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Logo SERZONE 100 mg tablets
SERZONE 200 mg tablets
SERZONE STARTER PACK

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

SERZONE 100 mg tablets
SERZONE 200 mg tablets
SERZONE STARTER PACK

COMPOSITION
SERZONE tablets contain 100 or 200 mg of
Nefazodone hydrochloride.
SERZONE starter pack contains 14 x 50 mg, 14 x 100 mg and
14 x 200 mg Nefazodone hydrochloride tablets.

PHARMACOLOGICAL CLASSIFICATION
Category A.1.2 Psychoanaleptics (Anti-depressants)

PHARMACOLOGICAL ACTION
Nefazodone, a phenylpiperazine antidepressant, blocks serotonin type 2 (5HT
2) receptors and inhibits serotonin uptake.
Pharmacokinetics
Nefazodone is completely absorbed, with peak plasma concentrations 1-3 h after oral administration. It undergoes extensive presystemic metabolism, and is more than 99% bound to plasma proteins. The estimated systemic bioavailability of Nefazodone is 15-23%. The plasma elimination half-life is 2-4 hours for Nefazodone, with elimination primarily by hepatic metabolism.
Steady state plasma Nefazodone concentrations are attained within 3-4 days after initiating treatment or making a dose adjustment. At steady state, Nefazodone exhibits non-linear pharmacokinetic parameters with relatively higher peak serum levels and greater AUC's occurring as doses are increased through the recommended dose range. Nefazodone is eliminated within 24 hours of discontinuing treatment.
Food delays the absorption of Nefazodone and decreases the bioavailability of Nefazodone by approximately 20%. These effects are not considered to be clinically significant.
Nefazodone is extensively metabolized after oral administration by n-dealkylation, and aliphatic and aromatic hydroxylation. One metabolite of Nefazodone, hydroxynefazodone (HO-NEF) possesses qualitively similar pharmacological profile to Nefazodone. The triazole-dione metabolite shows only weak 5HT
2 antagonist effects. The peak steady-state plasma concentrations of HO-NEF and triazole-dione were approximately 30% and 125%, respectively, of the peak concentration of Nefazodone; the third metabolite, m-chlorophenylpiperazine (mCPP) is present in very low concentration (3% of the peak concentration of Nefazodone at steady-state). Nefazodone and its metabolite HO-NEF were found to inhibit the hepatic drug metabolizing enzymes responsible for O-demethylation and N-demethylation reactions in vitro (see INTERACTIONS).
Nefazodone is widely distributed in body tissues, including the central nervous system. In humans, the volume of distribution of Nefazodone ranges from 0.22 to 0.87 L/kg.
After oral administration of radiolabelled Nefazodone, 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.
In patients with renal impairment (creatinine clearances ranging from 7 to 60 mL/min/1.7m2) steady state Nefazodone plasma concentrations were not affected.
In a multiple-dose study of patients with hepatic cirrhosis, the AUC values for Nefazodone and HO-NEF were approximately 20% to 40% greater than those observed in normal volunteers.
The AUC values for mCPP were approximately 3-fold greater than those observed in normal volunteers.
After single doses of 50 to 300 mg of Nefazodone the peak plasma concentration of nefazodone was up to 2-fold higher in elderly (65 years or older) subjects than that in younger subjects, Furthermore, a multiple-dose study in elderly subjects indicated that the pharmacokinetics and metabolism of Nefazodone are similar in young and elderly male volunteers. In a single and multiple-dose pharmacokinetics study, plasma concentrations of Nefazodone were 60% higher in elderly women than in young female volunteers. (see DOSAGE AND ADMINISTRATION).

INDICATIONS
Nefazodone is indicated for the symptomatic treatment of all types of depressive illness, including depressive syndromes accompanied by anxiety or sleep disturbances.

CONTRA-INDICATIONS
Nefazodone is contra-indicated in patients with known hypersensitivity to nefazodone or other phenylpiperazine antidepressants or to any of the inactive ingredient of SERZONE.
A history of liver disease or any degree of impairment of liver function
Chronic renal failure.
Concomitant use with carbamazepine, terfenadine, astimazole, cisapride, triazolam, monoamine oxidase inhibitors, pimozide, buspirone, cyclosporin, alcohol, fluoxetine.
Pregnancy and Lactation:
The safety of nefazodone for use in pregnancy has not been established.
It is not known whether nefazodone or its metabolites are excreted in human milk.
Children: Safety and effectiveness in children below the age of 18 years has not yet been established.

WARNINGS
Potential for Interaction with Monoamine Oxidase Inhibitors:
In patients receiving antidepressants with pharmacological properties similar but not identical to nefazodone (i.e., selective serotonin reuptake inhibitors) in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. Nefazodone must not be used within 14 days of discontinuing treatment with a MAOI. At least one week should be allowed after stopping nefazodone before starting a MAOI The use of nefazodone in combination with a MAOI is contra-indicated.
Potential Terfenadine, Astemizole, Pimozide and Cisapride Interactions: The concurrent use of terfenadine, astemizole, pimozide or cisapride with nefazodone is contra-indicated. Nefazodone has been shown in vitro to be an inhibitor of cytochrome P
450IIIA4. Terfenadine, astemizole, pimozide and cisapride are all metabolized by the cytochrome IIIA4, and it has been demonstrated that ketoconazole, erythromycin, and other inhibitors of IIIA4 can block the metabolism of these drugs, resulting in increased plasma concentrations of parent drug. Increased plasma concentrations of terfenadine, astemizole, pimozide and cisapride are associated with QT prolongation and with rare cases of serious cardiovascular adverse events, including death, due principally to ventricular tachycardia of the torsades de pointes type.
Potential for severe liver injury: Liver necrosis and liver failure which may be fatal or require liver transplantation have been reported. Nefazodone must be discontinued immediately in patients who develop signs or symptoms suggesting liver dysfunction, such as jaundice, dark urine, anorexia, nausea or abdominal pain, during treatment with Serzone and these patients must be evaluated with regard to possible liver damage.
Early warning signs of liver damage may be absent. Periodic serum transaminase testing has not been proven to prevent serious liver injury. The time to liver injury/failure resulting in death or transplant generally ranged from two weeks to six months but may occur at any stage of treatment. The occurrence of liver injury can be fatal even if properly recognised and managed.
Visual disturbances: In controlled clinical trials, blurred vision and visual disturbances including scotomata and visual trails occurred in significantly more nefazodone-treated patients then placebo-treated patients. These events have been reported at all doses.

DOSAGE AND DIRECTIONS FOR USE
Adults:
The recommended starting dose for nefazodone is 100-200 mg/day (50-100 mg BID) depending on the physician's clinical judgement. The dose may then be increased in increments of 100-200 mg/day, administered in two divided doses, at intervals of approximately one week, depending upon clinical response and tolerance.
In controlled clinical trials, the effective dose range was 300 to 600 mg per day.
While benefit is seen during the first week of treatment, as much as 4 weeks on treatment may be required to obtain the full anti-depressant effect in some patients. Beneficial responses are maintained with long-term therapy.
Elderly, Debilitated Patients: The recommended initial dose is 100 mg/day (50 mg twice a day) for elderly or debilitated patients. These patients often have reduced Nefazodone clearance and/or increased sensitivity to the side effects of CNS-active drugs. It may be appropriate to modify the rate of subsequent dose titration and final target dose based on a careful assessment of the patient's clinical response.
Renal impairment: No significant relationship between pharmacokinetic parameters and degree of renal impairment has been observed. However, with chronic administration, additional accumulation of nefazodone or its metabolites may occur in patients with severely impaired renal function. (See contra-indications)
Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI): At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with nefazodone. In addition, at least 7 days should be allowed after stopping nefazodone before starting an MAOI. (See CONTRA INDICATIONS, WARNINGS AND PRECAUTIONS).

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side effects:
The more commonly observed side effects (seen in more than 5% of patients taking Serzone) were dry mouth, nausea, somnolence, dizziness, constipation, asthenia, lightheadedness and blurred vision.
Side effects which occurred in 1% or more of patients treated with Serzone;
Body as a whole- Asthenia, chills and fever
Cardiovascular system- postural hypotension
Digestive system- nausea, dry mouth, constipation
Musculoskeletal system- arthralgia
Nervous system- somnolence, dizziness, lightheadedness, paresthesia vasodilation, confusion, abnormal dreams, memory impairment, incoordination, hypethesia, ataxia.
Special senses- blurred vision, visual disturbances.
Sinus bradycardia (<50 bpm and a decrease of >15 bpm) and other arrhythmias have been reported in nefazodone-treated patients. (See WARNINGS AND PRECAUTIONS).
Postmarketing Experience
Adverse events temporally associated with Serzone that have been reported since marketing that are not listed above and for which a causal relationship has not been established, include:
General: allergic reaction, urticaria, anaphylactic reactions, angioedema.
Cardiovascular: peripheral edema
Dermatologic: excessive sweating, rash, exfoliative dermatitis and Stevens-Johnson syndrome
Endocrine system: prolactinemia
Hepato-biliary system: increased liver enzymes, hepatitis, liver necrosis and liver failure, in some cases leading to liver transplantation and /or death (see Warnings and contra-indications)
Gastrointestinal system: taste disturbances, anorexia, increased appetite, diarrhea, vomiting, gastrointestinal bleeding.
Hematologic: leukopenia, thrombocytopenia, pancytopenia, ecchymosis, skin or mucosal bleeding.
Metabolic: hypoglycemia, hyponatremia.
Musculoskeletal system: myalgia, rhabdomyolysis involving patients receiving a combination of Serzone and lovastatin or simvastatin. (see precautions)
Nervous system: convulsions (including grand mal seizures) hallucinations, insomnia, agitation, headache, migraine, suicidal thoughts, tremor, serotonin syndrome, syncope.
Respiratory: dyspnoea
Special senses: ear-tinnitus; eye-visual disturbances including diplopia, visual field defects, blurred vision, scotomata, and visual trials including palinopsia (see warnings); mydriasis and increased intraocular pressure; dry/painful eye, photophobia
Urogenital: priapism, vaginal bleeding, urinary retention, urinary frequency, dysuria, enuresis, galactorrhoea, gynecomastia (male), breast enlargement
Special Precautions
EFFECTS ON ABILITY TO DRIVE AND USE OF MACHINES
SERZONE may impair judgement, cognitive, or motor skills, and patients should be cautioned about operating hazardous machinery, including driving, until they are certain that the treatment does not affect them adversely.
Postural Hypotension: Postural hypotension has occurred in association with nefazodone use. Therefore, nefazodone should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke), and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication).
Suicide: The possibility of a suicide attempt in seriously depressed patients may persist even during apparent improvement of symptoms on treatment. Close supervision of high-risk patients should accompany initial nefazodone therapy. Prescriptions should be written for the smallest quantity of tablets in order to reduce the risk of overdose.
Seizures: Nefazodone should be used with caution in patients with a history of seizures. Convulsions (including grand mal seizures) following SERZONE administration have been reported. Patients with epilepsy should receive concomitant adequate anti-epileptic therapy.
Priapism: If patients present with prolonged or inappropriate erections, they should discontinue therapy immediately and consult their physicians.
Use in patients with Concomitant Illness: Caution is advisable when using nefazodone in patients with diseases or conditions that could affect the metabolism and excretion of the drug. The AUC values of nefazodone and HO-NEF in patients with cirrhosis of the liver are increased by approximately 25%. With chronic administration, additional accumulation of nefazodone or its metabolites may occur in patients with severely impaired renal function, and use of a lower or less frequent dose is advised. No specific relationship between pharmacokinetic parameters and degree of renal impairment has been observed. (see Contra-indications)
Patients with a recent history of myocardial infarction or unstable heart disease were excluded from clinical studies. Evaluation of electrocardiograms (ECG) of patients who received nefazodone in placebo-controlled trials did not indicate that nefazodone is associated with the development of clinically significant ECG abnormalities. As sinus bradycardia has been observed in some of nefazodone treated-patients, patients with a recent history of myocardial infarction or unstable heart disease should be treated with caution.
Geriatric Use: Due to the increased systemic exposure to nefazodone seen in single dose trials in elderly patients, nefazodone treatment should be initiated at half the usual dose, with titration upward as needed to achieve a therapeutic response with optimal tolerability.
Hepatic or renal impairment: See CONTRAINDICATIONS. WARNINGS AND DIRECTIONS FOR USE".
Electro-Convulsive Therapy: There are no clinical studies involving the combined use of ECT and nefazodone.
History of Mania/Hypomania: Nefazodone should be used with caution in these patients as occurrences of activation of mania/hypomania have been reported.

INTERACTIONS WITH OTHER MEDICAMENTS AND OTHER FORMS OF INTERACTION
Co-administered Medicine Protein Binding:
Nefazodone is extensively (>99%) bound to plasma proteins in man. The effect of nefazodone on the plasma protein binding of potentially co-administered medicines should be considered.
Conversely adverse effects could result from displacement of nefazodone by other highly bound drugs.
Lithium: Co-administration of nefazodone with lithium has not been reported to cause any adverse interactions.
MAOIs: See Contra-indications and warnings
Antihypertensives: There have been reports of postural hypotension in nefazodone-treated patients. Concomitant administration of antihypertensive therapy and nefazodone may require a reduction in the dose of the antihypertensive drug. (See WARNINGS)
General Anaesthetics: Experience regarding potential for interaction between nefazodone and general anaesthetics is unknown; therefore, prior to elective surgery, nefazodone should be discontinued for as long as clinically feasible.
Central Nervous System (CNS) - Active Medicines
Triazolam:
The peak concentration, half-life, and AUC of triazolam, at steady state were increased 1.7,3 and 4 fold, respectively, when co-administered with nefazodone. Coadministration of nefazodone potentiates the adverse effects of triazolam on psychomotor performance tests. The concomitant use of Nefazodone and triazolam is contra-indicated.
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.
Alprazolam - When alprazolam (1 mg BID) and nefazodone (200 mg BID) were co-administered, peak concentrations, AUC and half life values for alprazolam increased by approximately 2 fold at steady state. Nefazodone plasma concentrations were unaffected by alprazolam. If alprazolam is co-administered with SERZONE, a reduction in the alprazolam dosage is recommended; no dosage adjustment is required for SERZONE.
Haloperidol: When a single oral dose of haloperidol was co-administered with nefazodone (200 mg twice a day) at steady state, the area under the concentration-time curve of haloperidol was increased by 35%, with no significant increase in C
max or Tmax. There were no changes in the pharmacokinetic parameters for nefazodone. This change is not considered clinically significant and dosage adjustments are not necessary for either drug.
Alcohol: Nefazodone does not potentiate the psychomotor or cognitive impairment of alcohol. However, it is prudent to avoid concomitant use of alcohol and nefazodone.
Fluoxetine: Pretreatment or coadministration of fluoxetine with nefazodone significantly increases the AUC values of the nefazodone metabolite mCPP by approximately 3-6 fold. Patients who are transferred immediately from fluoxetine to nefazodone may experience some transient adverse events (eg., nausea, light-headedness, headache). These adverse events may be minimized by allowing a washout period before initiating nefazodone therapy and reducing the initial dose of nefazodone. Because of the long half life of fluoxetine and its metabolites, this washout period may range from 1 to several weeks, depending on the dose of fluoxetine and other individual patients variables. Nefazodone does not affect the pharmacokinetics of fluoxetine or norfluoxetine. (See contra-indications)
Carbamazepine: The co-administration of nefazodone and carbamazepine to healthy volunteers resulted in 23% increases in both steady-state C
max and AUC of carbamazepine and a 21% and 20% reduction in steady-state Cmax and AUC, respectively for the active metabolite carbamazepine 10, 11 epoxide. The kinetics of nefazodone and hydroxynefazodone were significantly affected by co-administration of carbamazepine. The steady-state Cmax and AUC of nefazodone were decreased by 86% and 93% respectively. Similar reductions in the Cmax and AUC of hydroxynefazodone (85% and 94%) were also observed while the reductions in Cmax and AUC of m-chlorophenylpiperazine and triazole-dione were more modest (13% and 44% and 28% and 57% respectively).
(SEE CONTRA-INDICATIONS)
Cimetidine: No significant clinical or pharmacokinetic interactions between nefazodone and cimetidine were observed in a multiple-dose clinical trial involving healthy volunteers.
Digoxin: When nefazodone and digoxin were coadministered to healthy male volunteers who were phenotyped as P
450IID6 extensive metabolisers, Cmax, Cmin and AUC of digoxin were increased by 29%, 27% and 15%, respectively. Digoxin had no effects on the pharmacokinetics of nefazodone and its active metabolites. Because of the narrow therapeutic index of digoxin, caution should be exercised when nefazodone and digoxin is coadministered; the digoxin dose must be reduced and plasma level monitoring for digoxin is recommended.
Propranolol: The coadministration of nefazodone and propranolol to healthy male volunteers, including poor and extensive P
450IID6 metabolizers, resulted in 30% and 14% reductions in Cmax and AUC of propranolol, respectively, and a 14% reductions in Cmax for the metabolite, 4-hydroxypropranolol. The kinetics of nefazodone, hydroxynefazodone, and triazoledione were not affected by coadministration of propranolol. However, Cmax, Cmin, and AUC of m-chlorophenylpiperazine were increased by 23%, 54%, and 28%, respectively. No change in initial dose of either medicine is necessary and dose adjustments should be made on the basis of clinical response.
Buspirone:
See Contra-indications.
The coadministration of Serzone and buspirone to healthy volunteers resulted in increases up to 20-fold in buspirone
C
max and up to 50-fold in AUC. Significant decreases (~50%) in plasma concentrations of buspirone metabolite, 1-pyrimidinylpiperazine were also noted.
Medicines Metabolised by Cytochrome P450IIIA4Isozyme:Nefazodone has been shown in vitroto be an inhibitor of cytochrome P450IIIA4. This is consistent with the interaction observed between nefazodone and the triazolobenzodiazepines triazolam and alprazolam, drugs metabolised by this isozyme. Consequently, caution is indicated in the combined use of nefazodone with any medicine known to be metabolised by the IIIA4isozyme (eg., calcium channel antagonists, cyclosporine, tacrolimus, clarithromycin, erythromycin, ketoconazole, midazolam, vinblastina) particularly terfenadine, astemizole, pimozide or cisapride. (See Contra-indications, WARNINGS and PRECAUTIONS section).
Medicines Metabolised by Cytochrome P450IID6: A subset of the population has reduced activity of drug-metabolising enzyme Cytochrome P450IID6. Such individuals are referred to commonly as "poor metabolisers" of drugs such as quinidine, dextromethorphan, and the tricyclic antidepressants. The pharmacokinetics of nefazodone and its major metabolites are not altered in these "poor metabolisers." Plasma concentrations of m-CPP are increased in this population; the adjustment of nefazodone dosage is not required when administrated to "poor metabolisers." Nefazodone and its metabolites have been shown in vitro to be extremely weak inhibitors of P450IID6. Thus, it is not likely that nefazodone will decrease the metabolic clearance of medicines metabolised by this isozyme (e.g., alprenolol, metoprolol, timolol, flecainide paroxetine, fluoxetine, thioridazine, haloperidol).
Medicines Metabolised by IA
2Isozyme: Nefazodone and its metabolites have been shown in vitro not to inhibit cyctochrome P450IA2. Thus, metabolic interactions between nefazodone and medicines metabolised by this isozyme are unlikely (e.g., clozapine, tacrine, theophylline).
HMG-CoA Reductase Inhibitors: There have been reports of rhabdomyolysis involving patients receiving the combination of SERZONE and either of the HMG-CoA reductase inhibitors lovastatin or simvastatin, known substrates of CYP3A4. Since nefazodone is known to inhibit this isozyme, caution should be used if SERZONE is administered in combination with simvastatin, lovastatin, or atorvastatin. Metabolic interactions are unlikely between nefazodone and HMG-CoA reductase inhibitors that undergo little or no metabolism by the CYP3A4 isozyme, such as pravastatin or fluvastatin.
Cyclosporine: See Contra-indications
There have been occurrences of up to 7-fold increase in serum cyclosporine levels reported in patients receiving nefazodone and cyclosporine concomitantly. Cyclosporine is a substrate of CYP3A4 and nefazodone is known to inhibit this enzyme.

Physical and Psychological Dependence
Nefazodone showed no potential for abuse in a controlled study of abuse liability in human subjects. However, physicians should carefully evaluate patients for a history of drug abuse and closely observe them for signs of misuse or abuse.
Symptoms and signs suggestive of a withdrawal syndrome have been reported. These include dizziness, headache, nausea, vomiting, anxiety or paraesthesia. To prevent withdrawal reactions, discontinuation of nefazodone should be preceded by gradual dose reduction.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Commonly reported symptoms from overdose of nefazodone included nausea, vomiting, and somnolence. However, overdosage could cause an increase in incidence or severity of any of the reported adverse reactions.
Treatment: Any patient suspected of having taken an overdose should have the stomach emptied by gastric lavage. Treatment should be symptomatic and supportive. There is no specific antidote for nefazodone. In managing overdosage, consider the possibility of multiple drug involvement.

IDENTIFICATION
The tablets are hexagonal flat-faced, bevelled-edged with a bisect score on both tablet faces for 100 mg tablet. Tablets are imprinted with product strength on one side. The tablet colours and dimensions are as follows:
Tablet
Strength        Colour        Dimensions
50 mg        White        5,08 x 8,13 mm
100 mg White        6,6 x 10,7 mm
200 mg Light yellow        8,38 x 14,2 mm

PRESENTATION
SERZONE 100 mg and 200 mg tablets are available in blister packs of 56 tablets.
SERZONE starter pack contains 14 x 50 mg, 14 x 100 mg and 14 x 200 mg Nefazodone hydrochloride tablets in a blister pack unit.

STORAGE INSTRUCTIONS
Store at room temperature not exceeding 25°C.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBERS
SERZONE 100 mg :         28/1.2/717
SERZONE 200 mg :         28/1.2/719
SERZONE STARTER PACK :         32/1.2/417

NAME AND BUSINESS ADDRESS OF APPLICANT
BRISTOL-MYERS SQUIBB (PTY) LTD*
47 Van Buuren Road,
BEDFORDVIEW
2008.

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
February 2002

*Authorised user of the TM SERZONE

Updated on this site: January 2003
Source: Pharmaceutical Industry

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