DISCLAIMER: The following information was reproduced from literature received from Bristol-Myers Squibb Canada Inc.. No warranty is made for clerical accuracy or completeness and as this is a Canadian release it is highly recommended that this be used as nothing more than an informal overview until such time that the same literature is published and received from U.S. source. No interpretation or judgment has been used in providing this information by the writer but still should be considered third party information. Nefazodone Hcl TABLETS 100, 150 and 200mg THERAPEUTIC CLASSIFICATION: Antidepressant ACTIONS AND CLINICAL PHARMACOLOGY: Nefazodone is a synthetically derived analog of the phenylpiperazine series which is metabolized in vivo to compounds which likewise exhibit pharmacological activity. Nefazodone (NEF) and one of its active metabolites, hydroxynefazodone, exert dual effects on serotonergic neurotransmission through blockade of serotonin type 2 (5-HT/2) receptors and inhibition of serotonin uptake. The parent compound (NEF) and another active metabolite, m-chlorophenyl- piperazine (mCPP), also exhibit affinity for the 5-HT/1c receptor. Nefazodone lacks anticholinergic or antihistaminic effects but exhibits some affinity for alpha, adrenergic receptors. PHARMACOKINETCS and METABOLISM: Orally administered nefazodone is rapidly and completely absorbed, with peak plasma concentrations occurring 1 to 3 hours after dosing. However, nefazodone is subject to extensive presystemic metabolism, and its systemic bioavailability is estimated to range between 15% and 23% at doses of 50 to 200mg. Single doses of 50, 100 and 200 mg of nefazodone, administered as the hydrochloride salt in capsule formulation, result in mean peak plasma concentrations of 84, 196 and 392 ng/mL, respectively. Steady state is reached within 3 to 4 days of initiation or adjustment of bid dosing. At steady state, both the peak plasma concentrations and the mean area under the plasma concentration vs. time profiles (AUC) indicate that nefazodone's pharmacokinetic parameters are non-linear. The mean peak plasma concentrations for doses of 50, 100 and 200 mg bid were 270, 730 and 2050 ng/mL, respectively, and the corresponding AUC values were 540, 2270 and 9250 ng-h/mL. EFFECTS OF FOOD: Food delays the absorption of nefazodone and decreases its systemic exposure by approximately 20%. These effects are small and are unlikely to be clinically significant in light of the extensive inter- and intra-subject variability in pharmacokinetics. DISTRIBUTION: Following a 5 mg. IV dose, the volume of distribution at steady state (VD/ss) ranged from 0.23 - 0.87 L/kg, indicating that nefazodone is widely distributed in body tissues. METABOLISM: A clinical pharmacokinetic study using orally administered ^14C- radiolabelled nefazodone has demonstrated extensive presystemic metabolism. Nefazodone accounted for approximately 3% of the total radioactivity in the plasma. Nefazodone undergoes N-dealkylation as well as aliphatic and aromatic hydroxylation. Two metabolites of nefazodone (NEF), hydroxy-nefazodone (HO- NEF) and triazole dione (dione) have been shown to possess qualitatively similar pharmacological profiles to NEF, though triazole dione is markedly less potent. A third metabolite, m-chlorophenyl-piperazine (mCPP), has broader serotonergic effects. The pharmacokinetics of NEF, HO-NEF, and mCPP exhibit extensive inter- and intra-subject variability in humans. In healthy male volunteers receiving multiple 50 mg bid, 100 gm bid, and 200 mg bid doses of nefazodone, the peak plasma concentrations of HO-NEF and mCPP were approximately 25% and 2%, respectively, of those for the parent compound. The relative peak plasma concentration ratio of mCPP to NEF decreased from 2.9% to 1.4% as the dose of nefazodone was increased from 50mg bid to 200 mg bid. The pharmacokinetics of HO-NEF are nonlinear; however, mCPP exhibits linear pharmacokinetics. Triazole-dione, exhibits only weak 5-HT/2 antagonistic activity, but is present at steady state in peak plasma concentrations which are approximately 125% of those for nefazodone. ELIMINATION: The plasma elimination half-life of nefazodone is dose- dependent, In a three way crossover study in healthy male volunteers, steady- state t/(1/2) values were 1.9 h for a 50 mg bid dose. After oral administration, nefazodone is eliminated primarily by hepatic metabolism. When ~14C-labelled nefazodone is administered orally, about 5--65%^ of the radioactivity was excreted in the urine as metabolites. Less than 1% of the administered nefazodone was detected unchanged in urine; identified metabolites of nefazodone accounted for 80% of the radioactivity detected in urine. The excretion of nefazodone and HO-NEF is negligible; approximately 1% of the administered dose is excreted as mCPP and about 7% as para-hydroxy-mCPP (p-OH-mCPP). Fecal excretion accounted for 20-40% of the administered radiolabel. In 24 healthy male volunteers, the oral clearance (CL/F) at steady state decreased from 115 +/- 32 L/h (mean +/- sd) at a dose of 50 mg. to 29 +/- 13 L/h at dose of 300 mg. IN ELDERLY SUBJECTS: A multiple-dose pharmacokinetic study in elderly subjects indicated that the pharmacokinetics and metabolism of nefazodone are similar in young and elderly male volunteers. In elderly women, plasma concentrations of nefazodone were 60% higher than those in young female volunteers and the elimination half-life was increased from 5.4 to 8.9 hrs. The clinical significance of this finding is not known. Single doses of 50-300 mg nefazodone in elderly volunteers have been reported to result in peak plasma concentrations and area under the plasma concentration time curve values which are approximately double those observed in young volunteers. These data suggest that treatment in elderly patients should be initiated at one half of the usual dose of nefazodone. IN HEPATICALLY IMPAIRED PATIENTS: In a single dose study, mean AUC values for subjects with hepatic cirrhosis (n=12) receiving nefazodone at doses of 50-200 mg were double those observed in normal subjects (n=12). In a multiple- dose study of patients with mild hepatic impairment (n=13), the steady state AUC values for nefazodone and HO-NEF were approximately 20% to 40% greater than those observed in healthy volunteers. Therefore, if nefazodone is administered to patients with liver disease, treatment should be initiated at one-half the usual dose of nefazodone, with subsequent adjustments being performed on the basis of tolerance and therapeutic response. IN RENALLY IMPAIRED PATIENTS: The pharmacokinetics of nefazodone , HO- NEF, and mCPP were investigated in a multiple dose study of nefazodone involving patients with varying degrees of renal impairment (creatinite clearance ranging from 7 to 60 mL/min/1.73m^2). No significant relationships were observed between the pharmacokinetic parameters and the degree of renal impairment. However, in patients with severely impaired renal function, SERZONE should be used with caution. PROTEIN BINDING: At concentrations of 25-2500 ng/mL, nefazodone is extensively (> 99%) bound to plasma proteins in vitro. PHARMACODYNAMICS: HEMODYNAMIC EFFECTS: In one crossover study involving subjects at least 65 years old, nefazodone caused a modest decrease in mean supine blood pressure and pulse rate without producing orthostatic hypotension or alterations in cardiac conduction compared to placebo. PSYCHOMOTOR EFFECTS: In one study, psychomotor impairment in nefazodone-treated patients was shown after seven days of bid treatment, but not after acute dosing. In 12 elderly subjects (>=60yrs), chronic administration of nefazodone resulted in statistically significant decreases in driving performance (200m mg bid) and increased reaction times (100-200 mg bid). In young adult subjects (n=12), increased reaction times were observed during chronic dosing with 200 mg bid nefazodone. In another 7-day study involving subjects at least 65 years old, psychomotor and cognitive function tests generally sensitive to the effects of psychotropic medication were not markedly altered by nefazodone. SLEEP ARCHITECTURE: When given to healthy volunteers (n=12) at bedtime, nefazodone slightly decreased (15%) the time between sleep initiation and the first rapid eye movement (REM) episode. significantly increased total REM sleep time, did not affect the number of timing of REM episodes through the night and significantly decreased Stage 2 sleep. NOCTURNAL PENILE TUMESCENCE: In the sleep architecture study conducted in healthy volunteers, the percent total sleep time spent in the tumescent state was 28% for placebo and 37% for a 400mg dose of nefazodone. The difference between the two treatment groups was not statistically significant. ENDOCRINE EFFECTS: In normal male volunteers (n=8), single 50, 100, and 200 mg doses of nefazodone were associated with dose dependent increases in plasma prolactin and growth hormone levels. At 150 minutes post- administration of a 200 mg dose, mean plasma prolactin levels were double baseline values but remained within the normal range. This increase in prolactin was not evident following seven days of dosing with 100 mg bid of nefazodone. Mean plasma levels of growth hormone were increased approximately 15 fold over baseline levels 150 minutes after single 100 to 200 mg doses of nefazodone. When nefazodone was administered for 7 days according to a 100 mg bid regimen, plasma growth hormone levels were increased approximately 10 fold over baseline. The peak levels of growth hormone were in excess of the normal values but declined to normal range within the dosing interval. Plasma levels of ACTH and cortisol also tended to be increased (not significant) after single doses of 100 and 200 mg. The effects of nefazodone on hormonal levels in female subjects have not been investigated. INDICATIONS AND CLINICAL USE: SERZONE (nefazodone HCl) is indicated for the symptomatic relief of depressive illness. The effectiveness of nefazodone in long-term use (ie. for more than 6 to 8 weeks) has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use nefazodone for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. CONTRAINDICATIONS: SERZONE (nefazodone HCl) is contraindicated in patients with known hypersensitivity to nefazodone, any component of the formulation or other phenylpiperazine antidepressants. MONOAMINE OXIDASE INHIBITORS: SERZONE should not be used in combination with monoamine oxidase inhibitors or within two weeks of terminating treatment with monoamine oxidase inhibitors. Monoamine oxidase inhibitors should not be introduced until at least 2 weeks after the cessation of SERZONE therapy. WARNINGS: GENERAL: SUICIDE: The possibility of a suicide attempt in seriously depressed patients is inherent to the illness and may persist until significant remission occurs. Close supervision of high risk patients should continue through therapy and consideration should be given to the possible need for hospitalization. In order to reduce the risk of overdose, prescriptions of SERZONE (nefazodone HCl) should be written for the smallest quantity of tablets consistent with good patient management. SEIZURES: As with other antidepressants, nefazodone should be used with caution in patients with a history of seizures. During clinical trials, the overall incidence of seizures was 0.04% in patients treated with SERZONE. However patients with a history of convulsive disorders were excluded from these studies. The drug should be discontinued in any patient who develops seizures. ACTIVATION OF MANI/HYPOMANIA: As with most antidepressant agents, activation of mania/hypomania has been reported rarely in patients with Major Affective Disorder treated with SERZONE. In unipolar depressed patients in clinical trials, hypomania or mania occurred in 0.4%, 0.3% and 0.5% for nefazodone, tricyclic antidepressants and placebo. USE IN PATIENTS WITH CONCOMITANT ILLNESS: Clinical experience with SERZONE in patients with concomitant systemic illness is limited. Caution is advisable when using nefazodone in patients with diseases or conditions such as hepatic or renal impairment, that could affect the metabolism or hemodynamic responses. INTERFERENCE WITH COGNITIVE AND MOTOR PERFORMANCE: Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. Psychomotor impairment in nefazodone-treated subjects was evident after seven days of bid treatment, but not after acute dosing. CARDIOVASCULAR EFFECTS: SERZONE treatment was associated with modest blood pressure lowering effects in clinical trials. Orthostatic hypotension and syncope have been reported in some SERZONE-treated patients. Caution should be observed when SERZONE treatment is initiated in patients with pre- existing hypotension or a labile circulation. Sinus bradycardia and first degree AV block were observed in 1.2% and 1%% of patients who received recommended therapeutic doses of the drug in clinical trials. Corresponding rates of occurrence during placebo treatment were 0.4% and 0.6%. SERZONE has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Hence, the usual precautions should be observed in these patients. LABORATORY TEST: As with all new drugs for which post-marketing experience is not available, consideration should be given to performing periodic white blood cell counts. During clinical trials, there was no difference in the incidence of leukopenia between the placebo and nefazodone groups (0.2%). PROLACTIN LEVELS: In male volunteers, prolactin levels were increased to twice the baseline values following the acute administration of nefazodone, although individual values remained within the normal range (2-15 ng/mL). Such an increase was not seen following 7-day dosing. Prolactin levels were not determined in women, however, no clinical evidence of hyperprolactinemia (eg. amenorrhea, galactorrhea, abnormal menstrual cycle length) was observed in the 446 women who received nefazodone for more than 60 days in clinical studies. In women with existing breast cancer, or a history of this disease, the possible risk of hyperprolactinemia should be weighted against the benefits of therapy. Tissue culture experiments indicate that approximately 1/3 of human breast cancers are prolactin dependent in vitro. Neither clinical studies nor epidemiological studies conducted to date, however, have shown an association between administration of hyperprolactinemia-inducing drugs and mammary tumorigenesis; available evidence is considered too limited to be conclusive at this time. MALE SEXUAL FUNCTION: Nefazodone, a phenylpiperazine compound is structurally related to trazodone, a drug which has been associated with the occurrence of priapism during post marketing use. Priapism has not been reported in clinical trials with nefazodone. However, if patients present with prolonged or inappropriate erections, they should discontinue therapy immediately and consult their physician. If the condition persists for more than 24 hours, a urologist should be consulted to determine appropriate management. USE IN PREGNANCY: There are no adequate and well-controlled studies with nefazodone in pregnant women. NURSING MOTHERS: It is not know whether and, if so, in what amount nefazodone or its metabolites are excreted in human milk. In lactating rats, nefazodone and two of its metabolites (HO-NEF and mCPP) are excreted in milk. Because many drugs are excreted in human milk, lactating, women should not nurse their infants while receiving SERZONE. PEDIATRIC USE: Safety and effectiveness in children below the age of 18 have not been established. USE IN THE ELDERLY: Serzone has not been systematically studied in geriatric patients. No unusual adverse age-related phenomena were identified upon careful evaluation of all safety assessments in a cohort of 271 elderly patients treated with SERZONE. Due to the increased systemic exposure to nefazodone in elderly women, nefazodone treatment should be initiated at half the usual dose, with titration upward as needed to achieve a therapeutic response without producing limiting adverse experiences (see DOSAGE AND ADMINISTRATION). In clinical trials, most elderly patients achieved optimal therapeutic response at daily doses of 200 to 400 mg. The usual precautions should be observed in elderly patients who have concomitant medical illnesses or who are receiving concomitant drugs. DRUG ABUSE AND DEPENDENCE: Nefazodone showed no potential for abuse in a controlled study of abuse liability. Nefazodone has not bee systematically studied in humans for its potential for tolerance, physical dependence or withdrawal. Continued. - Victor G.L. Jasin jasin@uwo.ca "iki pasirasymo!" ÿ@FROM :jasin@julian.uwo.ca ÿ@SUBJECT:SERZONE (nefazodone HCl) repost part 2 of 3 Message-ID: Path: news.channel1.com!news1.channel1.com!wizard.pn.com!sundog.tiac.net news.kei.com!news.mathworks.com!hookup!uwm.edu!vixen.cso.uiuc.edu howland.reston.ans.net!torn!newshost.uwo.ca!ts1-78.slip.uwo.ca!jasin From: jasin@julian.uwo.ca (Vic Jasin) Newsgroups: sci.med.pharmacy Subject: SERZONE (nefazodone HCl) repost part 2 of 3 Date: Fri, 27 Jan 1995 00:24:55 EST Organization: Jasin's World of Experiences Lines: 291 Message-ID: NNTP-Posting-Host: ts1-78.slip.uwo.ca X-Authenticated: vjasin@ts1-78.slip.uwo.ca X-Newsreader: Trumpet for Windows [Version 1.0 Rev B final beta #4] ..continued DISCLAIMER: The following information was reproduced from literature received from Bristol-Myers Squibb Canada Inc.. No warranty is made for clerical accuracy or completeness and as this is a Canadian release it is highly recommended that this be used as nothing more than an informal overview until such time that the same literature is published and received from U.S. source. No interpretation or judgment has been used in providing this information by the writer but still should be considered third party information. DRUG INTERACTIONS: WITH TRIAZOLAM: When a single oral 0.25 dose of triazolam was CO- administered with nefazodone (200 mg bid) at steady state, triazolam peak concentrations, half-life, and AUC were increased 1.7, 3 and 4 fold respectively. The pharmacokinetics of nefazodone were not altered. The concomitant use of triazolam and nefazodone was also associated with an increase in psychomotor impairment presumably due to increased triazolam plasma concentrations. The interactive effects of higher doses of these agents have not been studied. The concomitant use of SERZONE and triazolam should be avoided. The metabolism of triazolam has bee attributed to the specific hepatic microsomal isozyme, P450IIIA4. Potential interactions between nefazodone and other drugs metabolized by this isozyme (eg. cyclosporine, midazolam, nifedipine, quinidine, lidocaine, and erythromycin) should be considered. WITH ALPRAZOLAM: When alprazolam (1mg bid) and nefazodone (200 mg bid) were CO-administered to steady state, peak concentrations, AUC and half-life values for alprazolam increased by approximately 2 fold. Nefazodone plasma concentrations were unaffected by alprazolam, although levels of the mCPP metabolite were increased. The concomitant use of alprazolam and nefazodone was also associated with an increase in psychomotor impairment presumably due to increased alprazolam plasma concentrations. If alprazolam is CO-administered with SERZONE, a reduction in the alprazolam dosage may be appropriate; no dosage adjustment is required for SERZONE. The interactive effects of higher doses of these agents, such as the dosage levels of alprazolam used in panic disorder, have not been studied. WITH LORAZEPAM: When lorazepam (2 mg bid) and nefazodone (200 mg bid) were CO-administered 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 CO- administered. WITH CNS-ACTIVE DRUGS: The risk of using SERZONE in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised if concomitant administration of SERZONE and such drugs is required. WITH ALCOHOL: Even though nefazodone did not demonstrate statistically significant alteration of the psychomotor or cognitive impairment caused by alcohol in a controlled trial with young normal volunteers., it is prudent to avoid concomitant use of alcohol and nefazodone. WITH HALOPERIDOL: In healthy volunteers, the AUC of haloperidol (single 5 mg. dose) was increased by 35%, with no significant increase in the C/max or T/max when CO-administered with nefazodone (200 mg bid) at steady state. Slight protein binding displacement of haloperidol (approximately 5% of control) was also noted. These changes are not considered clinically significant. There were no changes in the pharmacokinetic parameters of nefazodone. Therefore, dosage adjustment is not necessary for either drug when CO- administered. WITH LITHIUM: Concurrent administration of nefazodone (100 mg bid ) with lithium (800 mg/day) did not cause any untoward effects (eg tremor, hypothermia) associated with serotonin syndrome. WITH CIMETIDINE: No significant clinical or pharmacokinetic interactions between nefazodone (200 mg bid) and cimetidine (300 mg q.i.d.) were observed in a multiple dose clinical trial involving healthy volunteers. WITH ANTIHYPERTENSIVES: Although nefazodone is not a potent alpha- adrenergic blocking agent, there have been reports of orthostatic hypotension and syncope occurring in nefazodone-treaded patients. In a study in 12 elderly volunteers, nefazodone produced a modes lowering of blood pressure without accompanying orthostatic changes. Although interactions with cardiovascular medications have not been formally studied, concomitant administration of antihypertensive therapy and nefazodone should be initiated cautiously and a reduction in the dose of the antihypertensive drug may be required. WITH GENERAL ANESTHETICS: Little is known about the potential for interaction between nefazodone and general anesthetics; therefore, prior to elective surgery, nefazodone should be discontinued for as long as clinically feasible. PROTEIN BINDING: Nefazodone is extensively (>99%) bound to plasma proteins in man. The effect of nefazodone on plasma protein binding of potentially CO-administered drugs should be considered. The protein binding of chlorpromazine, desipramine, diazepam, diphenylhydantoin, lidocaine, prazosin, propranolol, verapamil and warfarin was not affected by nefazodone in vitro. ADVERSE REACTIONS: COMMONLY OBSERVED ADVERSE EVENTS: In clinical trials, the most commonly observed adverse experiences associated with the use of SERZONE (nefazodone HCl) which occurred at a higher rate than among placebo- treated patients were dry mouth, nausea, somnolence, dizziness, constipation, asthenia, light-headedness, and amblyopia. Adverse events are more frequent at the beginning of treatment and tend to subside with continued use. ADVERSE EVENTS ASSOCIATED WITH DISCONTINUATION OF TREATMENT: Approximately 11 percent of the 2256 patients who received SERZONE in short-term worldwide premarketing clinical trials discontinued treatment due to adverse experiences. The most common events causing discontinuation included: nausea (2.4%), headache (2.0%), dizziness (1.2%), asthenia (1.0%), and insomnia (1.2%). SERIOUS ADVERSE EVENTS: Serious adverse events occurring in all patients treated with SERZONE in clinical trials were: syncope (1 case), abdominal pain(1 case) and gastrointestinal bleeding (1 case). INCIDENCE IN CONTROLLED CLINICAL TRIALS: The table which follows enumerates adverse experiences that occurred at a frequency of 1% or more in patients who received flexible doses of SERZONE within low and high dose ranges in placebo-controlled clinical trials of 6 to 8 weeks duration. Adverse event rates are provided for the total data base of 664 nefazodone- treated patients as well as for the subsets of patients who received dosages in the low (n=271) and high (n=393) dose ranges. Patients included in the low dose range treatment groups were initiated at doses of 50 to 150 mg/day and were titrated to maximum doses of 250 to 300 mg/day. Mean modal doses of SERZONE at the last week of treatment ranged from approximately 250 to 275 mg/day in these studies. Patients included in the high dose range treatment groups were initiated at doses of 100 to 300 mg per day and were titrated to maximum doses of 500 to 600 mg/day. Mean modal doses of SERZONE at the last week of treatment ranged from approximately 350 to 500 mg/day in these studies. OTHER EVENTS OBSERVED DURING THE PREMARKETING EVALUATION OF NEFAZODONE: In the tabulations that follow, a dictionary based on COSTART terminology has been used to classify reported adverse experiences. The adverse events, arranged by body system, were reported on at least one occasion by patients during clinical trials with SERZONE (nefazodone). The frequencies reported are based on 2256 patients exposed to SERZONE. All reported events are included except those already listed in the previous table or those for which a drug cause was remote or the event term was mative. It is important to emphasize that, although the experiences reported did occur during treatment with SERZONE, they were not necessarily caused by it. Experiences are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: 1 or more occasions in at least 1/100 patients; infrequent adverse experiences are those occurring in less than1/100 but at least 1/1000 patients; rare adverse experiences are those occurring in less than 1/1000 patients. BODY AS A WHOLE: FREQUENT: Neck pain; INFREQUENT; Neck rigidity, allergic reaction, photosensitivity reaction, hangover effect, malaise, enlarged abdomen and face edema; RARE; Hernia, overdose, halitosis and cellulitis. CARDIOVASCULAR SYSTEM: FREQUENT: Hypotension; INFREQUENT: Presyncope, migraine, hypertension, tachycardia, extrasystoles, peripheral vascular disorder, AV block, bradycardia and syncope; RARE: Angina pectoris, atrial fibrillation, pallor, phlebitis, congestive heart failure and coronary artery disease. DIGESTIVE SYSTEM: FREQUENT: Anorexia and gastroenteritis; INFREQUENT: Nausea and vomiting, liver function tests abnormality, gastritis, abnormal stools, eructation, periodontal abscess, colitis, mouth ulceration, stomatitis, gingivitis, peptic ulcer and rectal hemorrhage; RARE: Glossitis, bloody diarrhea, dysphagia, esophagitis, hepatitis, GI hemorrhage, oral moniliasis, ulcerative colitis and salivary gland enlargement. HEMIC AND LYMPHATIC: INFREQUENT: Ecchymosis, leukopenia, lymphadenophathy and anemia; RARE: Eosinophilia and leukocytosis. METABOLIC AND NUTRITIONAL: INFREQUENT: Thirst and weight loss; RARE: Gout, hypercholesteremia, hypervolemia, hyponatremia and hypoglycemia. MUSCULOSKELETAL SYSTEM: FREQUENT: Arthralgia; INFREQUENT: Arthritis, muscle stiffness and tenosynovitis; RARE: Bursitis, myositis and tendinous contracture. NERVOUS SYSTEM: FREQUENT: CNS stimulation; INFREQUENT: Decreased or increased libido, vertigo, emotional lability, dysphoria, hypertonia, depersonalization, euphoria, amnesia, twitching, hallucinations, hypomanic reaction, derealization, manic reaction, neuralgia, suicidal thoughts, hostility, suicide attempt, decreased attention, paranoid reaction, abnormal gait, apathy and myoclonus; RARE: Affect abnormal, abnormal behavior, convulsion, delirium, delusions, drug dependency (other drug), hyperesthesia, increased salivation, neuropathy, neurosis, torticollis, disarthria, hypotonia, ptosis, ekathisia, hyperalgesia and personality disorder. RESPIRATORY SYSTEM: FREQUENT: Cough; INFREQUENT: Bronchitis dyspnea, hiccup, epistaxis, pneumonia, asthma and laryngitis; RARE: Emphysema, hyperventilation and pleural disorder. SKIN AND APPENDAGES: INFREQUENT: Dry skin, acne, urticaria, alopecia, herpes simples, herpes zoster, vesiculobullous rash and eczema; RARE: Hersutism, skin carcinoma, furunculosis, subcutaneous nodule and increased seating. SPECIAL SENSES: INFREQUENT: Eye pain, ear pain, visual field defect, dry eye, abnormality of accommodation, conjunctivitis, diplopia, keratoconjunctivitis, mydriasis and photophobia; RARE: Exophthalmos, glaucoma, hyperacusis, night blindness, taste loss, otitis media and retinal degeneration. UROGENITAL SYSTEM: FREQUENT: Dysmenorrhea and vaginitis; INFREQUENT: Cystitis, dysuria, breast pain, urinary urgency, impotence, metorrhagia, polyuria, amenorrhea, urinary retention, prostatic disorder, breast enlargement, breast neoplasm, hematuria, kidney calculus and urinary incontinence; RARE: Abnormal ejaculation, breast carcinoma, cervix neoplasm, dyspareunia, mastitis, menopause, menorrhagia, oliguria, enlarged uterine fibroids, vaginal hemorrhage, anorgasmia, nocturia and uterine hemorrhage. SYMPTOMS AND TREATMENT OF OVERDOSAGE: In clinical studies involving 2256 patients treated with nefazodone, there were no deaths attributed to overdose with nefazodone. Two patients attempted suicide by overdose. One patient ingested 3400 mg of nefazodone and the other ingested 3600 mg of nefazodone. Both patients recovered without important or life threatening symptoms and without sequelae. The reactions reported most frequently from overdose of SERZONE (nefazodone HCl) have been drowsiness and vomiting. Overdosage may cause an increase in incidence or severity of any of the reported adverse reactions. (See ADVERSE REACTIONS). TREATMENT: There is no specific antidote for SERZONE. Treatment should be symptomatic and supportive in the case of hypotension or excessive sedation. DOSAGE AND ADMINISTRATION: ADULTS: SERZONE (nefazodone HCl) should usually be initiated at 200 mg/day (100 mg bid) with dose increases for most patients after assessing response, following the first week of treatment. In controlled clinical trials designed to establish the efficacy of nefazodone, patients were given doses ranging from 100 mg to 600 mg per day, administered in divided doses. These studies indicate that most patients responded at daily doses ranging from 300 mg to 500 mg. The full antidepressant effect of SERZONE may be delayed for four weeks or longer. ELDERLY, DEBILITATED AND HEPATIC IMPAIRMENT: Not therapeutic clinical trials have been conducted to systematically investigate dose requirements in patients who are elderly, debilitated or hepatically impaired. However, as these patients often have reduced nefazodone clearance and/or increased sensitivity to the side effects of CND-active drugs, the recommended initial dose is 100 mg/day (50 mg bid). It may be appropriate to modify the rate of subsequent dose titration as well as the final target dose based on a careful assessment of the patient's clinical response. PHARMACEUTICAL INFORMATION: I. DRUGS SUBSTANCE Tradename: SERZONE Proper name: Nefazodone Hydrochloride Chemical Name: 2-[3-[4-(3-chlorophenyl)-1-peperazinyl]propyl]-5-ethyl- 2, 4-dihydro-4-(2-phenoxyethyl)-3H-1,2,3- triazol-3- one monohydrochloride Empirical Formula: C v H v CINvO v*HCL ( read v as the base number below it) 25 32 5 2 Structural Formula omitted due to graphics incompatibility. II. COMPOSITION: In addition to the active ingredients, nefazodone hydrochloride, each tablet contains microcrystalline cellulose, povidone, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, red ferric oxide (150 mg) and yellow ferric oxide (150 and 200 mg) AVAILABILITY: SERZONE (Nefazodone Hydrochloride) 100 mg. tablets are white, hexagonal, flat faced, bevelled-edged tablets engraved with "BMS 100" and a bisect score on one side and "32" and a bisect score on the other. SERZONE 150 mg. tablets are peach, hexagonal, flat faced, bevelled- edged tablets engraved with "BMS 150" and a bisect score on one side and "39" and a bisect score on the other. SERZONE 200 Mg. tablets are light yellow, hexagonal, flat faced, bevelled- edged tablets engraved with "BMS 200" on one side and "33" on the other. SERZONE 100, 150 and 200 mg tablets are available in bottles of 60. Store at room temperature (15-30deg C). Keep container tightly closed SERZONE is a schedule F drug. REFERENCES: 1. Serzone Product Monograph, Bristol-Myers Squibb Canada Inc, 1994 2. Sussman N. J Clin Psychiatry 1994;55(suppl2);45-51 3. A comparison of Serzone, fluvoxamine maleate, paroxetine HCl, fluoxetine HCl and sertraline HCl product monographs. 4. Fontaine R. Clin Neuropharmacol 1993;16(suppl 3);S45-S50 5. Sharpley AL Biol Psychiatry 1992;31;1070-1073. 6. Armitage R et al. The effects of nefazodone on sleep architecture in depression. Neuropsychopharmacology 1994;10(2). 7. Fawcett J. The relative efficacy of nefazodone in the treatment of symptoms of anxiety and agitation in major depression. In Pres: J Clin Psychiatry 1994. 8. Fontaine R. et al. A double-blind comparison of nefazodone, imipramine and placebo in major depression. In Press. Product Monographs available on request. BRISTOL-MYERS SQUIBB Pharmaceutical Group Montreal, Quebec, Member PMAC PAAB continue - Adverse Events Schedule follows - Victor G.L. Jasin jasin@uwo.ca "iki pasirasymo!" ÿ@FROM :jasin@julian.uwo.ca ÿ@SUBJECT:SERZONE (nefazodone HCl) repost part 3 of 3 Message-ID: Path: news.channel1.com!news1.channel1.com!wizard.pn.com!sundog.tiac.net news.kei.com!news.mathworks.com!hookup!uwm.edu!vixen.cso.uiuc.edu howland.reston.ans.net!torn!newshost.uwo.ca!ts1-78.slip.uwo.ca!jasin From: jasin@julian.uwo.ca (Vic Jasin) Newsgroups: sci.med.pharmacy Subject: SERZONE (nefazodone HCl) repost part 3 of 3 Date: Fri, 27 Jan 1995 00:28:28 EST Organization: Jasin's World of Experiences Lines: 146 Message-ID: NNTP-Posting-Host: ts1-78.slip.uwo.ca X-Authenticated: vjasin@ts1-78.slip.uwo.ca X-Newsreader: Trumpet for Windows [Version 1.0 Rev B final beta #4] ..........continued DISCLAIMER: The following information was reproduced from literature received from Bristol-Myers Squibb Canada Inc.. No warranty is made for clerical accuracy or completeness and as this is a Canadian release it is highly recommended that this be used as nothing more than an informal overview until such time that the same literature is published and received from U.S. source. No interpretation or judgment has been used in providing this information by the writer but still should be considered third party information. ----------------------------------------------------------------------- ------- ------------------------------ ---------------- ADVERSE EVENTS (INCIDENCE >= 1%) IN PLACEBO-CONTROLLED TRIALS (6-8 WEEKS) Body System/ Nefazodone Placebo Nefazodone Placebo Adverse Experience Low High Dose Dose 50-300mg/day 100-600mg/day n=271 n=272 n=393 n=394 BODY AS A WHOLE Headache 121(44.7) 110(40.4) 142(36.1) 130(33.0) Asthenia 25( 9.2)** 9( 3.3) 42(10.7)** 20( 5.1) Infection 17( 6.3) 14( 5.2) 30( 7.6) 21( 5.3) Abdominal Pain 13( 4.8) 17( 6.3) 22( 5.6) 27( 6.9) Flu Syndrome 12( 4.4) 10( 3.7) 13( 3.3) 9( 2.3) Pain 16( 5.9) 17( 6.3) 19( 4.8) 22( 5.6) Back Pain 10( 3.7) 11( 4.0) 15( 3.8) 15( 3.8) Accidental Injury 6( 2.2) 6( 2.2) 9( 2.3) 12( 3.1) Chills - - 7( 1.8) 2( 0.5) Fever 5( 1.8)* 0( 0.0) 6( 1.5) 2( 0.5) Chest Pain 3( 1.1) 10( 3.7) 7( 1.8) 13( 3.3) Neck Rigidity - - 4( 1.0) 0( 0.0) CARDIOVASCULAR SYSTEM Postural Hypotension 9( 3.3) 5( 1.8) 17( 4.3)** 4( 1.0) Palpitation - - 11( 2.8) 12( 3.1) Hypotension - - 7( 1,8) 2( 0.5) Migraine - - 5( 1.3) 2( 0.5) DIGESTIVE SYSTEM Dry Mouth 58(21.4)* 37(13.6) 98(24.9)** 53(13.5) Nausea 40(14.8) 34(12.5) 86(21.9)** 48(12.2) Constipation 31(11.4) 24( 8.8) 55(14.0)** 33( 8.4) Diarrhea 17( 6.3) 17( 6.3) 33( 8.4) 29( 7.4) Dyspepsia 16( 5.9) 14( 5.2) 34( 8.7) 29( 7.4) Increased Appetite 7( 2.6) 6( 2.2) 19( 4.8) 10( 2.5) Flatulence 4( 1.5) 12( 4.4) 11( 2.8) 11( 2.8) Vomiting 5( 1.9) 5( 1.8) 7( 1.8) 7( 1.8) Nausea & Vomiting 3( 1.1) 1( 0.4) 6( 1.5) 2( 0.5) Anorexia 3( 1.1) 3( 1.1) - - Gastroenteritis 3( 1.1) 1( 0.4) - - METABOLIC & NUTRITIONAL Peripheral Edema 3( 1.1) 4( 1.5) 10( 2.5) 5( 1.3) Weight Gain - - 8( 2.0) 6( 1.5) Edema - - 4( 1.0) 3( 0.8) Thirst - - 4( 1.0) 1( 0.3) MUSCULOSKELETAL Maylgia 5( 1.9) 7( 2.6) 8( 2.0) 7( 1.8) Cramp - - 5( 1.3) 5( 1.3) Arthralgia - - 4( 1.0) 1( 0.3) NERVOUS SYSTEM Somnolence 47(17.3) 35(12.9) 100(25.5)** 54(13.7) Dizziness 27(10.0)* 13( 4.8) 65(16.5)** 21( 5.3) Insomnia 25( 9.2) 21( 7.7) 42(10.7) 36( 9.1) Lightheadedness 17( 6.3) 12( 4.4) 40(10.2)** 13( 3.3) Confusion 5( 1.9) 3( 1.1) 27( 6.9)** 5( 1.3) Agitation 13( 4.8) 12( 4.4) 22( 5.6) 27( 6.9) Paresthesia 5( 1.9) 5( 1.8) 16( 4.1)* 6( 1.5) Vasodilatation 7( 2.6) 7( 2.6) 16( 4.1) 7( 1.8) Abnormal Dreams 8( 3.0) 5( 1.8) 13( 3.3) 7( 1.8) Memory Impairment 6( 2.2) 6( 2.2) 16( 4.1) 7( 1.8) Tremor 5( 1.9) 4( 1.5) 6( 1.5) 3( 0.8) Incoordination - - 11( 2.8)** 2( 0.5) Ataxia 4( 1.5) 0( 0.0) 4( 1.0) 0( 0.0) Decreased Concentration - - 10( 2.5) 4( 1.0) Hypesthesia 5( 1.9) 1( 0.4) 5( 1.3) 2( 0.5) Anxiety 7( 2.6) 13( 4.8) 8( 2.0)* 21( 5.3) Psychomotor Retard. 3( 1.1) 1( 0.4) 6( 1.5) 2( 0.5) Depression 4( 1.5) 3( 1.1) 5( 1.3) 3( 0.8) Euphoria 3( 1.1) 3( 1.1) - - Hypertonia - - 4( 1.0) 0( 0.0) Decreased Libido - - 4( 1.0) 1( 0.3) RESPIRATORY SYSTEM Pharyngitis 10( 3.7) 16( 5.9) 25( 6.4) 19( 4.8) Rhinitis 19( 7.0) 16( 5.9) 16( 4.1) 16( 4.1) Sinusitis 13( 4.8) 14( 5.2) 25( 6.4) 22( 5.6) Cough Increased - - 13( 3.3) 5( 1.3) SKIN & APPENDAGES Sweating 5( 1.9) 5( 1.8) 11( 2.8) 12( 3.1) Rash 3( 1.1) 4( 1.5) 8( 2.0) 5( 1.3) Pruritus 5( 1.9) 3( 1.1) 9( 2.3) 5( 1.3) SPECIAL SENSES Amblyopia 8( 3.0) 6( 2.2) 34( 8.7)** 11( 2.8) Eye Disorder - - 18( 4.6)** 2( 0.5) Taste Perversion 3( 1.1) 2( 0.7) 7( 1.8) 3( 0.8) Abnormal Vision - - 14( 3.6)* 4( 1.0) Tinnitus - - 8( 2.0) 5( 1.3) Visual Field Defect - - 6( 1.5)* 0( 0.0) UROGENITAL SYSTEM Urinary Frequency 3( 1.1) 4( 1.5) 9( 2.3) 5( 1.3) Urinary Retention - - 8( 2.0) 3( 0.8) Urinary Tract Infection - - 9( 2.3) 3( 0.8) Impotence M^2 4( 3.6) 0( 0.0) - - Dysmenorrhea F^1 4( 2.5) 11( 6.4) 9( 3.7) 6( 2.3) Vaginitis F^1 3( 1.9) 2( 1.2) 5( 1.9) 2( 0.8) Dysuria - - 5( 1.3) 5( 1.3) Breast Pain F^1 - - 3( 1.1) 1( 0.4) ----------------------------------------------------------------------- ------- ------------------------------ -------------- * Significant difference from placebo, p<=0.05 ** Significant difference from placebo, p<=0.01 1 Percentage corrected for gender Females: Placebo overall n=283, low n=172, high n=244 Nefazodone overall n=423, low n=159, high n=264 2 Percentage corrected for gender Males: Placebo overall n=171, low n=110, high n=150 Nefazodone overall n=241, low n=112, high n=129 PREVIOUSLY OMMITTED UNDER DRUG ABUSE AND DEPENDENCE While the premarketing clinical experience with nefazodone did not reveal any tendency for a withdrawal syndrome or any drug seeking behaviour, these observations were not systematic, and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of SERZONE (eg. development of tolerance, dose esalation, drug-seeking behaviour). WITH ELECTRO-CONVULSIVE THERAPY (ECT): There are no clinical studies establishing the benefit of the combined use of ECT and nefazodone. =============================END OF SERZONE INFO============== - Victor G.L. Jasin jasin@uwo.ca "iki pasirasymo!"