Nefazodone

Drug Interactions Drugs Highly Bound to Plasma Protein Because nefazodone is highly bound to plasma protein (see CLINICAL PHARMACOLOGY , Pharmacokinetics ), administration of nefazodone to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of nefazodone by other highly bound drugs. Warfarin – There were no effects on the prothrombin or bleeding times or upon the pharmacokinetics of R-warfarin when nefazodone (200 mg BID) was administered for 1 week to subjects who had been pretreated for 2 weeks with warfarin.

Although the coadministration of nefazodone did decrease the subjects’ exposure to S-warfarin by 12%, the lack of effects on the prothrombin and bleeding times indicates this modest change is not clinically significant. Although these results suggest no adjustments in warfarin dosage are required when nefazodone is administered to patients stabilized on warfarin, such patients should be monitored as required by standard medical practices. CNS-Active Drugs Monoamine Oxidase Inhibitors – See WARNINGS .

Haloperidol – When a single oral 5 mg dose of haloperidol was coadministered with nefazodone (200 mg BID) at steady state, haloperidol apparent clearance decreased by 35% with no significant increase in peak haloperidol plasma concentrations or time of peak. This change is of unknown clinical significance. Pharmacodynamic effects of haloperidol were generally not altered significantly. There were no changes in the pharmacokinetic parameters for nefazodone. Dosage adjustment of haloperidol may be necessary when coadministered with nefazodone.

Lorazepam – When lorazepam (2 mg BID) and nefazodone (200 mg BID) were coadministered to steady state, there was no change in any pharmacokinetic parameter for either drug compared to each drug administered alone. Therefore, dosage adjustment is not necessary for either drug when coadministered. Triazolam/Alprazolam – See CONTRAINDICATIONS and WARNINGS . Alcohol – Although nefazodone did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of nefazodone and alcohol in depressed patients is not advised.

Buspirone – In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg BID) with nefazodone (250 mg BID) resulted in marked increases in plasma buspirone concentrations (increases up to 20 fold in C max and up to 50 fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-pyrimidinylpiperazine. With 5 mg BID doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (17%) and mCPP (9%).

Subjects receiving nefazodone 250 mg BID and buspirone 5 mg BID experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either drug alone. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg QD) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Pimozide – See CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS , Pharmacokinetics of Nefazodone in ‘Poor Metabolizers’ and Potential Interaction With Drugs That Inhibit and/or Are Metabolized by Cytochrome P450 Isozymes.

Fluoxetine – When fluoxetine (20 mg QD) and nefazodone (200 mg BID) were administered at steady state there were no changes in the pharmacokinetic parameters for fluoxetine or its metabolite, norfluoxetine. Similarly, there were no changes in the pharmacokinetic parameters of nefazodone or HO-NEF; however, the mean AUC levels of the nefazodone metabolites mCPP and triazole-dione increased by 3 to 6 fold and 1.3 fold, respectively.

When a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient adverse events such as headache, lightheadedness, nausea, or paresthesia, possibly due to the elevated mCPP levels. Patients who are switched from fluoxetine to nefazodone without an adequate washout period may experience similar transient adverse events. The possibility of this happening can be minimized by allowing a washout period before initiating nefazodone therapy and by reducing the initial dose of nefazodone.

Because of the long half-life of fluoxetine and its metabolites, this washout period may range from one to several weeks depending on the dose of fluoxetine and other individual patient variables. Phenytoin – Pretreatment for 7 days with 200 mg BID of nefazodone had no effect on the pharmacokinetics of a single 300 mg oral dose of phenytoin. However, due to the nonlinear pharmacokinetics of phenytoin, the failure to observe a significant effect on the single-dose pharmacokinetics of phenytoin does not preclude the possibility of a clinically significant interaction with nefazodone when phenytoin is dosed chronically.

However, no change in the initial dosage of phenytoin is considered necessary and any subsequent adjustment of phenytoin dosage should be guided by usual clinical practices. Desipramine – When nefazodone (150 mg BID) and desipramine (75 mg QD) were administered together there were no changes in the pharmacokinetics of desipramine or its metabolite, 2-hydroxy desipramine. There were also no changes in the pharmacokinetics of nefazodone or its triazole-dione metabolite, but the AUC and C max of mCPP increased by 44% and 48%, respectively, while the AUC of HO-NEF decreased by 19%. No changes in doses of either nefazodone or desipramine are necessary when the two drugs are given concomitantly.

Subsequent dose adjustments should be made on the basis of clinical response. Lithium – In 13 healthy subjects the coadministration of nefazodone (200 mg BID) with lithium (500 mg BID) for 5 days (steady-state conditions) was found to be well tolerated. When the two drugs were coadministered, there were no changes in the steady-state pharmacokinetics of either lithium, nefazodone, or its metabolite HO-NEF; however, there were small decreases in the steady-state plasma concentrations of two nefazodone metabolites, mCPP and triazole-dione, which are considered not to be of clinical significance.

Therefore, no dosage adjustment of either lithium or nefazodone is required when they are coadministered. Carbamazepine – The coadministration of nefazodone (200 mg BID) for 5 days to 12 healthy subjects on carbamazepine who had achieved steady state (200 mg BID) was found to be well tolerated. Steady-state conditions for carbamazepine, nefazodone, and several of their metabolites were achieved by day 5 of coadministration.

With coadministration of the two drugs there were significant increases in the steady-state C max and AUC of carbamazepine (23% and 23%, respectively), while the steady-state C max and the AUC of the carbamazepine metabolite, 10,11 epoxycarbamazepine, decreased by 21% and 20%, respectively. The coadministration of the two drugs significantly reduced the steady-state C max and AUC of nefazodone by 86% and 93%, respectively. Similar reductions in the C max and AUC of HO-NEF were also observed (85% and 94%), while the reductions in C max and AUC of mCPP and triazole-dione were more modest (13% and 44% for the former and 28% and 57% for the latter).

Due to the potential for coadministration of carbamazepine to result in insufficient plasma nefazodone and hydroxynefazodone concentrations for achieving an antidepressant effect for nefazodone, it is recommended that nefazodone not be used in combination with carbamazepine (see CONTRAINDICATIONS and WARNINGS ). General Anesthetics – Little is known about the potential for interaction between nefazodone and general anesthetics; therefore, prior to elective surgery, nefazodone hydrochloride should be discontinued for as long as clinically feasible. Other CNS-Active Drugs – The use of nefazodone in combination with other CNS-active drugs has not been systematically evaluated.

Consequently, caution is advised if concomitant administration of nefazodone and such drugs is required. Cimetidine When nefazodone (200 mg BID) and cimetidine (300 mg QID) were coadministered for one week, no change in the steady-state pharmacokinetics of either nefazodone or cimetidine was observed compared to each dosed alone. Therefore, dosage adjustment is not necessary for either drug when coadministered. Theophylline When nefazodone (200 mg BID) was given to patients being treated with theophylline (600 to 1200 mg/day) for chronic obstructive pulmonary disease, there was no change in the steady-state pharmacokinetics of either nefazodone or theophylline.

FEV 1 measurements taken when theophylline and nefazodone were coadministered did not differ from baseline dosage (i.e., when theophylline was administered alone).…

Pregnancy Teratogenic Effects Pregnancy category C Reproduction studies have been performed in pregnant rabbits and rats at daily doses up to 200 and 300 mg/kg, respectively (approximately 6 and 5 times, respectively, the maximum human daily dose on a mg/m 2 basis). No malformations were observed in the offspring as a result of nefazodone treatment. However, increased early pup mortality was seen in rats at a dose approximately five times the maximum human dose, and decreased pup weights were seen at this and lower doses, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known.

The no-effect dose for rat pup mortality was 1.3 times the human dose on a mg/m 2 basis. There are no adequate and well-controlled studies in pregnant women. Nefazodone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers It is not known whether nefazodone or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nefazodone is administered to a nursing woman.