or triazolam, close observation for increased and prolonged midazolam or triazolam effect is recommended. Some investigators have suggested that midazolam dosage be reduced by at least 50% in patients who are receiving diltiazem or verapamil. Other investigators have suggested that triazolam be avoided in patients receiving diltiazem.

Phenytoin (oral), Mephenytoin, Ethotoin

MONITOR: Diltiazem and verapamil may increase plasma phenytoin levels. Toxicity has been reported. The proposed mechanism is inhibition of CYP450 3A4 metabolism. In addition, phenytoin may significantly decrease calcium channel blocker (CCB) serum levels by inducing first-pass metabolism and the systemic clearance. Other hydantoins may participate in these interactions as well.

MANAGEMENT: Close clinical and laboratory observation for evidence of altered effect of both drugs is recommended if a CCB and a hydantoin must be used together. Patients should be advised to notify their physician if they experience symptoms of phenytoin toxicity (e.g., drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia) or loss of effect of their CCB.

Digoxin (oral)

MONITOR: Diltiazem may cause increases in digoxin plasma levels although reports are conflicting. The mechanism for this possible interaction is unknown but is thought to be related to diltiazem-induced decreases in digoxin clearance. In addition, digoxin and diltiazem have additive effects in slowing AV conduction.

MANAGEMENT: Monitor for signs and symptoms of digoxin toxicity, checking digoxin levels when clinically necessary. Patients should be advised to notify their physicians if they experience signs of digoxin toxicity such as nausea, anorexia, visual changes, slow pulse, or irregular heartbeats. Calcium channel blockers such as felodipine, or amlodipine, isradipine, and nicardipine appear to affect digoxin levels to a lesser extent or not at all and may be considered as alternatives.

Nifedipine

MONITOR: Diltiazem may increase the bioavailability and decrease the metabolism of nifedipine. Serum levels and effect of nifedipine may be increased. In addition, nifedipine may increase plasma diltiazem concentrations. The pharmacologic effects of both medications may be additive. Increased risk of hypotension and conduction disturbances may result. The mechanism may be reduced hepatic clearance.

MANAGEMENT: If these agents must be used concomitantly, close monitoring for altered efficacy and safety is recommended. Dose adjustments may be required. Patients should be advised to notify their physician if they experience headaches, syncope, or slow heartbeats.

Cyclosporine

MONITOR: Diltiazem may inhibit the CYP450 3A4 hepatic metabolism of cyclosporine. Trough and steady state levels, and the risk of nephrotoxicity may be increased.

MANAGEMENT: Cyclosporine levels and renal function should be monitored, and dosage should be adjusted as needed and appropriate during therapy. Other calcium channel blockers that have lesser effects on cyclosporine metabolism may be considered as alternatives (e.g., amlodipine, isradipine, nifedipine, nitrendipine).

Theophylline, Oxtriphylline, Aminophylline

MONITOR: Diltiazem may inhibit the CYP450 3A4 hepatic metabolism of theophylline. Significant increases in serum theophylline levels may result. Data are limited.

MANAGEMENT: Clinical monitoring of patient response and tolerance and serum theophylline levels is recommended. Patients should be advised to report any signs of theophylline toxicity including nausea, vomiting, diarrhea, headache, restlessness, insomnia, or irregular heartbeat to their physicians.

Imatinib (oral)

MONITOR: Imatinib is a substrate of the CYP450 3A4 isoenzyme as well as a potent competitive inhibitor of the CYP450 2C9, 2D6 and 3A4 isoenzymes. Some drugs that are known inhibitors of CYP450 3A4 are also metabolized by one or more of the isoenzymes inhibited by imatinib. Theoretically, coadministration of imatinib with those drugs may result in mutually elevated plasma drug concentrations due to competitive and noncompetitive inhibition of CYP450 activities.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of imatinib, including serious adverse effects such as edema, hematologic toxicity and immunosuppression, should be considered during concomitant therapy, particularly with potent CYP450 3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, nefazodone, and erythromycin. In addition, clinical and laboratory monitoring for potentially increased pharmacologic effects of coadministered medications is recommended, especially those with a narrow therapeutic range.

Tacrolimus (oral), Sirolimus

MONITOR: In vitro data suggest that some calcium channel blockers inhibit the CYP450 3A4 hepatic metabolism and produce elevated blood levels of macrolide immunosuppressants. In healthy subjects, diltiazem 120 mg increased the maximum plasma concentration of sirolimus 1.4-fold and the AUC 1.6-fold.

MANAGEMENT: Careful monitoring of macrolide immunosuppressant blood concentrations is recommended if these drugs must be used together. Dose reductions of the immunosuppressant may be required.

Itraconazole

MONITOR: Itraconazole may have negative inotropic effects which may be additive with those of calcium channel blockers (CCBs). Theoretically, coadministration may be associated with elevated risk of ventricular dysfunction, peripheral edema and pulmonary edema, particularly in patients with preexisting risk factors (e.g., a history of congestive heart failure; cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disorder; and edematous disorders such as renal failure). Caution is advised if itraconazole must be used concomitantly with CCBs. In addition, both itraconazole and its major metabolite, hydroxyitraconazole, inhibit metabolism via the CYP450 3A4 enzymatic pathway and may interfere with the clearance of certain CCBs like the dihydropyridines (amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine), diltiazem, and verapamil. Significant increases of several fold in felodipine and nifedipine plasma concentrations have been observed during coadministration with itraconazole, and there have been case reports of leg and ankle edema associated with various itraconazole-dihydropyridine combinations.

MANAGEMENT: Patients receiving this combination should be monitored for clinical response and tolerance, and be advised to report edema or swelling of the lower extremities, or unexplained weight gain to their physician. Appropriate dosage adjustment may be necessary for these agents when used with itraconazole.

Tolmetin, Flurbiprofen, Ketorolac, Mefenamic acid, Nabumetone, Piroxicam, Diclofenac, Etodolac, Oxaprozin, Meclofenamate, Meloxicam

MONITOR: Limited data indicate that some cyclooxygenase inhibitors may attenuate the antihypertensive effects of some calcium channel blockers. The mechanism appears to be related to an alteration of vascular tone, which is dependent on prostacyclins and other vasodilatory prostanoids. When a nonsteroidal anti-inflammatory drug (NSAID) is added to the regimen of a patient who is already taking a calcium channel blocker, increased blood pressure may result. Also, the clinician should be aware that the risk of hypotension is increased when NSAIDs are withdrawn from the regimen.

MANAGEMENT: Monitoring for altered blood pressure control is recommended.

Nortriptyline, Desipramine, Amitriptyline, Doxepin, Imipramine, Trimipramine, Amoxapine, Protriptyline, Clomipramine, Maprotiline

MONITOR: Limited data suggest that diltiazem can increase the plasma concentrations of cyclic antidepressants. Data are available for nortriptyline, trimipramine, and imipramine. The proposed mechanism is inhibition of first-pass metabolism by diltiazem. ECG changes (first and second degree heart block) have been reported.

MANAGEMENT: Close monitoring for clinical response and tolerance is recommended whenever diltiazem is added to or discontinued from an antidepressant regimen. Patients should be advised to notify their physician if they experience excessive antidepressant effects such as dry mouth, blurry vision, irregular or fast heartbeat, constipation, urinary retention, dizziness, or orthostatic hypotension. Dose adjustments may be necessary.

Nitroglycerin (oral/buccal/sublingual/spray), Nitroglycerin topical (patches and ointment)

MONITOR: Marked, symptomatic orthostatic hypotension has been reported when calcium channel blockers were used in combination with oral controlled-release nitroglycerin.

MANAGEMENT: Dosage adjustments of either class of agents may be necessary. All patients treated with nitroglycerin--with or without calcium channel blockers--should be made aware of possible adverse effects such as dizziness, lightheadedness, and orthostasis, and advised to arise slowly from a sitting or recumbent position.

Mefloquine

MONITOR: Mefloquine is a myocardial depressant and can cause ECG abnormalities. Theoretically, coadministration with other agents that can affect cardiac conduction (e.g., antiarrhythmic agents, beta blockers, calcium channel blockers, certain antihistamines, tricyclic antidepressants, phenothiazines, some neuroleptics) may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential. Parenteral studies in animals have shown that mefloquine possesses 20% of the antifibrillatory action of quinidine and can cause 50% of the increase in PR interval reported with quinine. ECG alterations reported with mefloquine include sinus bradycardia, sinus arrhythmia, first degree AV block, prolongation of the QTc interval, and abnormal T waves. According to mefloquine labeling, there has been one report of cardiopulmonary arrest, with full recovery, in a patient who was taking a beta blocker (propranolol).

MANAGEMENT: Caution and clinical monitoring are recommended if mefloquine is used concurrently with other medications that can prolong the QT interval or otherwise affect cardiac conduction. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of arrhythmia such as dizziness, palpitations, or syncope.

Clozapine, Risperidone (oral), Olanzapine, Quetiapine, Ziprasidone, Aripiprazole, Paliperidone

MONITOR: Neuroleptic agents may potentiate the hypotensive effect of some medications secondary to their peripheral alpha-1 adrenergic blocking activity. Orthostatic hypotension and syncope associated with vasodilation may occur, particularly during the initial dose titration period of neuroleptic therapy.

MANAGEMENT: Close clinical monitoring for development of hypotension is recommended if neuroleptic agents are prescribed with antihypertensive medications or vasodilators. Patients should be advised to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. A lower starting dosage and slower titration of the neuroleptic agent may be appropriate in patients receiving antihypertensive therapy, especially if they are elderly.

Vardenafil

MONITOR: Phosphodiesterase-5 (PDE5) inhibitors such as sildenafil and vardenafil may potentiate the hypotensive effect of calcium channel blockers. These agents inhibit PDE5-mediated degradation of cyclic guanosine monophosphate (cGMP), which in vascular smooth muscles can cause peripheral vasodilation that may be additive with that induced by calcium channel blockers. In addition, most calcium channel blockers are inhibitors and/or substrates of CYP450 3A4 and may increase the plasma levels of sildenafil and vardenafil by inhibiting their metabolism via the isoenzyme. In hypertensive patients, coadministration of sildenafil (100 mg) and amlodipine (5 mg or 10 mg) resulted in mean additional reductions of supine blood pressure of 8 mmHg systolic and 7 mmHg diastolic. Similarly, coadministration of vardenafil (20 mg) and nifedipine (slow-release 30 mg or 60 mg once daily) resulted in mean additional reductions of supine blood pressure of 6 mmHg systolic and 5 mmHg diastolic compared to placebo. However, no significant alterations in the pharmacokinetics of nifedipine or vardenafil were observed.

MANAGEMENT: Caution is advised if PDE5 inhibitors are prescribed to patients treated with calcium channel blockers. Patients receiving the combination should be advised to avoid rising abruptly from a sitting or recumbent position and to contact their physician if they experience symptoms of hypotension such as dizziness, lightheadedness, or fainting. In addition, patients should promptly notify their physician if they experience excessive adverse effects of PDE5 inhibitors such as pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

Pioglitazone (oral)

MONITOR: Pioglitazone is metabolized by CYP450 3A4 microsomal enzymes in the liver. The clinician should be aware of the potential for an interaction when pioglitazone is used in combination with another medication that inhibits and is also metabolized by CYP450 3A4.

MANAGEMENT: Monitoring for clinical and laboratory evidence of altered safety and efficacy of both drugs if pioglitazone is added to or removed from the patients medication regimen is recommended. Patients should be advised to regularly monitor their blood sugar, counseled on how to recognize and treat hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, tremor, hunger, weakness, or palpitations) and to notify their physician if it occurs.

Lithium

MONITOR: Several case reports have suggested that the combination of lithium and calcium channel blockers may cause neurotoxicity and psychiatric effects such as psychosis. The mechanism is unknown. Data have been conflicting. Cases have been reported for diltiazem and verapamil.

MANAGEMENT: Patients who must take both drugs should be closely monitored for adverse neurologic and psychiatric effects. Patients should be advised to notify their physician if they experience symptoms of possible lithium toxicity such as drowsiness, dizziness, confusion, ataxia, vomiting, diarrhea, thirst, blurry vision, tinnitus, or tremor.

Aspirin (oral), Aspirin (rectal)

MONITOR: Several case reports have suggested that verapamil and aspirin may have synergistic antiplatelet effects. The mechanism of this interaction has not been fully elucidated. Also, one study of five patients has suggested that aspirin may reverse the antihypertensive effect of verapamil. The mechanism may be related to antagonism of the effect of verapamil on prostacyclin. Diltiazem has been shown to interact with aspirin in a similar manner.

MANAGEMENT: Close observation for prolonged bleeding time and reduced antihypertensive effect is recommended if these drugs must be used together. Patients should be advised to notify their physician if they experience unusual bleeding, bruising, or petechiae. Aspirin should be discontinued if an interaction is suspected.

Octreotide (injectable)

MONITOR: Somatostatin analogs (e.g., octreotide, lanreotide) can decrease heart rate and may potentiate the bradycardic effects of drugs like beta-blockers or calcium channel blockers. Octreotide has commonly been associated with bradycardia (less than 50 bpm), conduction abnormalities, and arrhythmias in acromegalic patients. Occasional cases of sinus bradycardia and ventricular tachycardia have also been reported with lanreotide.

MANAGEMENT: Caution is advised if somatostatin analogs are prescribed with a beta-blocker or calcium channel blocker. Heart rate and blood pressure should be monitored, and the beta-blocker or calcium channel blocker dosage adjusted as necessary.

Amlodipine

MONITOR: The coadministration with diltiazem may increase the plasma concentrations of amlodipine. The mechanism is decreased clearance of amlodipine due to inhibition of the CYP450 3A4 enzymatic pathway by diltiazem. In an open-label study consisting of eight subjects with essential hypertension, diltiazem (180 mg orally daily for 3 days) increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single dose of amlodipine (5 mg) by 57% each. Associated systolic, diastolic, and standing blood pressures decreased compared to those obtained with amlodipine alone.

MANAGEMENT: Caution is advised during concomitant therapy with diltiazem and amlodipine. Blood pressure should be monitored closely and the amlodipine dosage adjusted accordingly, particularly following initiation or discontinuation of diltiazem in patients who are stabilized on their amlodipine regimen.

Toremifene

MONITOR: The coadministration with drugs that are inhibitors of the CYP450 3A4, 3A5 and/or 3A6 enzymatic pathways may increase the plasma concentrations of toremifene, which is metabolized by these isoenzymes. While clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of toremifene should be considered.

MANAGEMENT: Clinical and laboratory monitoring for altered efficacy and safety of toremifene (e.g., hypercalcemia, elevated liver enzymes, leukopenia, or thrombocytopenia) may be appropriate whenever a CYP450 inhibitor is added to or withdrawn from therapy.

Cevimeline

MONITOR: The coadministration with drugs that are inhibitors of the CYP450 3A4 enzymatic pathway may increase the plasma concentrations of cevimeline, which is metabolized by CYP450 3A4.

MANAGEMENT: Dosage adjustments and clinical monitoring may be appropriate whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be monitored for and advised to report prolonged and/or increased effects of cevimeline, including cholinergic adverse effects such as sweating, diarrhea, salivation and urinary frequency.

Citalopram (oral)

MONITOR: The coadministration with drugs that are inhibitors of the CYP450 3A4 enzymatic pathway may increase the plasma concentrations of citalopram, which is partially metabolized by CYP450 3A4. While clinical data are lacking, the possibility of increased pharmacological effects and/or serotonin syndrome should be considered.

MANAGEMENT: Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever an enzyme inhibitor is added to or withdrawn from therapy. Close monitoring is recommended for signs and symptoms of excessive serotonergic activity such as CNS irritability, altered consciousness, confusion, myoclonus, ataxia, abdominal cramping, hyperpyrexia, shivering, pupillary dilation, diaphoresis, hypertension, and tachycardia.

Zonisamide

MONITOR: The coadministration with drugs that are inhibitors of the CYP450 3A4 enzymatic pathway may increase the plasma concentrations of zonisamide, which is metabolized by CYP450 3A4. While clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of zonisamide should be considered.

MANAGEMENT: Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to notify their physician if they experience symptoms such as severe drowsiness, confusion, loss of coordination, depression, aphasia, decreased sweating, fever, loss of seizure control, or slow pulse.

Chlorpromazine, Lorazepam, Bupropion (oral), Diphenhydramine, Fluphenazine, Hydromorphone (oral), Morphine, Oxycodone, Prochlorperazine, Propoxyphene, Temazepam, Thioridazine (oral), Promethazine (oral), Perphenazine, Trifluoperazine, Loxapine, Hydroxyzine, Carisoprodol, Methocarbamol, Orphenadrine, Baclofen, Paroxetine, Venlafaxine (oral), Chloral hydrate, Chloral hydrate rectal, Hydromorphone (injection), Hydromorphone (rectal), Meprobamate, Promethazine (rectal), Promethazine (injection), Cabergoline, Escitalopram

MONITOR: The concomitant administration of agents with hypotensive effects and psychotherapeutic agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics), narcotic analgesics, alcohol, or muscle relaxants may additively increase hypotensive and/or central nervous system depressant effects.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for hypotension and excessive or prolonged CNS depression. Ambulatory patients should be made aware of the possibility of additive effects (e.g., drowsiness, dizziness, lightheadedness, confusion, orthostasis, fainting) and be cautioned about driving, operating machinery, or performing other hazardous tasks, and to arise slowly from a sitting or lying position. Patients should also be advised to notify their doctor if they experience excessive side effects that interfere with their normal activities, or dizziness and fainting.

Aldesleukin

MONITOR: The concomitant administration of antihypertensive agents may potentiate the hypotensive effects of aldesleukin. Life-threatening (grade 4) hypotension has been reported with aldesleukin alone.

MANAGEMENT: Blood pressure should be monitored during concomitant administration. Aldesleukin doses should be held if systolic blood pressure falls to less than 90 mmHg.

Buspirone

MONITOR: The concomitant administration of diltiazem may increase buspirone levels and the risk of adverse effects. In one study (n=9), buspirone AUC increased by 5.5-fold and maximum plasma concentrations increased 4.1-fold after 5 doses of diltiazem. The proposed mechanism is inhibition of CYP450 3A4 first pass metabolism by diltiazem.

MANAGEMENT: The patient should be monitored carefully for signs of buspirone toxicity (e.g., drowsiness, dizziness, nervousness, insomnia, headache, nausea, vomiting). Alternatively, use of a dihydropyridine calcium channel blocker or an anxiolytic which is not a substrate of CYP450 3A4 may be appropriate.

Treprostinil

MONITOR: The concurrent use of treprostinil and agents with hypotensive or vasodilator effects may have additive blood pressure lowering effects. Treprostinil has been used concurrently with diuretics and calcium channel blockers in clinical trials.

MANAGEMENT: If these drugs are used together, it is generally recommended that blood pressure be measured more frequently until a stable blood pressure pattern is observed. Patients should be advised to notify their physician if they experience dizziness or syncope.

Levodopa

MONITOR: The hypotensive effects of levodopa and antihypertensive agents may be additive. Postural hypotension may occur.

MANAGEMENT: Hemodynamic responses should be monitored during coadministration, especially during the first few weeks of therapy. Dose adjustments of the antihypertensive agent may be required. Patients should be advised to notify their physician if they experience dizziness or syncope.

Paclitaxel, Paclitaxel protein-bound

MONITOR: Theoretically, coadministration with drugs that are inhibitors of CYP450 2C8 and/or 3A4 may increase the plasma concentrations of paclitaxel, which is metabolized by these isoenzymes.

MANAGEMENT: Clinicians should recognize the potential for interaction with drugs that inhibit CYP450 2C8 and/or 3A4 and monitor for evidence of dose-related toxicities of paclitaxel during coadministration. Patients should be advised to contact their physician if they develop signs and symptoms of myelosuppression (eg., pallor, dizziness, fatigue, lethargy, easy bruising or bleeding, or signs of infection such as fever, chills, or sore throat) or neuropathy (e.g., visual disturbances and burning, tingling, or numbness in the hands and feet).

Iloprost

MONITOR: Theoretically, iloprost may potentiate the hypotensive effect of vasodilators and antihypertensive agents. Iloprost is a synthetic analogue of prostacyclin PGI2 and can dilate both systemic and pulmonary arterial vascular beds.

MANAGEMENT: Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Vital signs and blood pressure should be monitored regularly.

Cimetidine

MONITOR: The plasma concentration of some oral calcium channel blockers may be increased by cimetidine. The mechanism is related to inhibition of CYP450 3A4 hepatic metabolism and/or increased gastric pH.

MANAGEMENT: Clinical monitoring of patient response and tolerance is recommended and calcium channel blocker dosage adjustments may be indicated. Dose adjustments may be required. Alternatively, ranitidine is not expected to have clinically significant effects. Patients should be advised to notify their physician if they experience headache, dizziness, orthostasis, or syncope.

Phenelzine, Tranylcypromine, Selegiline (oral), Procarbazine, Isocarboxazid, Selegiline (transdermal), Linezolid, Rasagiline

Monoamine oxidase inhibitors (MAOIs) may theoretically potentiate the hypotensive effect of some medications. This effect may stem from a gradual MAOI-induced accumulation of false neurotransmitters in peripheral adrenergic neurons that have minimal activity at alpha- and beta-adrenergic receptors, resulting in a functional block of sympathetic neurotransmission. Indeed, MAOIs alone quite commonly produce orthostatic hypotension. In addition, bradycardia has been reported with the concomitant use of beta blockers and MAOIs. The clinical significance of these effects is unknown. If these drugs are coadministered, patients should be monitored for evidence of an interaction (e.g., hypotension, orthostasis, bradycardia, tachycardia, dizziness, or syncope).

Mifepristone

The coadministration with drugs that are inhibitors of the CYP450 3A4 enzymatic pathway may increase the plasma concentrations of mifepristone, which is metabolized by CYP450 3A4. While clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of mifepristone should be considered. Patients should be advised to notify their physician if they experience excessive or prolonged bleeding or cramping, or severe nausea, vomiting, diarrhea, headache, or dizziness.

Sibutramine (oral)

The coadministration with drugs that are inhibitors of the CYP450 3A4 enzymatic pathway may increase the plasma concentrations of sibutramine and its active metabolites, which are metabolized by CYP450 3A4. Inhibitors such as ketoconazole, cimetidine and erythromycin have led to moderate increases in the peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of the active metabolites. The data suggest that although the potential for such interaction exists, the magnitude appears to be small. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy. Patients should be advised to notify their physician if they experience symptoms of possible toxicity, such as high blood pressure (fast or irregular heartbeat, severe headache, blurry vision) or seizures.

Nitroprusside

The dosage of nitroprusside required to achieve a given hypotensive response is reduced by an average of 50% when diltiazem is coadministered. The mechanism is unknown. Since the risk of side effects from nitroprusside may be significantly decreased with a lower dose, this interaction may be advantageous.

Apraclonidine ophthalmic

The manufacturer reports that apraclonidine ophthalmic may cause additive or synergistic effects on heart rate and blood pressure if used concomitantly with other medications that affect these parameters, including ophthalmic and systemic beta blockers, cardiac glycosides, and antihypertensive agents. Caution and particular attention to the possibility of more pronounced cardiac effects is recommended when using this combination. Patients should be advised to notify their physician if they experience a slow pulse, irregular heartbeats, dizziness, or syncope.

Brimonidine ophthalmic

The manufacturer reports that brimonidine ophthalmic may cause additive or synergistic effects on heart rate and blood pressure if used concomitantly with other medications that affect these parameters. Caution and particular attention to the possibility of more pronounced cardiac effects is recommended when using this combination. Patients should be advised to notify their physician if they experience a slow pulse, irregular heartbeats, dizziness, or syncope.

Pimecrolimus topical

Theoretically, coadministration with CYP450 3A inhibitors may increase the plasma concentrations of pimecrolimus due to inhibition of its metabolism by CYP450 3A isoenzymes. Although clinically significant drug interactions are not expected due to minimal systemic absorption of topically administered pimecrolimus, the possibility cannot be ruled out. The manufacturer recommends caution in patients with widespread or erythrodermic disease.

Zolpidem

Use of drugs that inhibit the isoenzyme CYP450 3A4 may decrease the metabolism and increase the plasma levels of zolpidem. This can result in increased clinical effectiveness and risk of toxicity associated with zolpidem. Monitoring for signs and symptoms of altered zolpidem effect is recommended. Patients should be advised to notify their physician if they experience nausea, vomiting, diarrhea, confusion, daytime sedation, dizziness, or unconsciousness. A reduction in zolpidem dosage may be necessary.

Zileuton

Zileuton is believed to be a weak inhibitor of cytochrome P450 3A4 enzymes, of which calcium channel blockers are a known substrate. Although no studies have been conducted to verify or quantify the interaction, caution is recommended when using this combination until further data is available.

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