drug-information.ru

|Nefazodone Hydrochloride

Nefazodone Hydrochloride

Trade Names:
Nefazodone Hydrochloride
- Tablets 50 mg
- Tablets 100 mg
- Tablets 150 mg
- Tablets 200 mg
- Tablets 250 mg

Mechanism of Action

Pharmacology

Undetermined; inhibits neuronal uptake of serotonin and norepinephrine; antagonizes alpha-1 adrenergic receptors.

Pharmacokinetics

Absorption

Absorbtion is rapid and complete. Absolute bioavailability is approximately 20%, T _max is about 1 hr, and steady state is 4 to 5 days (parent and metabolite). Food delays absorption and decreases bioavailability.

Distribution

Nefazodone is widely distributed in body tissues, including CNS, and exhibits nonlinear kinetics for dose and time. Nefazodone Vd is 0.22 to 0.87 L/kg and plasma protein binding is more than 99%.

Metabolism

Nefazodone is extensively metabolized in the liver by n-dealkylation and aliphatic and aromatic hydroxylation. Three active metabolites are hydroxynefazodone (HO-NEF), meta-chlorophenylpiperazine (mCPP), and triazole-dione.

Elimination

Nefazodone is eliminated in urine (less than 1% excreted as unchanged) and feces. The t _½ is 2 to 4 hr (parent compound), 1.5 to 4 hr (HO-NEF), 4 to 8 hr (mCPP), and 18 hr (triazole-dione).

Special Populations

C _max and AUC for nefazodone and HO-NEF were twice as high. Initiate at half the dose, especially in elderly women.

Nefazodone has a higher C _max and AUC in women in single dose, but no difference after multiple doses.

AUC for nefazodone and HO-NEF at steady state were approximately 25% greater.

Indications and Usage

Treatment of depression.

Contraindications

Coadministration with carbamazepine, cisapride, or pimozide; hypersensitivity to nefazodone or other phenylpiperazine antidepressants (eg, trazodone).

Dosage and Administration

PO 100 mg bid initially; increase by 100 to 200 mg increments q wk (max, 600 mg/day).

PO 50 mg bid initially; increase by 100 mg increments q wk (max, 600 mg/day).

General Advice

• Administer without regard to meals. Administer with food if GI upset occurs.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F).

Drug Interactions

Increased plasma concentrations and effects of alprazolam and triazolam.

Elevated buspirone concentrations and decreased buspirone metabolite plasma concentrations.

Elevated serum carbamazepine concentrations with possible increase in side effects may occur.

Increased cisapride plasma concentrations with cardiotoxicity may occur.

Increased plasma levels of digoxin.

Decreased haloperidol clearance; may need to adjust haloperidol dose.

The risk of rhabdomyolysis occurrence may be increased.

Do not use nefazodone concurrently or within 14 days of discontinuing an MAOI; do not start MAOIs within 1 wk of stopping nefazodone.

Increased plasma concentrations of pimozide may occur associated with QT prolongation and rare cases of serious cardiovascular adverse events, including death, principally caused by ventricular tachycardia of the torsades de pointes type.

Nefazodone may decrease propranolol serum concentration; propranolol may interfere with nefazodone metabolism.

Increased sedative-hypnotic effects may occur.

Serotonin syndrome, including irritability, increased muscle tone, shivering, myoclonus, and altered consciousness may occur.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Postural hypotension, vasodilation (4%); hypotension (2%); sinus bradycardia (1.5%).

CNS

Headache (36%); somnolence (28%); dizziness (22%); asthenia, insomnia (11%); lightheadedness (10%); confusion (8%); memory impairment, paresthesia (4%); abnormal dreams, decreased concentration (3%); ataxia, incoordination, psychomotor retardation, tremor (2%); hypertonia, decreased libido (1%); convulsions (postmarketing).

Dermatologic

Pruritus, rash (2%); Stevens-Johnson syndrome (postmarketing).

EENT

Abnormal vision (10%); blurred vision (9%); pharyngitis (6%); tinnitus (3%); taste perversion, visual field defect (2%).

GI

Dry mouth (25%); nausea (23%); constipation (17%); dyspepsia (9%); diarrhea (8%); increased appetite (5%); nausea and vomiting (2%); gastroenteritis (at least 1%).

Genitourinary

Urinary frequency, UTI, urinary retention, vaginitis (2%); breast pain (1%); impotence (at least 1%); gynecomastia (male), priapism (postmarketing).

Hematologic

Thrombocytopenia (postmarketing).

Hepatic

Liver necrosis, liver failure (postmarketing).

Lab Tests

Decreased hematocrit (3%).

Metabolic

Peripheral edema (3%); thirst (1%); galactorrhea, hyponatremia, increased prolactin (postmarketing).

Musculoskeletal

Arthralgia (1%).

Respiratory

Increased cough (3%); dyspnea, bronchitis (at least 1%).

Miscellaneous

Infection (8%); flu-like syndrome (3%); chills, fever (2%); neck rigidity (1%); anaphylactic reactions, angioedema, serotonin syndrome (postmarketing).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Initiate treatment at half the usual dose. Dosage range same as younger patients.

Bradycardia

Sinus bradycardia reported in 1.5% of patients; use with caution in patients with recent MI or unstable heart disease.

Mania/Hypomania

May activate mania/hypomania; use with caution in patients with history of mania.

Postural hypotension

Use with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (eg, history of MI, angina, ischemic stroke) and conditions that would predispose to hypotension (eg, dehydration, hypovolemia, treatment with antihypertensive medications).

Priapism

Priapism (eg, prolonged, painful, inappropriate penile erection) has been reported with closely related antidepressants. Discontinuation of therapy is necessary.

Seizures

Rare cases of petit mal and grand mal seizures reported.

Suicide

Closely monitor patients at risk, and do not give them access to excessive quantities.

Visual disturbances

Visual disturbances, including blurred vision, scotoma, and visual trails reported.

Overdosage

Symptoms

Nausea, vomiting, somnolence.

Patient Information

• Advise patient to read the patient information leaflet before starting therapy and with each refill.
• Advise patient that medication will be started at a low dose and then gradually increased as tolerated until max benefit is obtained.
• Advise patient to take prescribed dose bid without regard to meals but to take with food if stomach upset occurs.
• Advise patient that if a dose is missed to skip that dose and take the next dose at the regularly scheduled time. Caution patient to never take 2 doses at the same time.
• Advise patient not to change the dose or stop taking unless advised by health care provider.
• Inform patient that it may take 1 to 4 wk to note improvement in symptoms and to continue with the prescribed therapy once improvement has been noted.
• Advise patient to take frequent sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
• Advise patient to avoid alcoholic beverages.
• Advise patient that drug may cause drowsiness or impair judgment, thinking, or reflexes and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
• Advise patient to immediately report any of the following to health care provider: nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine, yellowing of the skin or eyes, seizure, or fainting.
• Advise patient to contact health care provider if rash, hives, or other symptoms of an allergic reaction develop, if a painful or prolonged erection occurs, or if experiencing bothersome side effects such as visual disturbances, headache, insomnia, or drowsiness.