The P-I-E-N-O Parkinsn's List Drug Database

nefazodone / SerzoneTM

ANTIDEPRESSANT:

SSRI

Description: Nefazodone is a new oral antidepressant with a mechanism of action distinct from other antidepressants. Nefazodone is structurally similar to trazodone but nefazodone causes less sedation or orthostatic hypotension. Nefazodone is as effective as other antidepressants in treating major depression but lacks cardiovascular toxicity seen with tricyclics and does not cause restlessness or insomnia frequently associated with the selective serotonin reuptake inhibitors and does not inhibit REM sleep. Nefazodone was FDA approved in December 1994 for treatment of major depression.

Mechanism of Action: The pharmacologic actions of nefazodone involve both the serotonergic and, to a lesser extent, the noradrenergic systems. Within the serotonergic system, nefazodone is a potent antagonist at type 2 serotonin (5-HTA) post-synaptic receptors. Nefazodone also inhibits pre-synaptic serotonin (5-HT) reuptake (similar to fluoxetine-type antidepressants) but this mechansim is secondary in importance. Both mechanisms increase the amount of serotonin available to interact with 5-HT receptors. Within the noradrenergic system, nefazodone inhibits norepinephrine uptake minimally and this effect is lost with chronic dosing. In addition, nefazodone has been shown to antagonize ›A-adrenergic receptors. Blockade of ›A-adrenergic receptors produces sedation, muscle relaxation, and cardiovascular effects such as hypotension, reflex tachycardia, and minor changes in ECG patterns. Nefazodone has no significant affinity for benzodiazepine, cholinergic, dopaminergic, histaminic, or œ or ›A-adrenergic receptors. As with other antidepressants, nefazodone's antidepressant effects may not be noticeable for several weeks. Nefazodone does not inhibit REM sleep.

Pharmacokinetics: Following oral administration, nefazodone is rapidly and completely absorbed. Absolute bioavailability is about 20% due to extensive first-pass metabolism. Food delays the absorption of nefazodone and further decreases bioavailability by about 20%. Peak plasma concentrations of nefazodone occur in about 1 hour. Steady-state concentrations are achieved in about 5 days. In elderly patients, both Cpmax and AUC are twice as high as for younger patients. Nefazodone is distributed in most body tissues including the central nervous system. Protein binding is approximately 99% and metabolism occurs by n-dealkylation and aliphatic and aromatic hydroxylation via the hepatic cytochrome PA šIIIAA isoenzyme. At least 2 major active metabolites have been identified: hydroxynefazodone and triazoledione. Hydroxynefazodone has the same pharmacologic profile as the parent drug whereas the triazoledione metabolite has one-seventh the activity of nefazodone at 5HT-2A receptors and no serotonin reuptake activity. One minor metabolite, mCPP, also exists and has nonselective serotonin agonist activity at 5HT-1A, 5HT-1C, and 5HTA receptors. The half-life of nefazodone ranges from 2-8 hours. The half-lives of the metabolites are 1.5-4 hours for hydroxynefazodone, 4-8 hours for mCPP, and 18 hours for triazoledione. Excretion of nefazodone and its metabolites occur through both the urine (55%) and feces (20-30%). Elimination is expected to be prolonged in patients with hepatic and/or renal impairment.

CONTRAINDICATIONS/PRECAUTIONS: Nefazodone is contraindicated in and should not be administered to patients receiving terfenadine or astemizole because nefazodone inhibits cytochrome PAšIIIAA, the enzyme which metabolizes all three drugs (see Drug Interactions). Inhibition of terfenadine and astemizole metabolism results in increased plasma concentrations of both drugs. Increased plasma concentrations of terfenadine or astemizole have been associated with QT prolongation and rare cases of serious cardiovascular adverse events, including death due to torsade de pointes have been reported.

All effective antidepressants can transform depression into mania in predisposed individuals. The usual presentation of this switch is the sudden appearance of insomnia. Nefazodone should be held and appropriate therapy initiated to treat the manic symptoms. Therapeutic doses of lithium (and possibly carbamazepine or valproate) are effective in suppressing the switch process.

All antidepressants should be used with caution in depressed patients because of the possibility of suicidal ideation. Close monitoring of the patient is essential in the initial stages of nefazodone therapy and the drug should be prescribed in the smallest quantity possible.

Nefazodone should be used with caution in patients with hepatic disease because metabolism can be delayed and bioavailability may be increased by as much as 25%. Lower doses may be necessary.

Nefazodone should be used cautiously in patients with a recent history of myocardial infarction or unstable cardiac disease because these patients were excluded from clinical trials. In addition, nefazodone can cause bradycardia and/or postural hypotension. It should be used cautiously in patients with a history of myocardial infarction, angina, ischemic stroke, dehydration or hypovolemia, or in patients receiving antihypertensive agents.

Nefazodone should be used with caution in breast-feeding mothers because it is unknown if the drug or its metabolites are excreted into breast milk. Patients should advise their physician of their intention to breast-feed.

Nefazodone is classified pregnancy category C. Nefazodone should be used cautiously during pregnancy because full evaluation of its effects has not been performed.

Use of nefazodone in elderly patients has shown that there is an increase in AUC and Cmax in these patients (see Pharmacokinetics). However, with multiple dosing, this difference is much smaller. It is recommended that these patients be started at one-half the initial dose and titrated as normally indicated.

The safe and effective use of nefazodone in adults under 18 years of age has not been established.

DRUG INTERACTIONS: Nefazodone has been shown to have an effect on the pharmacokinetics of digoxin. The digoxin Cmax, Cmin, and AUC were increased by 29%, 27%, and 15%, respectively, when nefazodone was administered to healthy male volunteers receiving digoxin. Nefazodone's pharmacokinetics were not affected by digoxin.

Nefazodone inhibits the reuptake of serotonin and, to a lesser extent, norepinephrine. Thus, nefazodone has the potential to interact with MAOIs (including furazolidone, pargyline, phenelzine, procarbazine, selegiline, and tranylcypromine), possibly producing confusion, seizures, hypertension, and other other less severe symptoms. Although severe reactions have been seen when drugs with a similar pharmacological profile were used with MAOI therapy, no controlled trials have been done with nefazodone. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of nefazodone therapy, or vice versa.

Nefazodone should not be administered to patients receiving terfenadine or astemizole because nefazodone inhibits cytochrome PAšIIIAA, the enzyme which metabolizes all three drugs. Inhibition of this enzyme by nefazodone results in increased plasma concentrations of both terfenadine and astemizole. Increased plasma concentrations of terfenadine or astemizole are associated with QT prolongation and rare cases of serious cardiovascular adverse events, including death due to torsade de pointes.

Dosage adjustments are necessary when triazolobenzodiazepines (alprazolam and triazolam) are administered with nefazodone because nefazodone inhibits cytochrome PAšIIIAA, the enzyme that metabolizes all three drugs. The half-life and AUC for triazolam are increased 4-fold and for alprazolam, they are increased 2-fold. Peak concentrations are increased 1.7 and 2-fold for triazolam and alprazolam, respectively. Neither alprazolam nor triazolam has an effect on nefazodone plasma concentrations. Initial doses of alprazolam and triazolam should be reduced by 50% and 75%, respectively.

Although no reports of a clinical interaction have been identified, an interaction with nefazodone may occur due to the ability of nefazodone to inhibit the activity of the cytochrome IIIAA isoenzyme. Drugs that are known to be metabolized by this particular isoenzyme include cocaine, cyclosporine, nifedipine and possibly other dihydropyridine calcium channel blockers, and testosterone. Toxicity with any of these agents is possible if nefazodone is added or used concurrently.

ADVERSE REACTIONS: Adverse events reported by the manufacturer during 6-8 week placebo-controlled clinical trials involving 787 patients (393 nefazodone and 394 placebo) are listed below. Side effects of nefazodone that had a significantly greater incidence as compared with placebo include dizziness (17% vs. 5%), drowsiness (25% vd 14%), asthenia (11% vs. 5%), xerostomia (25% vs. 13%), nausea/vomiting (22%/2% vs. 12%/1%), blurred vision (9% vs. 3%), confusion (7% vs. 2%), somnolence (25% vs. 14%), lightheadedness (10% vs. 3%), orthostatic hypotension (4% vs. 1%), scotomata (7% vs. 1%), and constipation (14% vs. 8%). Events that were not significantly greater than placebo and had an incidence of " 5% include headache (36% vs. 33%), infection (8% vs. 6%), dyspepsia (9% vs. 7%), diarrhea (8% vs. 7%), appetite stimulation (5% vs. 3%), and insomnia (11% vs. 9%). Nefazodone can also cause bradycardia, which may, in turn, predispose patients to developing orthostatic hypotension.

Adverse events with an incidence of " 1% and less than 5% for both nefazodone and placebo include flu-like symptoms, fever and chills, neck rigidity, hypotension, pruritus and rash, peripheral edema, polydipsia, arthralgia, memory impairment, paresthesias, flushing, abnormal dreams, decreased concentration, ataxia, incoordination, psychomotor impairment, tremor, hypertonia, decreased libido, increased cough, tinnitus, dysgeusia, urinary urgency or urinary retention, vaginitis, and breast pain.

Although not specifically associated with nefazodone, priapism has been associated with trazodone, a structurally similar drug. If priapism occurs, therapy should be discontinued and a physician consulted.

PATIENT INFORMATION:

What do nefazodone tablets do?

Nefazodone (SerzoneTM ) is an antidepressant. It helps lift severe depression that has no obvious cause. It is chemically different from all other antidepressant medicines. Because it acts differently, nefazodone can benefit patients who have unusual or limiting side effects from other antidepressants. Generic nefazodone tablets are not yet available.

What should my doctor, dentist, or pharmacist know before I take nefazodone?

They need to know if you have any of these conditions:

How should I take this medicine?

Take nefazodone tablets by mouth. Follow the directions on the prescription label. Swallow tablets with a drink of water. Take nefazodone on an empty stomach, 1 to 2 hours before, or at least 2 hours after eating. Take your doses at regular intervals. Do not take your medicine more often than directed.

Special precautions for use in children:

This medicine is not for use in children or adolescents under 18 years old

What if I miss a dose?

If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.

You must leave a suitable interval between doses. If you are taking one dose a day and have to take a missed dose, make sure there is at least 10 to 12 hours between doses. If you are taking two doses a day and have to take a missed dose, make sure there is at least 5 to 6 hours between doses.

Which other medicines may interact with nefazodone?

Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.

What side effects may I notice from taking nefazodone?

Serious side effects with nefazodone include:

Call your doctor as soon as you can if you get any if these side effects.

Minor side effects with nefazodone include:

Let your doctor know about these side effects if they do not go away or if they annoy you.

What do I need to watch for while I take nefazodone?

If you are taking this medicine for a long time, you must visit your doctor for regular checks on your progress. Call your doctor if you faint or notice an uneven heart beat.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how nefazodone affects you. Do not sit up (from a lying position) or stand up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells.

If you are going to have surgery, tell your doctor or dentist that you are taking nefazodone.

This medicine may make your mouth dry. Chewing sugarless gum or sucking hard candy, and drinking plenty of water will help.

Where can I keep my medicine?

Keep out of the reach of children in a container that small children cannot open.

Store at room temperature between 15 and 30C (59 and 86F). Throw away any unused medicine after the expiration date.

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