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Logo EDRONAX 4 mg

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

EDRONAX 4 mg
(Tablets)

COMPOSITION:
Each tablet contains reboxetine methanesulphonate equivalent to 4 mg
reboxetine free base.

PHARMACOLOGICAL CLASSIFICATION:
A 1.2 Central nervous system stimulants: Psychoanaleptics (antidepressants)

PHARMACOLOGICAL ACTION:
EDRONAX is a selective inhibitor of norepinephrine uptake.
In vitro studies have shown that reboxetine has no significant affinity for adrenergic (alpha1, alpha2, beta) and muscarinic receptors.
The pharmacokinetics of reboxetine after single or multiple oral doses have been studied in healthy young or elderly volunteers, in depressed patients and in subjects with renal or liver insufficiency. After oral administration of a single 4 mg reboxetine dose to healthy volunteers, peak levels of about 130 ng/mL are achieved within 2 hours post-dosing. Data indicate that absolute bioavailability is at least 60%. Reboxetine plasma levels decay monoexponentially with a half-life of about 13 hours. Steady-state conditions are observed within 5 days. Linearity of the pharmacokinetics was shown in the range of single oral doses in the clinically recommended dose-ranges.
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 significant dependence of the concentration of the drug.
The amount of radioactivity excreted in the urine accounts for 78% of the dose. Even though unchanged drug is predominant in the systemic circulation (70% of total radioactivity, in terms of AUC), only 10% of the dose is excreted as unchanged drug in urine. These findings suggest that biotransformation rules the overall elimination of reboxetine and that the metabolites’ excretion is limited by their formation. The main metabolic pathways identified are 2-O-dealkylation, hydroxylation of the ethoxyphenoxy ring and oxidation of the morpholine ring, followed by partial or complete glucuro- or sulphoconjugation.
The drug is available as a racemic compound (with both enantiomers being active in the experimental models); no chiral inversion, nor reciprocal pharmacokinetic interferences between enantiomers have been observed. Plasma levels of the more potent SS enantiomers 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.
Some increase in systemic exposure and half-life up to two-fold is observed in patients with renal insufficiency; similar findings, though less relevant and not consistently observed, were apparent in elderly subjects and patients with hepatic insufficiency.

INDICATIONS:
EDRONAX tablets are indicated for the acute treatment of depressive illness/major depression.

CONTRA-INDICATIONS:
Hypersensitivity to the compound.
Seizure disorders.
Pregnancy and lactation.
Use in children, as safety and efficacy have not been demonstrated.

WARNINGS:
Plasma levels and half-lives increase in subjects with renal impairment, especially in severe renal impairment (CL
CR < 20 mL/min) where a dose adjustment is required. Similar findings were apparent in elderly subjects and patients with hepatic insufficiency.
Combined usage of MAO inhibitors and reboxetine should be avoided until further data are available.
Switches to mania/hypomania have occurred during the clinical studies. Close supervision of bipolar patients is therefore recommended.
The risk of a suicidal attempt is inherent in depression, and may persist until significant remission occurs: close patient supervision during initial drug therapy is therefore recommended.
Clinical experience with reboxetine in patients affected by serious concomitant systemic illnesses is limited. Close supervision should be applied in patients with current evidence of urinary retention and glaucoma.
Orthostatic hypotension has been observed. Particular attention should be paid when administering reboxetine with other drugs known to lower blood pressure.
Clinical experience with reboxetine in the long-term treatment of elderly patients is limited. Lowering of mean potassium levels was found starting from week 14; the magnitude of this reduction did not exceed 0.8 mmol/litre and potassium levels never dropped below normal limits.

DOSAGE AND DIRECTIONS FOR USE:
Use in adults
The recommended therapeutic dose is 4 mg b.i.d. (8 mg/day) administered orally. The full therapeutic dose can be given upon starting treatment. After 3 - 4 weeks, this dose can be increased to 10 mg/day in case of incomplete clinical response.
Use in the elderly
In elderly depressed patients, particularly in the presence of concomitant systemic illnesses and medications, the recommended therapeutic dose is 2 mg b.i.d. (4 mg/day) administered orally.
This dose can be increased to 6 mg/day in case of incomplete clinical response after 3 weeks from starting reboxetine.
Use in children
The use of reboxetine in patients less than 18 years of age is not recommended, since safety and efficacy have not been established.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Undesirable effects:
About 1500 patients received reboxetine in clinical studies, 200 of which received reboxetine for up to one year.
Taking into account the placebo-controlled studies, in acute depression 373 adults received reboxetine and 373 received placebo. In these studies adverse events were reported in 69% of reboxetine-treated patients and in 57% of placebo-treated patients. Adverse events were the main reason for discontinuation in 8% of the reboxetine-treated patients and 7,5% of the placebo-treated patients. Adverse events associated with discontinuation with a frequency of at least twice that on placebo were: insomnia (1,3% vs 0,5% of the exposed patients), increased sweating (1,1% vs 0,3%), dizziness or hypotension (0,8% vs 0%), paraesthesia (0,8% vs 0,3%), and impotence, urinary tract infection or dysuria (0,5% vs 0%).
Adverse events with significantly higher risk of development on reboxetine than on placebo included: dry mouth (reported in 27% vs 16% of the patients on reboxetine and placebo respectively), constipation (17% vs 8%), insomnia (14% vs 5%), increased sweating (14% vs 7%), tachycardia (5% vs 2%), vertigo (2% vs 0%), urinary hesitancy/retention (5% vs 2%, of which retention is 2% vs 1%), and impotence (5% vs0%), the latter mainly observed in patients treated with doses higher than 8 mg/day.
As for long-term tolerability, 143 reboxetine-treated and 140 placebo-treated adult patients participated in a long-term placebo-controlled study. Adverse events newly emerged on long-term treatment was 28% of the reboxetine-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 reboxetine and placebo. Among events seen more than occasionally, no individual events not seen on short-term were apparent.
The most relevant between gender difference in adverse event rate was related to the frequency of urinary hesitancy/retention complained of mainly by male patients (10% vs 2% females on short-term treatment: 14% vs 1% in females on long-term treatment).
In the elderly population, frequency of total adverse events, as well as of individual events, was never higher than that reported above.
No indication of withdrawal syndrome upon reboxetine 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 reboxetine (4%) than in those treated with placebo (6%).
Vital signs, including blood pressure and heart rate, body weight and temperature, were evaluated in the majority of reboxetine-treated patients, and the only modification observed was related to heart rate, particularly on standing, significantly increased vs baseline (>20%, to values >100 beats/min) 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).
Apart from tachycardia in a minority of cases, no consistent changes of ECG tracings were observed during reboxetine 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 at ECG in a minority of cases.
Abnormal laboratory test values have been uncommon during reboxetine therapy.

Special precautions:
Effects on ability to drive and use machines:
Patients should be cautioned about operating machinery and driving during treatment.
Interactions with other medicaments and other forms of interaction: Reboxetine is extensively bound to plasma proteins; the available data indicate that the drug is almost exclusively bound to alpha1 acid glycoprotein. Therefore, the concurrent administration ofdrugs with a high affinity for this fraction of plasma proteins (such as dipyridamole, propranolol, alprenolol, methadone, lidocaine and other local anaesthetics, but also imipramine and chlorpromazine) may cause a shift in plasma concentration of either drug, potentially resulting in an adverse reaction.
Plasma pharmacokinetics of reboxetine are not significantly modified when cytochrome P450 2D6 activity is blocked. Therefore, no modification of reboxetine metabolism is expected in poor metabolisers with deficiency of this isoenzyme.
Repeated doses of reboxetine do not affect cytochrome P450 3A activity as documented by the unmodified urinary excretion of 6-beta-hydroxycortisol. As a consequence, no modification is expected in the metabolism of oral contraceptives or other steroids, triazolam, alprazolam, terfenadine, nifedipine, erythromycin, lidocaine and cyclosporine A, when they are co-administered with reboxetine.
No significant reciprocal pharmacokinetic interaction has been found between reboxetine and lorazepam. During their co-administration in healthy volunteers, mild to moderate drowsiness and short lasting orthostatic acceleration of heart rate have been observed.
Reboxetine does not appear to potentiate the effect of alcohol on cognitive functions in healthy volunteers.
Concomitant use of reboxetine with other antidepressants (tricyclics, MAO inhibitors, SSRIs and lithium) has not been evaluated during clinical studies.
The extent of absorption of reboxetine is not significantly influenced by concomitant food intake.
The possibility of hypokalaemia with concomitant use of potassium losing diuretics should be considered.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
The acute toxicity studies carried out in animals indicate a very low toxicity, with a wide safety margin with respect to the pharmacologically active doses. Clinical signs and cause of death were related to CNS stimulation (mainly convulsive symptoms).
In a few cases doses higher than those recommended were administered to patients (12 mg to 20 mg/day) for a period ranging from a few days to some weeks during clinical studies: newly reported complaints include postural hypotension, anxiety and hypertension.
Two cases of self-overdosing with reboxetine were reported by the patients during the clinical studies. No major adverse events were observed.
In case of overdose, monitoring of cardiac function and vital signs is recommended. General symptomatic supportive and/or emetic measures might be required.

IDENTIFICATION:
A white, round, convex, 8 mm diameter tablet with a breakline on one side. A “P”is marked on the left side of the breakline. A “U” is marked on the right side of the breakline. The side opposite the breakline is marked “7671”.

PRESENTATION:
The tablets are contained in aluminium-PVDC/PVC-PVDC opaque blisters.
Each pack contains 20 or 60 tablets in blisters.

STORAGE INSTRUCTIONS:
Store below 25°C.
KEEP OUT OF THE REACH OF CHILDREN.

REGISTRATION NUMBER:
33/1.2/0246

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Pharmacia South Africa (Pty) Ltd
Alphen West G
George St
MIDRAND 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
3 September 1999

New addition to this site: February 2005
Source: Pharmaceutical Industry

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