Abbreviated Prescribing Information for Edronax Full Prescribing Information
Reboxetine mesylate
Pharmacia
Section: 3(d) Antidepressants
Consumer Medicine Information: Available
Pregnancy Category: B1
Permitted in sport
Uses/Indications: Selective noradrenaline reuptake inhibitor. Major depression incl prevention of relapse
Contraindications: Concomitant MAOIs; narrow angle glaucoma
Precautions: Seizure history; bipolar disorders; suicidal ideation; cardiac, cerebrovascular disease, hypertension esp in elderly; high doses; hypovolaemia, dehydration; hyperthyroidism; urinary retention, prostatic hypertrophy; renal, hepatic impairment; pregnancy, lactation
Adverse Reactions: Headache; tachycardia; nausea; insomnia; hypotension, dizziness; sweating; constipation; dry mouth; urinary retention/ hesitancy esp in males; others, see full PI
Drug Interactions: MAOIs (see Contra); antihypertensives; CYP3A4 inhibitors eg azole antifungals, macrolides, fluvoxamine; CYP3A4 inducers eg carbamazepine; lithium (monitor); ergot derivatives; K+ depleting diuretics
EDRONAX (Tablets) Prescription required. S4 CMI. Reboxetine mesylate; white, scored;
Dose: Adults: 4 mg twice daily; if incomplete response after 3 weeks, incr to 10 mg/day. Elderly: 2 mg twice daily; if incomplete response after 3 weeks, incr to 6 mg/day. Renal, hepatic impairment: 2 mg twice daily initially; incr as tolerated
Pack: 4 mg [60] : Restricted - PBS/RPBS (Rp 5) [Restricted benefit indication(s): Major depressive disorders.] PBS: $41.19
Refer: MIMS Annual 2003 p. 3-329
MIMS Full Prescribing Information for Edronax Abbreviated Prescribing Information
Pharmacia Australia Pty Limited
Section: 3(d) Antidepressants
Composition Active. Reboxetine mesylate.
Inactive. Magnesium stearate, microcrystalline cellulose, silicon dioxide, crospovidone and calcium hydrogen phosphate.
Description Chemical name: (2RS, alphaRS)-2-[alpha-(2-ethoxyphenoxy) benzyl] morpholine methanesulfonate. CAS: 141425-90-3. Molecular formula: C19H23NO3 -CH4O3S. MW: 409.50. Reboxetine mesylate is freely soluble in water (> 20% w/v).
Actions Pharmacology. Pharmacodynamics. Reboxetine is a highly selective and potent inhibitor of noradrenaline reuptake. It has only a weak effect on the 5-HT reuptake and does not affect the uptake of dopamine. Noradrenaline reuptake inhibition and the consequent increase of noradrenaline availability in the synaptic cleft and modification of noradrenergic transmission, is among the most relevant mechanisms of action of known antidepressant drugs.
In vitro, studies have shown that reboxetine has no significant affinity for adrenergic (alpha1, alpha2, beta) or muscarinic receptors. Binding to such receptors has been described as being associated with cardiovascular, anticholinergic and sedative side effects of other antidepressant drugs. Reboxetine is devoid of in vitro binding to either alpha1 or alpha2 adrenoreceptors, however a functional interference with alpha-adrenoreceptors at high doses in vivo cannot be excluded.
In healthy volunteers the administration of reboxetine single doses of 1 and 3 mg was followed by dose dependent CNS effects with EEG modifications (decreased power of theta and fast beta-waves in the frontocentral derivative) and performance improvement (peg-board test).
Clinical trials. The Edronax clinical program consists of 15 phase II and III clinical trials that were conducted in adult (aged 18 to 65 years) and elderly (aged > 65 years) patients diagnosed with major depressive disorder (MDD).
The Hamilton Depression Rating Scale (HAMD) was used as the primary instrument for the assessment of the change in depressive symptoms in all clinical trials. The Montgomery and Asberg Rating Scale for Depression (MADRS) and the Clinical Global Impressions Scales (CGI) were used as secondary efficacy parameters. For the short-term studies in nonelderly patients (i.e. those 18 to 65 years of age), the study endpoint was defined as the absolute decrease of the mean HAMD total score or as the frequency of response (defined as greater than or equal to 50% decrease of the HAMD total score), as measured at the last available assessment. This allowed for a global evaluation of the consistency of the results of the studies and for conclusions on the antidepressant efficacy of Edronax to be drawn.
The clinical program has demonstrated that Edronax is effective in the therapy of acute episodes of depression as well as in the prevention of relapses and recurrences of depressive illness when administered for long-term therapy. The results of the studies indicate that the primary effect of Edronax is on the primary symptom (depressed mood) of depressive illness. The remission of the acute phase of the depressive illness is associated with an improvement in the patient's quality of life in terms of social adaptation.
Short-term placebo controlled studies. The results of the analysis of the HAMD total score for the five short-term (four to eight weeks), placebo controlled studies in nonelderly patients (18 to 65 years) with MDD are summarised in Table 1. Please refer to table 1.
The mean HAMD total score improvement associated with Edronax treatment ranged from 9.2 to 23.1 points. The mean HAMD improvement associated with placebo was always lower than that associated with Edronax, with an average decrease of 4.5 to 11.3 points. The difference between Edronax and placebo was statistically significant in three of the five studies above. In two studies, the difference between Edronax and placebo was not statistically significant on the mean HAMD total score. In one of these studies, the active comparator imipramine also failed to show a statistically significant difference over placebo. In the other study, a number of secondary efficacy measures demonstrated statistically significant differences in favour of Edronax over placebo.
The frequency of clinically relevant improvement with Edronax was, on the average, 16% greater than with placebo, providing an unequivocal indication of the efficacy of Edronax in the acute treatment of depressive illness.
Active controlled studies. Imipramine controlled studies. Two six-week studies were conducted to determine the benefits of Edronax relative to those of imipramine in the treatment of patients with MDD. A total of 237 patients were treated with Edronax compared to 233 receiving imipramine. The mean HAMD score improvement associated with Edronax treatment ranged from 13.5 to 15.8, compared to 13.8 to 14.3 for imipramine. The results of both these studies therefore confirmed equivalent efficacy for Edronax and imipramine.
Fluoxetine controlled studies. Two eight-week studies were conducted to determine the benefits of Edronax relative to those of fluoxetine in the treatment of patients with MDD. A total of 200 patients were treated with Edronax compared to 213 receiving fluoxetine. The mean HAMD score improvement associated with Edronax treatment ranged from 13.4 to 19.2, compared to 13.3 to 16.8 for fluoxetine. The results of both these studies confirmed equivalent efficacy for Edronax and fluoxetine.
Long-term placebo controlled study. The long-term efficacy of Edronax for the treatment of patients with MDD was investigated in a one year, double blind, randomised, parallel group, placebo controlled study. In this study, patients received open label treatment with Edronax (8 mg/day) for six weeks; thereafter, the patients who responded to therapy (minimum 50% decrease of the HAMD total score) were randomised to receive treatment with Edronax or placebo until relapse occurred or for up to one year. 283 patients participated in the double blind, long-term portion of the study: 143 were treated with Edronax and 140 were treated with placebo.
This study demonstrated the efficacy of Edronax in the maintenance therapy of depressive illness. 61 and 40%, respectively, of the responder patients on Edronax and placebo remained relapse free during the initial six months following randomisation, and 88 and 59%, respectively, of the patients on Edronax and placebo who entered the last six months of treatment remained relapse free up to the end of the study. Edronax showed a 29% advantage in relapse rate over placebo, thus confirming the efficacy of Edronax in the prevention of recurrences of new depressive episodes.
Pharmacokinetics. The pharmacokinetics of reboxetine after single and multiple oral doses have been studied in healthy young and elderly volunteers, in depressed patients, and in subjects with renal or liver insufficiency.
Absorption. After oral administration of a single 4 mg reboxetine dose to healthy volunteers, peak levels of about 130 nanogram/mL are achieved within two hours postdosing. The administration of reboxetine with food delayed the rate of absorption by approximately two hours while not affecting the extent of absorption. Reboxetine displays linear pharmacokinetics in a dose range of up to 4 mg twice daily (BID). Data indicate that absolute bioavailability is approximately 94%. Reboxetine plasma concentrations decay monoexponentially with a half-life of about 13 hours. Steady-state conditions are observed within five days. Linearity of the pharmacokinetics was shown in the range of single oral doses in the clinically recommended dose ranges.
Distribution. The drug appears to be distributed into total body water. Reboxetine is 97% bound to human plasma proteins (with affinity markedly higher for alpha1 acid glycoprotein than albumin) with no clinically relevant dependence on the concentration of the drug. The volume of distribution of reboxetine at steady state following intravenous administration is 26 L and 63 L for the RR and SS diastereomers, respectively.
The amount of radioactivity excreted in urine accounts for 78% of the dose. Even though unchanged drug is predominant in the systemic circulation (70% of total radioactivity, in terms of area under the plasma concentration time curve (AUC)), only 10% of the dose is excreted as unchanged drug in urine.
Metabolism. Reboxetine is extensively metabolised after oral administration. The drug is predominantly metabolised through hydroxylation of the ethoxyphenoxy ring, o-dealkylation and oxidation of the morpholine ring. In vitro studies indicate that CYP3A4 is the isozyme of cytochrome P450 that is primarily responsible for the metabolism of reboxetine. In vitro studies show that reboxetine has no effect on the activity of the following isozymes of cytochrome P450: CYP1A2, CYP2C9, CYP2C19 and CYP2E1. At high concentrations, reboxetine inhibits CYP2D6. In vitro studies show that reboxetine is a weak inhibitor of CYP3A4. In vitro studies have shown that the major circulating metabolite, the 3-morpholine oxidation product of reboxetine, has little or no activity on noradrenergic or serotonergic uptake, and is unlikely to contribute to the pharmacological activity of reboxetine.
The drug is available as a racemic compound: the SS enantiomer is two times more potent than the racemate, and the RR enantiomer is ten times less potent than the racemate. No chiral inversion or reciprocal pharmacokinetic interferences between enantiomers have been observed. Plasma concentrations of the more potent SS enantiomer are about two times lower and urinary excretion two times higher than those of the enantiomeric counterpart. No significant differences were observed in the terminal half-lives of the two enantiomers.
Excretion. The systemic clearance of reboxetine is 43 mL/minute. About 10% of the dose of reboxetine is excreted unchanged in urine. The renal clearance of reboxetine is excreted unchanged in urine. The renal clearance of SS and RR diastereomers of reboxetine is 9.3 mL/minute and 2.0 mL/minute, respectively.
Elimination of reboxetine is mainly via hepatic metabolism (by cytochrome P4503A4) with a mean terminal half-life of about 12 hours. No significant difference was observed in the terminal half-lives of the RR and SS diastereomers.
Elderly. The pharmacokinetics of reboxetine were assessed in three studies of elderly volunteers. In the first study, middle aged (50 to 63 years) and elderly (68 to 77 years) subjects showed only moderate differences in area under the plasma concentration time curve and half-life. The AUC increased by 20 to 25% and half-life was three to five hours longer in the elderly compared to healthy young volunteers given the same 4 mg dose. In the second study, elderly subjects (66 to 98 years) showed a fourfold increase in AUC and twofold increase in half-life compared to young healthy males following a single 4 mg reboxetine oral dose. In the third study, the mean AUC in elderly depressed females (75 to 87 years) was approximately three times higher than in young males. A reduction in dose is warranted in elderly patients (see Dosage and Administration).
Children. There have been no pharmacokinetic studies in children.
Sex. In a study in six males and six females, no differences in reboxetine pharmacokinetics were observed between genders following a 1 mg oral reboxetine dose.
Race. The effect of race on reboxetine pharmacokinetics has not been studied.
Hepatic impairment. Compared with young healthy volunteers receiving the same 4 mg reboxetine dose, AUC and t1/2 were approximately doubled in patients (n = 6) with alcoholic liver disease (moderate, i.e. Child-Pugh score of 7 to 9, and severe, i.e. Child-Pugh score of 10 to 13). A reduction in dose is warranted in patients with hepatic insufficiency (see Dosage and Administration).
Renal impairment. An increase in systemic exposure and t1/2 up to threefold was observed in patients (n = 6) with severe renal insufficiency (creatinine clearance 10 to 20 mL/minute) following a 4 mg oral dose of reboxetine. A reduction in dose is warranted in patients with compromised renal function (see Dosage and Administration).
Indications Treatment of major depression; effective in preventing the relapse of depressive symptoms.
Contraindications Hypersensitivity to reboxetine or any of the excipients.
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs).
Since reboxetine has a weak mydriatic effect, its use is not recommended in patients with narrow angle glaucoma.
Precautions Seizures. Since rare cases of seizures have been reported in clinical studies, Edronax should be given under close supervision to subjects with a history of convulsive disorder and it should be discontinued if the patient develops seizures.
Activation of mania/ hypomania. As with all antidepressants, switches to mania/ hypomania have occurred. Close supervision of patients with bipolar disorders is recommended.
Suicide. The risk of a suicide attempt is inherent in depression and may persist until significant remission occurs. Patient supervision during initial drug therapy is recommended.
Cardiovascular. Patients (particularly those aged > 65 years) with a history of cardiac disease, including hypertension, should be closely supervised when being treated with reboxetine.
Orthostatic hypotension. Orthostatic hypotension has been observed with greater frequency at doses higher than the maximum recommended. Close supervision is recommended when administering Edronax with other drugs known to lower blood pressure. Edronax should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemia, heart failure or conduction abnormalities), cerebrovascular disease and conditions that would predispose patients to hypotension (dehydration, hypovolaemia and treatment with antihypertensive medications).
Hypertension. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure, e.g. those with pre-existing hypertension, heart failure or recent myocardial infarction.
Tachycardia. Reboxetine should be used with caution in patients whose underlying medical conditions might be compromised by increases in heart rate, e.g. patients with hyperthyroidism, heart failure or recent myocardial infarction.
Use in patients with concomitant illness. Clinical experience with reboxetine in patients affected by serious concomitant illness is limited. Close supervision is recommended in patients with current evidence of urinary retention, prostatic hypertrophy and glaucoma.
Carcinogenesis, mutagenesis, impairment of fertility. Carcinogenicity studies in mice and rats showed no drug related increases in tumour incidences at oral reboxetine doses up to 45 and 90 mg/kg/day, respectively. Systemic exposure (plasma AUC) to unbound drug at the highest dose levels was approximately twofold higher than that in humans at the maximum recommended dose. No genotoxic activity was observed in a series of tests for gene mutations, chromosomal effects and DNA damage.
Impairment of fertility. No effect on fertility of male or female rats was observed at oral dose levels up to 90 mg/kg/day. Systemic exposure (plasma AUC) to unbound drug at the highest dose levels was approximately twofold higher than that in humans at the maximum recommended dose.
Use in pregnancy. (Category B1)
Development studies in rats and rabbits have not shown clear evidence of teratogenic effects at dose levels up to 320 and 100 mg/kg/day respectively. However, in both species, there were increases in postimplantation loss, decreases in mean fetal weight and an increased incidence of skeletal anomalies, including delayed ossification. Compared with human exposure (plasma AUC at the maximum recommended dose), estimated exposure in rats was less than human exposure, and exposure in rabbits was approximately sixfold (reboxetine, SS enantiomer) and 16-fold (RR enantiomer) higher at the highest dose tested. At the no-effect dose in rabbits (25 mg/kg/day), reboxetine exposure was similar to human exposure. Reboxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Use in lactation. Reboxetine is excreted in milk in lactating rats. Oral doses of 25 to 125 mg/kg/day reduced survival of offspring and retarded postnatal growth and development. Plasma drug levels at these doses were similar to or lower than those in humans at the maximum recommended dose. Therefore, while no information on the excretion of reboxetine in maternal milk in humans is available, Edronax administration is not recommended in women who are breastfeeding.
Effect on ability to drive or operate machinery. No cognitive or psychomotor impairment has been observed with Edronax in clinical studies, or when the compound was coadministered with alcohol.
Adverse Reactions Clinical trial data. About 1,700 patients have received Edronax in clinical studies, 216 of whom received Edronax for at least 12 months.
Short-term clinical trials. Adverse events reported during the four to eight week studies are reported in Table 2. Please refer to table 2.
The most relevant between gender difference in adverse event rate was related to the frequency of urinary hesitancy/ retention which occurred more often in male patients (10% versus 2% in females on short-term treatment; 14% versus 1% in females on long-term treatment).
There was an increase in heart rate upon standing to values greater than or equal to 100 beats/minute mainly in adult patients (20% of the patients on short-term treatment compared with 6% on placebo, and 23% of the patients on long-term treatment compared with 17% on placebo). In all short-term controlled studies in depression, the mean change in pulse (in beats/minute) for reboxetine treated patients was 2.9, 8.3 and 3.0 in the supine, sitting and standing positions respectively, compared with -0.5, 0 and 0 for placebo treated patients in the corresponding positions.
In the short-term controlled studies in depression, no significant mean change in blood pressure was observed. Diastolic blood pressures > 105 mmHg were observed in 5.6, 1.0 and 3.8% of reboxetine treated patients in the supine, sitting and standing positions respectively, compared with 1.5, 1.0 and 2.8% for placebo treated patients in the corresponding positions. Analyses of data from the phase II and III studies in depression have demonstrated no increase in systolic blood pressure.
Impotence was mainly observed in patients treated with doses higher than 8 mg/day.
Long-term clinical trials. Based on data from long-term studies which included 328 patients who were treated with Edronax for longer than six months, the frequency of the most common adverse events (e.g. dry mouth, constipation, tachycardia, hypotension) did not increase over time but, rather, decreased or remained constant over time. Table 3 summarises the treatment emergent symptoms (TES) that were reported in greater than or equal to 1% of the reboxetine treated patients by duration of therapy (less than or equal to six months or > six months). Although small, the placebo group is provided for reference purposes. Please refer to table 3.
For long-term tolerability, 143 Edronax treated and 140 placebo treated adult patients participated in a long-term placebo controlled study. Adverse events newly emerged on long-term treatment in 28% of the Edronax treated patients and 23% of the placebo treated patients, and caused discontinuation in 4% and 1% of the cases, respectively. There was a similar risk of the development of individual events with Edronax and placebo. Among events seen more than occasionally, no individual events not seen on short-term treatment were apparent.
No indication of a withdrawal syndrome upon Edronax discontinuation emerged from the results of the clinical trials. Signs and symptoms newly reported on abrupt discontinuation were infrequent and less frequent in patients treated with Edronax (4%) than in those treated with placebo (6%).
Apart from tachycardia, no consistent changes in ECG tracings were observed during Edronax treatment in adult patients. Similarly, no consistent changes were observed at the ophthalmological examination carried out upon long-term treatment. In the elderly population, newly observed rhythm disorders (mainly tachycardia) and conduction disorders were apparent in the ECG in approximately 15% of cases.
In a long-term study, treatment emergent rhythm disorders (including sinus tachycardia and occasional atrial and ventricular ectopics), conduction disorders, ischaemic changes (including myocardial ischaemia, repolarisation changes and nonspecific ST-T changes) and other changes (including left ventricular hypertrophy) occurred more frequently in elderly patients with a history of cardiovascular disease at baseline than in elderly patients without such a history. A similar pattern was also observed in a short-term study in elderly patients.
Abnormal laboratory test values were uncommon during Edronax therapy.
Interactions In vitro studies show that reboxetine has no effect on the activity of the following isozymes of cytochrome P450: CYP1A2, CYP2C9, CYP2C19 and CYP2E1. Specifically, in vitro and in vivo studies show that reboxetine is not metabolised by CYP2D6 and therefore no special precautions are necessary for individuals deficient in this enzyme.
Inhibitors of CYP2D6, such as fluoxetine and paroxetine, are unlikely to have an effect of Edronax pharmacokinetics. This was confirmed in a multiple dose study performed in healthy volunteers where no clinically significant interaction between fluoxetine and Edronax was observed.
In vitro metabolism studies indicate that reboxetine is metabolised by the 3A4 isozymes of cytochrome P450. Therefore compounds that decrease the activity of CYP3A4 are expected to increase plasma concentrations of reboxetine. In a study in healthy volunteers, ketoconazole, a potent inhibitor of CYP3A4, was found to increase plasma concentrations of the reboxetine enantiomers by approximately 50%. Similar interactions are expected with other inhibitors of CYP3A4, such as azole antifungals, macrolide antibiotics and fluvoxamine.
In vitro studies show that reboxetine is a weak inhibitor of CYP3A4. However, an in vivo study has shown that Edronax did not alter the clearance of alprazolam. This is expected to apply to other CYP3A4 substrates.
Carbamazepine induces CYP3A4 and is therefore expected to induce clearance of reboxetine and lower plasma concentrations. Therefore doses of Edronax may need to be increased if given concomitantly with carbamazepine.
Concomitant use of Edronax with lithium has not been evaluated in clinical trials but in view of the small degree of glomerular filtration of unbound reboxetine, no effect of Edronax on lithium elimination is expected. However, monitoring of lithium levels is recommended where the two drugs are coadministered.
Concomitant use of Edronax with tricyclic antidepressants has not been evaluated during clinical studies.
No significant reciprocal pharmacokinetic interaction has been found between Edronax and lorazepam.
Edronax does not appear to potentiate the effect of alcohol on cognitive functions in healthy volunteers.
The small degree of glomerular filtration of unbound reboxetine means there is little likelihood that Edronax will affect the renal clearance of cardiac glycosides such as digoxin.
Coadministration of antihypertensive agents may exacerbate the orthostatic hypotensive effects of Edronax.
Concomitant use of ergot derivatives and Edronax may result in increased blood pressure.
Although data are not available from clinical studies, the possibility of hypokalaemia with concomitant use of potassium depleting diuretics should be considered.
The extent of absorption of reboxetine is not significantly influenced by concomitant food intake.
Overdosage In a few cases doses higher than those recommended (12 to 20 mg/day) were administered to patients during the clinical studies for a period ranging from a few days to a few weeks. Treatment emergent adverse events included postural hypotension, anxiety and hypertension.
Two cases of self-overdosing with up to 52 mg reboxetine have been reported and no serious adverse events were observed.
In case of overdose, treatment should consist of those general measures employed in the management of overdose with any antidepressant.
Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended.
Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, haemoperfusion and exchange perfusion are unlikely to be of benefit. No specific antidotes for reboxetine are known.
In managing overdosage, consider the possibility of multiple drug involvement. The doctor should consider contacting a poisons information centre for additional information on the treatment of any overdose.
Dosage and Administration The onset of clinical effect is usually seen after 14 days of treatment.
Adults. The recommended therapeutic dose is 4 mg twice daily (BID) (8 mg/day) administered orally. After three weeks the dose can be increased up to 10 mg/day in case of incomplete clinical response.
Use in children. There are no data available on the use of reboxetine in children.
Use in the elderly. (Age > 65.) The recommended therapeutic dose is 2 mg twice daily (BID) (4 mg/day) administered orally. After three weeks the dose can be increased up to 6 mg/day in case of incomplete clinical response.
Use in patients with renal or hepatic insufficiency. The starting dose in patients with renal or moderate to severe hepatic insufficiency should be 2 mg twice daily (BID), increased according to patient tolerance.
Presentation Tablets, 4 mg equiv. reboxetine mesylate 5.2 mg (white, scored, marked P/U, 7671 on reverse): 60's.
Edronax 4 mg.
Edronax 4 mg
Edronax 4 mg
Edronax 4 mg
Poison Schedule S4.
Date of TGA Approval or Manufacturer's Last Amendment 17/09/2002
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Extra Information and Explanatory Notes
Manufacturer Details
Pharmacia Australia Pty Limited
Address: 59 Kirby Street,
Rydalmere NSW,
2116
Phone: (02) 9848 3000
Fax: (02) 9848 3333
Prescription required
Where "Prescription Required" appears against a product formulation, this product is available only on prescription (i.e. it belongs to Poisons Schedule 4, 7 or 8). Further information is displayed in brackets, e.g. Prescription required (Vic) means a prescription is required in Victoria only. Prescription required (S8) indicates Schedule 8 of the Poisons Schedule applies (States included within brackets if not all S8).
Drowsiness
Where "This product may cause drowsiness" appears against a product formulation, this medication may cause drowsiness and may increase the effects of alcohol. If affected, do not drive a motor vehicle or operate machinery (refer SUSDP No.11). Non-appearance of this warning should not be taken to mean that a product will definitely not cause drowsiness.
Pharmaceutical Benefits
Pharmaceutical Benefits are shown as:
PBS = General Benefit
RPBS = Repatriation Benefit
Restricted = Restricted Purpose
Authority = Authority Required
See product formulation for approved indications for authority. Authority prescriptions require prior approval. Dial free call 1800 888 333 HIC or 1800 552 580 DVA.
Brand price premium
The premium a patient must pay for this brand on the PBS.
Private price
Prices quoted in MIMS are intended as a guide only and include dispensing fees where appropriate. PBS: $xx.xx is the price to the PBS; Private: $xx.xx is the price to the patient if not written as an 'authority item'.
Therapeutic group premium
The premium a patient must pay for any brand of this drug on the PBS.
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Explanation of Pregnancy Categories
Category A
Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.
Category B1
Drugs that have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals[1] have not shown evidence of an increased occurrence of fetal damage.
Category B2
Drugs that have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals[1] are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.
Category B3
Drugs that have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals[1] have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
Category C
Drugs that, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts within product monographs appearing in MIMS Annual should be consulted for further details.
Category D
Drugs that have caused, are suspected to have caused or may be expected to cause an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts within product monographs appearing in MIMS Annual should be consulted for further details.
Category X
Drugs that have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy.
Note
For drugs in categories B1, B2 and B3, human data are lacking or inadequate and subcategorisation is therefore based on available animal data. The allocation of a B category does not imply greater safety than the C category. Drugs in category D are not absolutely contraindicated in pregnancy (e.g. anticonvulsants). Moreover, in some cases the D category has been assigned on the basis of `suspicion'.
Due to legal considerations in this country, sponsor companies have, in some cases, applied a more restrictive category than can be justified on the basis of available data. In some cases there may be discrepancies between the official product information appearing in MIMS Annual and the information in the Medicines in Pregnancy booklet due to the lead times involved in printing.
[1] Animal studies submitted in support of new drug applications must conform to the Australian Guidelines for the Registration of Drugs - Volume 1, Prescription and other specified Drug Products, 2nd Edition.
