INFORMATION FOR HEALTH PROFESSIONALS
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SERZONE is supplied as hexagonal tablets containing 100 mg or 200 mg, of nefazodone hydrochloride. Tablets are imprinted with the strength on one side. The 100mg strength tablets have a bisect bar scored on both tablet faces. Tablet colours are white (100 mg) and light yellow (200 mg). The tablet is approximately 0.660 x 1.07 cm and the 200 mg tablet 0.838 x 1.42 cm.
SERZONE® (nefazodone hydrochloride) is an antidepressant for oral administration with a chemical structure unrelated to selective serotonin reuptake inhibitors, tricyclics, tetracyclics, or MAO-inhibitors.
The antidepressant action of nefazodone is presumed to be linked to potentiation of serotonergic activity in the central nervous system. Unlike selective serotonin reuptake inhibitors, nefazodone exerts dual effects on serotonergic neurotransmission through blockade of serotonin type 2 (5HT2) receptors and inhibition of serotonin reuptake. These two properties combine to increase serotonergic neurotransmission through other serotonin receptors such as the 5-HT1A receptor.
In in-vitro studies nefazodone was found to have no significant affinity for α2 and β adrenergic, histaminergic, dopaminergic, cholinergic, benzodiazepine receptors, or serotonergic receptors of the 5-HT1A subtype. Nefazodone has weak alpha 1-adrenergic blocking activity. In clinical studies, adverse effects suggestive of anticholinergic effects were noted.
Unlike most antidepressants, nefazodone does not adversely affect sleep architecture. It decreases the number of awakenings but does not suppress REM sleep.
The pharmacokinetics of nefazodone and its major metabolites are subject to considerable inter- and intra-subject variability.
Nefazodone is rapidly and completely absorbed with peak plasma concentrations occurring at 1-3 hours after an oral dose. Food delays the absorption of nefazodone and decreases the bioavailability of nefazodone by approximately 20%. These effects are unlikely to be clinically significant.
Nefazodone is subject to extensive pre-systemic metabolism, and its systemic bioavailability is estimated to range between 15% and 23% at doses of 50-200 mg. Steady-state plasma nefazodone concentrations are attained within 3-4 days of initiation of twice a day dosing or upon dose increase or decrease. Nefazodone exhibits nonlinear pharmacokinetics with steady-state peak plasma nefazodone concentrations and AUCs increasing more than proportionally with dose increases.
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.
Protein Binding - At concentrations of 25-2500 ng/ml nefazodone is extensively (>99%) bound to human plasma proteins in vitro. However, nefazodone does not alter the in-vitro protein binding of chlorpromazine, desipramine, diazepam, diphenylhydantoin, lignocaine, prazosin, propranolol, verapamil, or warfarin. There is a 5% decrease in the protein binding of haloperidol; this is probably of no clinical significance.
Nefazodone is extensively metabolised after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation.Three major metabolites have been identified in the plasma: hydroxynefazodone (OH-NEF), meta-chlorophenyl-piperazine (m-CPP), and a triazole-dione metabolite.
Hydroxynefazodone (HO-NEF), possesses a pharmacological profile qualitatively similar to nefazodone. Metachlorophenylpiperazine has a profile similar to nefazodone, but also has agonist activity at some serotonergic receptor subtypes. The pharmacologic profile of the triazole-dione metabolite has not been well characterized.
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).
After oral administration of radio-labelled nefazodone, approximately 50%-65% of the administered radioactivity was excreted in urine as metabolites and approximately 20%-40% of the administered radio-label was excreted in the faeces. 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 mean elimination half life of nefazodone is 2-4 hours over the dose range of 50-200 mg.
The elimination half-lives for HO-NEF, m-CPP and the triazole-dione metabolite are 1.5 - 4 hours, 4 - 8 hours, and 18 hours, respectively.
In studies involving renally-impaired patients, renal impairment (creatinine clearances ranging from 7 to 60 ml/min/1.73m2) had no effect on steady state nefazodone plasma concentrations. However, in the presence of severe renal failure SERZONE should be used with caution.
In a multiple-dose study of patients with liver cirrhosis, the AUC values for nefazodone and HO-NEF were approximately 20% to 30% greater than those observed in normal volunteers. The AUC values for mCPP were approximately 3-fold greater than those observed in normal volunteers.
The use of SERZONE is contraindicated in patients who are withdrawn from SERZONE because of liver injury (see Contraindications) and is not recommended in patients with active liver disease, or with elevated baseline serum transaminases (see Warnings and Precautions - Potential for Severe Liver Injury)
After single doses of 300mg nefazodone the peak plasma concentration and AUC of nefazodone and hydroxynefazodone are up to 2-fold higher in elderly (65 years or older) subjects than those in younger subjects. After multiple doses, however , these parameters are 10 -20% higher in older patients.
SERZONE is indicated for the treatment of depression including depression accompanied by anxiety or sleep disturbances.
Systematic evaluation of the effectiveness of nefazodone in placebo-controlled, double-blind, continuation-treatment trials has shown that therapeutic benefit is maintained during continued treatment for periods of up to one year. Nevertheless, the physician who elects to use SERZONE for extended periods should periodically re-evaluate the long-term usefulness of the medicine for the individual patient.
The recommended starting dose is 100 mg twice daily. 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 - 600mg /day. As seen with all antidepressants several weeks on treatment may be required to obtain the full therapeutic effect.
The recommended initial dose is 100 mg/day (50mg twice a day) for elderly or debilitated patients, or patients with severe impairment of renal function. These patients often have reduced nefazodone clearance and/or increased sensitivity to the side effects of CNS-active medicines. 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.
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 with an MAOI (See Contraindications & Interactions)
No significant relationship between pharmacokinetics and the 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, and use of the lower end of the dose range is advised.
There is no body of evidence available from controlled trials to indicate how long the depressed patient should be treated with SERZONE. It is generally agreed that pharmacologic treatment for acute episodes of depression should continue for six months or longer. Systematic evaluation of the effectiveness of nefazodone in placebo-controlled, double-blind, continuation-treatment trials has shown that therapeutic benefit is maintained during continued treatment for periods of up to one year. The response observed during an initial course of treatment can be maintained by using the same dose.
Tapering the dose may reduce the risk of withdrawal effects.
SERZONE is contraindicated in patients with known hypersensitivity to nefazodone, other phenylpiperazine antidepressants or any of the excipients.
SERZONE is contraindicated in patients who were withdrawn from SERZONE because of liver injury (See Warnings and Precautions - Potential for Severe Liver Injury)
Co-administration of MAOIs, terfenadine, astemizole, pimozide or cisapride with SERZONE is contraindicated (see Interactions ).
Based on experience with all antidepressants, including SERZONE, the following precautions should be observed:
(see Contraindications and Interactions - Medicines Metabolised by Cytochrome CYP3A4 or Monoamine Oxidase Inhibitors).
Potential for Severe Liver Injury:
Very rare cases of liver necrosis and life-threatening liver failure have been reported during marketed use of nefazodone.The reported rate (US data) of liver failure resulting in death or liver transplant is 1 case per 250,000 to 300,000 patient years of SERZONE treatment. This rate is an underestimate because of under reporting, and the true risk could be considerably greater than this. The time to liver injury for the reported liver failure cases resulting in death or transplant generally ranged from 2 weeks to 6 months on SERZONE therapy. Although some reports described dark urine and non specific prodromal symptoms (eg anorexia, malaise, and gastrointestinal symptoms), other reports did not describe the onset of clear prodromal symptoms prior to the onset of jaundice.
Patients should be alerted to the signs and symptoms suggesting liver dysfunction, such as jaundice, dark urine, anorexia, nausea, malaise, gastrointestinal complaints, or abdominal pain and told to report these to their doctor immediately.
If signs or symptoms or evidence of hepatocellular injury occur during treatment with SERZONE, the patient should be withdrawn from the drug. These patients should be presumed to be at increased risk of liver injury if SERZONE is reintroduced. Accordingly, such patients should not be considered for re-treatment. (see Adverse Effects and Contraindications ). Initiation of treatment with Serzone is not recommended in individuals with active liver disease or with elevated baseline serum transaminases.
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. The rates for adverse events characterized as postural hypotension in clinical trials with nefazodone were as follows : nefazodone (3.0%), tricyclic antidepressants (10.9%), SSRI (2.2%), and placebo (1.0%). 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 ischaemic stroke), and conditions that would predispose to hypotension ( dehydration, hypovolemia, and treatment with antihypertensive medication).
As with other anti-depressant agents activation of mania/hypomania is a known risk in a small proportion of patients with major affective disorder treated with antidepressants, and also occurred during clinical trials with nefazodone (0.3% of unipolar and 1.6% of bipolar patients). Nefazodone should be used cautiously in patients with a history of mania.
As with other antidepressants, SERZONE should be used with caution in patients with a history of seizures. SERZONE should be discontinued in any patient who develops seizures.
During premarketing testing, there were no grand mal or focal seizures observed. There was a recurrence of a petit mal seizure in one patient. Rare occurrences of convulsions (including grand mal seizures) following nefazodone administration have been reported since the marketing of SERZONE. A causal relationship to nefazodone has not been established.
The possibility of a suicide attempt in seriously depressed patients is inherent to the illness and may persist even during the apparent improvement of symptoms. Close supervision of high risk patients should continue throughout therapy and consideration should be given to the possible need for hospitalisation. Prescriptions for SERZONE should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.(see Overdosage "Clinical Experience" and "Treatment" )
Clinical experience with nefazodone in patients with concomitant systemic illness is limited. Caution is advisable when using SERZONE in patients with diseases or conditions such as hepatic or severe renal impairment, that could affect the metabolism and / or excretion of the drug (see Pharmacokinetics ). The AUC values of nefazodone and of 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.
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 important ECG abnormalities. However, sinus bradycardia was observed in 1.5% of nefazodone treated patients. Patients with a recent history of myocardial infarction or unstable heart disease should be treated with caution.
Any psychoactive medicine may impair judgement or affect cognitive or motor skills, and patients should be cautioned about operating hazardous machinery, including motor vehicles,until they are certain that the treatment does not adversely affect their ability to engage in such activities.
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 hyperprolactinaemia (e.g. amenorrhoea, galactorrhoea, abnormal menstrual cycle length) was observed in the 446 women who received nefazodone for more than 60 days in clinical studies. Some of the aforementioned effects have been reported, however, in other clinical trials and since market introduction. (see Adverse Effects, "Postmarketing Experience")
In women with existing breast cancer, or a history of this disease, the possible risk of hyperprolactinaemia should be weighed 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 not epidemiological studies conducted to date, however, have shown an association between administration of hyperprolactinaemia-inducing medicine s and mammary tumorigenesis: available evidence is considered too limited to be conclusive at this time.
While priapism did not occur during premarketing experience with nefazodone, rare occurrences of priapism have been reported since the marketing of SERZONE: a causal relationship to nefazodone has not been established. If patients present with prolonged or inappropriate erections, they should discontinue therapy immediately and consult their doctor. If the condition persists for more than 24 hours, a urologist should be consulted to determine appropriate management.
In controlled clinical trials, blurred vision and visual disturbances including scotomata and visual trails, occurred in significantly more nefazodone-treated patients than placebo-treated patients. Dose-dependency was observed for these events in these trials, with none of the scotomata, and visual trails at doses below 300mg/day. However, scotomata and visual trails observed at doses below 300mg/day have been reported in post-marketing experience with nefazodone. (see Adverse Effects )
There have been no clinical studies involving the combined use of ECT and SERZONE.
The safety of nefazodone in human pregnancy has not been established. An evaluation of experimental animal studies in rats and rabbits does not indicate direct or indirect harmful effects with respect to development of the embryo; however, both maternal and foetal/neonatal toxicities occurred in rats (75 to 300 mg/kg/day). Findings consisted of a nonspecific delay in foetal development and increased mortality and decreased body weights in neonates. Because animal reproductive studies are not always predictive of human response, this medicine should be used during pregnancy only if the potential benefits outweigh the potential risk .
The effect of SERZONE on labour and delivery in humans is unknown.
It is not known whether nefazodone or its metabolites are excreted in human milk. Studies in lactating rats have found nefazodone and/or its metabolites were present in the milk at levels slightly higher than maternal plasma. Therefore, caution should be exercised when nefazodone is administered to a woman who is breast feeding.
Safety and effectiveness in children below the age of 18 have not been established.
No unusual adverse age-related clinical phenomena were identified upon evaluation of safety elderly patients (>65 years) treated with SERZONE.
Of the approximately 7000 patients in clinical studies who received nefazodone for the treatment of depression, 18% were 65 years and older, while 5% were 75 years and older. Based on monitoring of adverse events, vital signs, electrocardiograms, and results of laboratory tests, no overall differences in safety between elderly and younger patients were observed in clinical studies. Efficacy in the elderly has not been demonstrated in placebo-controlled trials. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Due to the increased systemic exposure to nefazodone in elderly patients (see Pharmacokinetics ), treatment should be initiated at half the usual dose with titration upward to achieve a therapeutic response with optimal tolerability. (see Dosage and Administration ) . The usual precautions should be observed in elderly patients who have concomitant medical illnesses or who are receiving concomitant medicines.
The more commonly observed adverse experiences (seen in more than 5% of patients taking SERZONE that occurred with a significantly greater incidence in nefazodone treated patients than among the placebo-treated patients were dry mouth, nausea, somnolence, dizziness, constipation, asthenia, lightheadedness and blurred vision.
The following table shows adverse events that occurred with a significantly greater incidence in nefazodone treated patients than in placebo treatment ( p ≤ 0.05) and which occurred in 1% or more of patients treated with SERZONE who participated in controlled clinical trials of 6 to 8 weeks duration.
| Body System/ Adverse Events |
Number (%) of patients | |
|---|---|---|
| Nefazodone 50 - 600 mg/day n=1489 |
Placebo n=1007 |
|
| Body as a Whole | ||
| Asthenia | 175 (11.8)* | 72 ( 7.2) |
| Chills | 42 ( 2.8)* | 7 ( 0.7) |
| Fever | 27 ( 1.8)* | 8 ( 0.8) |
| Cardiovascular System | ||
| Postural Hypotension | 44 ( 3.0)* | 10 ( 1.0) |
| Digestive System | ||
| Nausea | 327 (22.0)* | 144 (14.3) |
| Dry Mouth | 282 (18.9)* | 127 (12.6) |
| Constipation | 168 (11.3)* | 72 ( 7.2) |
| Musculoskeletal System | ||
| Arthralgia | 33 ( 2.2)* | 8 ( 0.8) |
| Nervous System | ||
| Somnolence | 297 (20.0)* | 132 (13.1) |
| Dizziness | 184 (12.4)* | 63 ( 6.3) |
| Lightheadedness | 165 (11.1)* | 46 ( 4.6) |
| Paresthesia | 73 ( 4.9)* | 16 ( 1.6) |
| Vasodilatation | 65 ( 4.4)* | 25 ( 2.5) |
| Confusion | 53 ( 3.6)* | 12 ( 1.2) |
| Abnormal Dreams | 52 ( 3.5)* | 17 ( 1.7) |
| Memory Impairment | 52 ( 3.5)* | 12 ( 1.2) |
| Incoordination | 44 ( 3.0)* | 10 ( 1.0) |
| Hypesthenia | 20 ( 1.3)* | 5 ( 0.5) |
| Ataxia | 17 ( 1.2)* | - ( - ) |
| Special Senses | ||
| Blurred Vision | 83 ( 5.6)* | 31 ( 3.1) |
| Visual Disturbances | 46 ( 3.1)* | 6 ( 0.6) |
* Significant difference from placebo, p ≤ 0.05
During short-term placebo controlled trials, the incidence of headache in patients receiving placebo and nefazodone was virtually identical (over 35 %) in each treatment group, and not statistically different from each other.
In placebo controlled clinical trials nefazodone was not associated with the development of clinically important ECG changes. However, sinus bradycardia ( equal to or less than 50 bpm and a decrease of equal to or more than 15 bpm) was observed in 1.5% of nefazodone - treated patients compared to 0.4% of placebo-treated patients (p ≤ 0.05) (see Warnings and Precautions )
Over a 6-week period there was evidence of progressive adaptation with continued therapy to the adverse experiences asthenia, blurred vision, constipation, dizziness, dry mouth, lightheadedness, nausea and somnolence.
Postmarketing experience with SERZONE has shown an adverse event profile similar to that seen during premarketing clinical trials.
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, Stevens-Johnson syndrome.
Endocrine system: prolactinemia.
Hepato-biliary system: Cases of increased liver enzymes and hepatitis have been reported, and some of these have been in patients in whom no other possible causative factors were identified. Very rare occurrences of liver necrosis and liver failure, in some cases leading to liver transplantation and/or death have been reported; it is not possible to exclude SERZONE as a possible etiology.(see Warnings and Precautions )
Gastrointestinal system: taste disturbance, anorexia, increased appetite, diarrhoea, vomiting.
Hematologic: leucopenia, thrombocytopenia.
Metabolic: hypoglycemia, hyponatremia.
Musculoskeletal system: myalgia, rhabdomyolysis involving patients receiving a combination of SERZONE and lovastatin or simvastatin (see Warnings and Precautions )
Nervous system: convulsions (including grand mal seizures); hallucinations, insomnia, agitation, headache, migraine, suicidal thoughts, tremor, serotonin syndrome, syncope.
Respiratory: dyspnea.
Special senses: ear - tinnitus; eye - visual disturbances including diplopia, visual field defects, blurred vision, scotomata, and visual trails including palinopsia (see Warnings and Precautions ); mydriasis and increased intraocular pressure; dry/painful eye, photopobia.
Urogenital: priapism, (see Warnings and Precautions ); urinary retention, urinary frequency, dysuria, enuresis; galactorrhea, gynecomastia (male), breast enlargement.
Nefazodone showed no potential for abuse in a controlled study of abuse liability in human subjects. Nefazodone has not been systematically studied in humans for its potential for tolerance, or physical dependence. In animal studies, nefazodone did not act as a reinforcer for intravenous self-administration in monkeys trained to self-administer cocaine, suggesting no abuse liability. However, doctors should carefully evaluate patients for a history of drug abuse and closely observe them for signs of misuse or abuse.
Withdrawal events are uncommon following abrupt withdrawal of nefazodone. Symptoms may include nausea, dizziness, headache, paraesthesias, insomnia and agitation. Tapering the dose may reduce the risk of withdrawal effects.
This medicine has been included in the IMMP.
The potential for interaction by a variety of mechanisms exists (i.e., synergistic pharmacodynamic effects or alteration of the medicine's pharmacokinetics, etc.). The use of SERZONE with concomitant therapy, therefore, should be based on the consideration by the physician that expected benefits of therapy outweigh potential risks.
MAOIs.
In patients receiving antidepressants with pharmacological properties similar but not identical to nefazodone (ie 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 medicines and who have been started on an MAOI. Because nefazodone is an inhibitor of serotonin reuptake, it is recommended that nefazodone not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. At least one week should be allowed after stopping nefazodone before starting an MAOI.
Benzodiazepines.
If alprazolam is co-administered with SERZONE, a 50% reduction in the initial alprazolam dosage is recommended; no dosage adjustment is required for SERZONE. When alprazolam (1 mg twice daily) and nefazodone (200 mg twice daily ) were co-administered to steady state, 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. The interactive effects of higher doses of these agents, such as the dosage levels of alprazolam used in panic disorder, have not been studied.
The concomitant use of SERZONE and triazolam should be avoided. When a single oral 0.25 mg dose of triazolam was co-administered with nefazodone (200 mg twice daily) at steady state, triazolam peak concentrations, half life, and AUC were increased 1.7-, 3- and 4-fold, respectively. Nefazodone concentrations were unaffected by triazolam. 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 metabolism of triazolam has been attributed to the specific hepatic microsomal isozyme, CYP3A4.
When lorazepam (2 mg twice daily) and nefazodone (200 mg twice daily) were coadministered to steady state, there was no change in any pharmacokinetic parameter for either medicine compared to each medicine administered alone and there was no additional decrement in psychomotor performance tests beyond that induced by lorazepam. Therefore, dosage adjustment is not necessary for either medicine when coadministered.
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, lightheadeness, 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 one to several weeks, depending on the dose of fluoxetine and other individual patient variables. Nefazodone does not affect the pharmacokinetics of fluoxetine or norfluoxetine.
The co-administration of nefazodone and carbamazepine to healthy volunteers resulted in 23% increases in both steady-state Cmax 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 coadministration 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 were also observed (85% and 94%) while the reductions in Cmax and AUC of m-chlorophenylpiperazine and triazole dione were more modest (13% and 44%; and 28% and 57% respectively). Due to the potential for coadministration of carbamazepine to result in insufficient plasma nefazodone and hydroxynefazodone concentrations for achieving an antidepressant effect for SERZONE, it is recommended that SERZONE not be used in combination with carbamazepine when more appropriate alternatives exist.
When a single oral 5 mg dose of haloperidol was co-administered with nefazodone (200 mg bid) at steady state, haloperidol AUC values increased by 35% with no significant increase in peak haloperidol plasma concentrations or time of peak. Slight protein binding displacement of haloperidol (approximately 5% of control) was also noted. Although these changes are not considered to be clinically significant and there were no changes in the pharmacokinetic parameters for nefazodone that necessitate dosage adjustments of either medicine, caution should be exercised when using nefazodone and haloperidol concomitantly.
Although nefazodone did not potentiate the cognitive and psychomotor effects of alcohol in experiments with young normal subjects, the concomitant use of SERZONE and alcohol in depressed patients is not advised.
Concurrent administration of nefazodone and lithium has not been reported to cause any adverse interactions.
In a steady-state pharmacokinetics study in healthy volunteers, coadministration of buspirone (2.5 or 5 mg) with nefazodone (250mg twice daily) resulted in negligible changes in the Cmax and AUC of nefazodone and HO-NEF following 2.5mg twice daily doses of buspirone. With 5mg twice daily doses of buspirone, increases in AUC were observed for for nefazodone (23%) and its metabolites HO-NEF (17%) and mCPP (9%). Slight increases in Cmax were observed for nefazodone (9%) and its metabolite HO-NEF (11%). Further, the coadministration of nefazodone and buspirone to healthy volunteers resulted in increases up to 20-fold in buspirone Cmax and up to 50-fold in AUC. Significant decreases (~ 50%) in plasma concentrations of buspirone metabolite, 1-pyrimidinylpiperazine were also noted. If buspirone and nefazodone are to be used in combination, a low dose of buspirone (e.g. 2.5mg once a day) is recommended. Subsequent dose adjustments of either drug should be based on clinical assessment.
In common with other medications, pharmacodynamic and/or pharmacokinetic interactions between nefazodone and the herbal remedy St John's wort may occur.
Little is known about the potential for interaction between SERZONE and general anaesthetics; therefore, prior to elective surgery, SERZONE should be discontinued for as long as clinically feasible.
The use of SERZONE in combination with other CNS-active medicines has not been systematically evaluated. Consequently, caution is advised if concomitant administration of SERZONE and CNS medicines is required. (see Medicines Metabolised by Cytochrome CYP3A4 and CYP2D6 below).
Nefazodone has been shown in vitro to be an inhibitor of cytochrome CYP3A4. This is consistent with the interaction observed between nefazodone and the triazolobenzodiazepines triazolam and alprazolam, medicines metabolised by this isozyme. Consequently, caution is indicated in the combined use of nefazodone with any medicines known to be metabolised by the CYP3A4 isozyme (eg.calcium channel antagonists, cyclosporin, midazolam,quinidine, lignocaine, ketoconazole, itraconazole,vinblastin, clarithromycin and erythromycin). In particular, the combined used of nefazodone with terfenadine, astemizole, pimozide or cisapride is contraindicated.
Terfenadine, astemizole, pimozide and cisapride are all metabolised by the CYP3A4 isozyme, and it has been demonstrated that ketaconazole, erythromycin, and other inhibitors CYP3A4 can block the metabolism of these medicines, resulting in increased plasma concentrations of parent compound. 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.
There have been rare reports of rhabdomyolysis involving patients receiving the combination of Serzone and either of the HMG-CoA reductase inhibitors lovastatin or simvastatin, known subtrates of CYP3A4 ( see Adverse Effects : Postmarketing Experience ). Rhabdomyolysis has been observed in patients receiving HMG-CoA reductase inhibitors administered alone (at recommended dosages) and in particular, for certain drugs in this class, when given in combination with inhibitors of the CYP3A4 isozyme. When single 40mg doses of simvastatin or atorvastatin, both substrates of CYP3A4, were given to healthy adult volunteers who had received nefazodone 200mg twice daily for 6 days, approximately 20-fold increases in plasma concentrations of simvastatin and simvastatin acid and 3- to 4-fold increases in plasma concentrations of atorvastatin and atorvastatin lactone were seen. These effects appear to be due to the inhibition of CYP3A4 by nefazodone because, in the same study, nefazodone had no significant effect on the plasma concentrations of pravastatin, which is not metabolized by CYP3A4 to a clinically significant extent. 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.
There have been reports of increased blood concentrations of cyclosporin and tacrolimus into toxic ranges when patients received these drugs concomitantly with nefazodone. Both cyclosporin and tacrolimus are substrates of CYP3A4 and nefazodone is known to inhibit this enzyme. If either cyclosporin or tacrolimus is administered with nefazodone, blood concentrations of the immunosuppressive agent should be monitored and dosage adjusted accordingly.
There have been reports of postural hypotension in nefazodone-treated patients. Concomitant administration of antihypertensive therapy and SERZONE should be initiated cautiously and a reduction in the dose of the antihypertensive medicine may be required (see Medicines Metabolised by Cytochrome CYP3A4 above).
When nefazodone and digoxin were co-administered to healthy volunteers, who were phenotyped as CYP2D6 extensive metabolizers, Cmax, Cmin and AUC of digoxin were increased by 29%, 27% and 15% respectively. Digoxin had no effects on the pharmacokinetics of nefazodone or its active metabolites. The usual clinical precautions should be exercised when SERZONE and digoxin are co-administered because of the narrow therapeutic index of digoxin. Plasma level monitoring for digoxin is recommended.
No change in initial dose of either drug is necessary and dose adjustments should be made on the basis of clinical response. The coadministration of nefazodone and propranolol to healthy male volunteers, including poor and extensive CYP2D6 metabolizers resulted in 30% and 14% reductions in Cmax and AUC of propranolol, respectively, and a 14% reduction in the Cmax for the metabolite, 4-hydroxypropranolol. The kinetics of nefazodone, hydroxynefazodone, and triazole-dione were not affected by co-administration of propranolol. However, Cmax, Cmin, and AUC of m-chlorophenylpiperazine were increased by 23%, 54%, and 28%, respectively.
No significant clinical or pharmacokinetic interactions between nefazodone and cimetidine were observed in a multi-dose clinical trial involving healthy volunteers.
A small subset of the population has reduced activity of drug -metabolizing enzyme cytochrome CYP2D6. Such individuals are referred to commonly as "poor metabolizers" of medicines such as quinidine, debrisoquin, dextromethorphan, and the tricyclic antidepressants. The pharmacokinetics of nefazodone and its major metabolites are not altered in these "poor metabolizers." Plasma concentrations of one minor metabolite (mCPP) are increased in this population; the adjustment of SERZONE dosage is not required when administered to "poor metabolizers".
Nefazodone and its metabolites have been shown in vitro to be extremely weak inhibitors of CYP2D6. Thus, it is not likely that nefazodone will decrease the metabolic clearance of medicines metabolized by this isozyme ( e.g. alprenolol, metoprolol, timolol, flecainide, paroxetine, fluoxetine, thioridazine, haloperidol)
Nefazodone and its metabolites have been shown in vitro not to inhibit cytochrome 1A2
Thus, metabolic interactions between nefazodone and medicines metabolized by this isozyme are unlikely (e.g. clozapine, tacrine, theophylline)
Nefazodone is extensively (>99%) bound to plasma proteins in man. The effect of nefazodone on plasma protein binding of potentially co-administered medicines should be considered.Conversely, adverse effects could result from displacement of nefazodone by other highly bound compounds.
During interaction studies, no significant pharmacokinetic or pharmacodynamic interactions were observed when nefazodone was co-administered with theophylline or warfarin.
During premarketing clinical studies, there were seven overdoses with nefazodone alone or in combination with other pharmacological agents. The amount of nefazodone ingested ranged from 1000 mg to 11,200 mg. Commonly reported symptoms from overdose of nefazodone were nausea, vomiting, and somnolence. However, overdosage could cause an increase in incidence or severity of any of the reported adverse reactions. (see Adverse Effects ).One non-study participant took 2000-3000 mg of nefazodone with methocarbamol and alcohol; this person reportedly experienced a convulsion (type not documented). None of the patients died.
In postmarketing experience, overdose with nefazodone alone and in combinations with alcohol and/ or other substances has been reported. Commonly reported symptoms were similar to those reported from overdose in premarketing experience. While there have been rare reports of fatalities in patients taking overdoses of nefazodone, predominantly in combination with alcohol and/or other substances, no causal relationship to nefazodone has been established.
Treatment: There is no specific antidote for SERZONE. Treatment should be symptomatic and supportive Any patient suspected of having taken an overdose should have the stomach emptied by gastric lavage. In managing overdosage consider the possibility of multiple drug involvement. Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to the wide distribution of nefazodone in body tissues, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.
Store SERZONE tablets below 30°C.
Prescription Medicine.
Tablets 100 mg in blister calendar pack of 56.
Tablets 200 mg in blister calendar packs of 56.
The following is a list of the excipients that are used in Serzone tablets:
microcrystalline cellulose, povidone, sodium starch glycollate, anhydrous colloidal silica, magnesium stearate and yellow iron oxide as a colorant in the 200mg strength.
In a series of standard assays for gene mutations, chromosomal damage and DNA damage, nefazodone showed no genotoxic activity.
Carcinogenic effects were not seen in rats and mice dosed orally with nefazodone for 2 years at doses up to 200 and 800 mg/kg/day, respectively. However, exposure (AUC) of mice to nefazodone at these dose levels was less than one-tenth the human exposure levels (exposure to the metabolites, mCPP and the triazole dione, were 8-12 times higher in humans). There was little information on the extent of absorption of nefazodone upon dietary dosing in rats.
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5 March 2002
Serz21c.doc