PARAX™ 20 (film coated tablets)
PARAX™ 40 (film coated tablets)

SCHEDULING STATUS:
S5

PROPRIETARY NAME
(and dosage form):

PARAX™ 20 (film coated tablets)
PARAX™ 40 (film coated tablets)

COMPOSITION
Each PARAX20 film coated tablet contains 20mg of the anhydrous free base of paroxetine.
Each PARAX40 film coated tablet contains 40mg of the anhydrous free base of paroxetine

PHARMACOLOGICAL CLASSIFICATION
A1.2 Psychoanaleptics (Antidepressants)

PHARMACOLOGICAL ACTION
Paroxetine is a selective serotonin re-uptake inhibitor (SSRI). The antidepressant effect of paroxetine is thought to be related to its effect on serotonergic neurotransmission.
Pharmacokinetics:
After oral administration, paroxetine is readily absorbed from the gastrointestinal tract. Absorption is not influenced by the presence of food, milk or antacids. Paroxetine is highly protein bound (95%) and undergoes extensive first-pass metabolism in the liver where it is metabolised in part by cytochrome P4502D6 (CYP2D6). The metabolites appear to be clinically inactive. The elimination half-life is about 24hours, but there is wide intersubject variability. Steady-state is achieved in 7 to 14days in most patients. Paroxetine is excreted renally (approximately 64%) and in the faeces (approximately 36%) mainly as inactive metabolites.

INDICATIONS

•	Depression
•	Obsessive Compulsive Disorder (OCD)
•	Social phobia
•	Panic disorder

CONTRA-INDICATIONS

•	Hypersensitivity to paroxetine or any of the ingredients of PARAX.
•	MAO Inhibitors: PARAX should not be used in combination with MAO inhibitors or within 2weeks of terminating treatment with MAO inhibitors. MAO inhibitors should not be introduced within 2weeks of cessation of therapy with PARAX.
•	Children under the age of 18years (see WARNINGS and SIDE-EFFECTS AND SPECIAL PRECAUTIONS).
•	Co-administration with thioridazine.

WARNINGS
Safety and efficacy in children under 18 years have not been established. (See CONTRA-INDICATIONS and SIDE-EFFECTS AND SPECIAL PRECAUTIONS.)
Patients with major depressive disorder, both adults and children, may experience worsening of their depression and or the emergence of suicidal ideation and behaviour, whether or not they are taking antidepressant medicines. This risk may persist until significant remission occurs. A causal role, however, for antidepressant medicines in inducing such behaviour has not been established. Patients being treated with PARAX should, nevertheless, be observed closely for clinical worsening and suicidality, especially at the beginning of a course of therapy, or at any time of dose changes, either increases or decreases.
Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and non-psychiatric disorders.
The following symptoms have been reported in patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric: anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness, impulsivity, akathisia, hypomania, and mania. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing PARAX, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision is made to discontinue treatment, PARAX should be tapered (See PRECAUTIONS and DOSAGE AND DIRECTIONS FOR USE).

PARAX should be used with caution in:

•	patients with a history of mania.
•	patients already receiving neuroleptics, since symptoms suggestive of Neuroleptic Malignant Syndrome may occur with this combination.
•	patients concomitantly treated with medicines that give an increased risk for bleeding, and in patients with a known tendency for bleeding or those with predisposing conditions. Treatment with PARAX may cause skin and mucous membrane bleedings.

Co-administration with risperidone may lead to increased toxicity thereof (see INTERACTIONS).
Patients should be cautioned about their ability to drive a car and operate machinery.
The concomitant use of PARAX and alcohol is not advised.

INTERACTIONS
Cimetidine, a drug metabolising inhibitor, can increase the bioavailability of PARAX, whereas the drug metabolising inducer phenytoin can decrease it.
When PARAX is to be co-administered with a known drug metabolising enzyme inhibitor, consideration should be given to using doses at the lower end of the range. No initial dosage adjustment of PARAX is considered necessary when the medicine is to be co-administered with known drug metabolising enzyme inducers. Any subsequent dosage adjustment should be guided by clinical effects (tolerability and efficacy).
PARAX inhibits the specific hepatic cytochrome P450 isozyme CYP2D6 responsible for the metabolism of debrisoquine and sparteine. This may lead to enhanced plasma levels of those co-administered medicines which are metabolised by this isozyme.
Drugs metabolised by this isozyme include certain tricyclic antidepressants (e.g. nortriptyline, amitriptyline, imipramine and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine) risperidone, Type 1c antiarrhythmics (e.g. propafenone) and metoprolol.
Co-administration with risperidone may lead to increased toxicity thereof.
Interaction between PARAX and monoamine oxidase (MAO) inhibitors (See CONTRA-INDICATIONS), and also between PARAX and tryptophan medication may occur, resulting in a "serotonin syndrome".
Concurrent administration of PARAX and lithium should be undertaken with caution. Lithium levels should be monitored.
Co-administration of PARAX and phenytoin is associated with decreased plasma concentrations of paroxetine and increased adverse experiences (diarrhoea, indifference, imbalance, nervousness, ataxia and vertigo). No initial dosage adjustment of paroxetine is considered necessary when these agents are co-administered. Any subsequent adjustments should be guided by clinical effect.
Co-administration of PARAX with anti-convulsants may be associated with an increased incidence of adverse events.
Daily administration of PARAX may significantly increase the plasma levels of procyclidine; other anti-cholinergic drugs may be similarly affected. If anti-cholinergic effects are seen, the dose of procyclidine should be reduced.
PARAX should be administered with great caution to patients receiving oral anticoagulants (See WARNINGS).
Co-administration of PARAX with warfarin may result in increased bleeding in the presence of unaltered prothrombin times.

PREGNANCY AND LACTATION
The safety of PARAX in pregnancy or lactation has not been established.

DOSAGE AND DIRECTIONS FOR USE
It is recommended that PARAX is administered in the morning with food. PARAX should be swallowed rather than chewed.
Depression: 20mg daily. This dose can be increased gradually if needed by 10mg increments to a maximum of 50mg daily according to the patient's response.
Panic Disorder: The recommended dose is 40mg daily. The initial starting dose is 10mg daily, which may be increased by 10mg increments. The maximum dose is 60mg daily. The low initial starting dose is recommended to minimise the potential worsening of panic symptoms when initiating treatment with PARAX.
Obsessive Compulsive Disorder: The recommended dose is 40mg daily. The initial starting dose is 20mg daily, which may be increased by 10mg increments to a maximum of 60mg daily.
Social Phobia: The recommended daily dose is 20mg. This dose may be increased gradually if needed by 10mg increments to a maximum of 60mg according to the patient's response.

Children: The safety and efficacy of PARAX in children under the age of 18years have not been established. In children hostility, suicide ideation and self-harm may occur with PARAX.

Elderly: Elderly subjects may experience increased plasma concentrations with PARAX. Dosing should commence at the adult starting dose and may be increased gradually by 10mg increments up to 40mg daily.
Hepatic and renal impairment: Increased plasma concentrations of PARAX may occur in patients with severe renal impairment (creatinine clearance <30mL/min) or severe hepatic impairment. The dosage should therefore be restricted to the lower end of the dosage range.
Patients should be treated for a sufficient period to ensure that they remain free from symptoms. This may be several months or longer.
Abrupt discontinuation of PARAX should be avoided (See SIDE-EFFECTS AND SPECIAL PRECAUTIONS).

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects:
Definition of frequencies:
rare (>1/10000, <1/1000)
very rare (<1/10000), including isolated reports.
very common (>1/10)
common (>1/100, <1/10)
uncommon (>1/1000, <1/100)

Blood and lymphatic system disorders
Uncommon: abnormal bleeding, predominantly of the skin and mucous membranes (mostly ecchymosis, but also in the gastrointestinal tract, central nervous system and eye).
Endocrine disorders
Very rare: syndrome of inappropriate anti-diuretic hormone secretion (SIADH).
Psychiatric disorders
Common: somnolence, insomnia
Uncommon: confusion, hallucinations
Rare: manic reactions.
Immune system disorders
Very rare: allergic reactions (including urticaria and angioedema).
Metabolism and nutrition disorders
Common: decreased appetite.
Rare: hyponatraemia.
Hyponatraemia, which may occur predominantly in elderly patients, is sometimes due to syndrome of inappropriate anti-diuretic hormone secretion (SIADH).
Nervous system disorders
Common: dizziness, tremor.
Uncommon: extrapyramidal disorders.
Rare: convulsions.
Very rare: serotonin syndrome (symptoms may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering tachycardia and tremor).
Extrapyramidal disorders may occur in patients using neuroleptic medication.
General disorders and administration site conditions
Common: asthenia.
Very rare: peripheral oedema.
Eye disorders
Common: blurred vision.
Very rare: acute glaucoma.
Respiratory, thoracic and mediastinal disorders
Common: yawning.
Renal and urinary disorders
Uncommon: urinary retention.
Reproductive system and breast disorders
Very common: sexual dysfunction.
Rare: hyperprolactinaemia / galactorrhoea.
Gastrointestinal disorders
Very common: nausea.
Common: constipation, diarrhoea, dry mouth.
Hepato-biliary disorders
Rare: elevation of hepatic enzymes.
Very rare: hepatic events (such as hepatitis, sometimes associated with jaundice and/or liver failure).
Elevation of hepatic enzymes may occur. Hepatic events, which may be fatal (such as hepatitis, sometimes associated with jaundice, and/or liver failure) may occur. Discontinuation of PARAX should be considered if there is prolonged elevation of liver function test results.
Skin and subcutaneous tissue disorders
Common: sweating.
Uncommon: skin rashes.
Very rare: photosensitivity reactions.
Symptoms seen on discontinuation of PARAX treatment
Common: Dizziness, sensory disturbances, sleep disturbances, anxiety, headache.
Uncommon: Agitation, nausea, tremor, confusion, sweating, diarrhoea.
Abrupt discontinuation of PARAX may lead to withdrawal symptoms such as dizziness, sensory disturbances, (including paraesthesia and electric shock sensations), sleep disturbances, insomnia, tremor, confusion, agitation or anxiety, headache, nervousness, vertigo, nausea and sweating. It is therefore advised that when PARAX treatment is no longer required, gradual discontinuation by dose tapering be carried out (See DOSAGE AND DIRECTIONS FOR USE, and SPECIAL PRECAUTIONS).
Special precautions:
Safety and efficacy in children under 18years of age have not been established. (See CONTRA-INDICATIONS and DOSAGE AND DIRECTIONS FOR USE).
Cardiac Condition:
Administration of PARAX to patients with a serious cardiovascular disorder such as (unstable) angina pectoris, poorly monitored cardiac decompensation, ventricular rhythm disorder and acute myocardial infarction, has not been studied and must therefore be avoided. If antidepressant medication is nevertheless indicated for such patients, PARAX should be administered with caution.
Epilepsy:
Seizures:
PARAX should be used with caution in patients with epilepsy.
Seizures:
Seizures may occur in patients treated with PARAX.
PARAX should be discontinued in any patient who develops seizures.
Electro-Convulsive Therapy (ECT):
Clinical experience of the concurrent administration of PARAX and electro-convulsive therapy is lacking.
Hyponatraemia:
Hyponatraemia, which is generally reversible on discontinuation of PARAX, may occur predominantly in the elderly.
Glaucoma:
PARAX may cause mydriasis and should be used with caution in patients with narrow angle glaucoma.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
(See SIDE-EFFECTS AND SPECIAL PRECAUTIONS)
Symptoms of overdose:
Vomiting, dilated pupils, fever, blood pressure changes, headache, involuntary muscle contractions, agitation, anxiety, tachycardia, coma, and ECG changes.
Treatment of overdose:
Treatment is symptomatic and supportive.
There is no specific antidote. To decrease absorption, the stomach should be emptied by gastric lavage or induction of emesis or both. This should be followed by administration of 20 to 30g of activated charcoal every four to six hours during the first 24 hours after ingestion. Frequent monitoring of vital signs and careful observation is recommended.

IDENTIFICATION

Parax 20mg:	A white, round, divisible, bisected tablet encoded PX 20; Diameter: 9mm
Parax 40mg:	A white, round, divisible, quadrisect tablet encoded PX 40; Diameter: 11mm

PRESENTATION
White opaque polyethylene (PE-HD) containers and closures (tamper evident) containing 30tablets OR
White opaque PVC/aluminium blister packs containing 30tablets per carton

STORAGE INSTRUCTIONS
Polyethylene containers:
Store in tightly closed containers, below 25°C. Protect from light.
Blister packs:
Store below 25°C. Do not remove the blisters from the outer carton until required for use.
Protect from light.
KEEP OUT OF THE REACH OF CHILDREN.

REGISTRATION NUMBERS
Parax 20: 36/1.2/0158
Parax 40: 36/1.2/0159

NAME AND BUSINESS ADDRESS APPLICANT
HEXAL Pharma (SA) (Pty) LTD
46 Mahogany Road
Mahogany Ridge
Pinetown
3610

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
June 2005

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