Triptafen Tablets

1. Name Of The Medicinal Product

Triptafen Tablets

2. Qualitative And Quantitative Composition

Each pink sugar coated tablet contains 25mg amitriptyline hydrochloride BP and 2mg perphenazine BP.

100 tablets are supplied in cartons, with 10 foil strips of 10 tablets.

3. Pharmaceutical Form

Tablets

4.1 Therapeutic Indications

Triptafen tablets are indicated for the treatment of depression associated with anxiety.

4.2 Posology And Method Of Administration

Dosage: Adults and Elderly

One tablet three times a day. An additional tablet may be taken at night if necessary.

Failure to obtain a response within 4 weeks indicates that the treatment should be reviewed.

Treatment with Triptafen should not continue beyond three months.

Children

Triptafen tablets are not suitable for use in children under 18 years of age.

Method of Administration: Oral

4.3 Contraindications

Triptafen tablets should not be used in those who are hypersensitive to any of the ingredients of the tablets, in patients with glaucoma, porphyria, urinary retention, congestive heart failure, arrhythmias, coronary artery disease, recent myocardial infarction, heart block, epilepsy, severely impaired liver function, mania; concurrent administration of other antidepressant drugs especially monoamine oxidase inhibitors (MAOI'S). Triptafen should not be used for patients with leucopenia, or with drugs liable to cause bone marrow depression.

4.4 Special Warnings And Precautions For Use

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Exacerbation of schizophrenia or pre-existing agitation mania may occur. Patients with severe depression should be kept under close surveillance, particularly during the early stages of treatment.

Patients receiving this agent should be kept under regular surveillance with particular attention to effects on cerebral function, haemopoietic function, cardiac conduction disorders, liver function and the eye particularly if other concurrently administered drugs also have potential effects on these systems.

If patients on tricyclic anti-depressants require surgery, the anaesthetist should be informed of medications in advance in view of the risk of cardiovascular complication.

Hyponatraemia (usually in the elderly and possibly due to inappropriate secretion of antidiuretic hormone) has been associated with all types of antidepressants and should be considered in all patients who develop drowsiness, confusion or convulsions while taking an antidepressant. (See section 4.8 Undesirable Effects).

Persistent oral dyskinesia has been reported occasionally, particularly in elderly female patients, after long term treatment with potent phenothiazine drugs including perphenazine. Consequently Triptafen should be prescribed with regular patient reassessments

The drug should only be used with great caution in the young and the elderly who are likely to show behavioural effects or postural hypotension and in patients with a history of epilepsy or recent convulsions, schizophrenia, hepatic insufficiency, urinary retention, narrow-angle glaucoma, hyperthyroidism, or cardiovascular disorders, or in conjunction with electroconvulsive therapy, or with existent blood dyscrasias.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factor for VTE, all possible risk factors for VTE should be identified before and during treatment with Triptafen Tablets and preventive measures undertaken.

Increased Mortality in Elderly people with Dementia

Data from two large observational studies showed that elderly people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.

Triptafen Tablets is not licensed for the treatment of dementia-related behavioural disturbances.

Excipient Warnings:

Butyl hydroxybenzoate is contained in this product which may cause allergic reactions (possibly delayed).

Triptafen Tablets contain lactose and sucrose. Patients with rare hereditary problem of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

MAO inhibitors: Triptafen should not be given concurrently with monoamine oxidase inhibitors (MAOIs). Because of the persistent action of MAOIs, at least 14 days must have elapsed after withdrawal of MAOI treatment before Triptafen therapy is started.

CNS depressants: Concomitant administration of this product with other medications such as central nervous system depressants (including alcohol and anaesthetics), may result in accentuation of their effects, while potentiation of action may occur with analgesics.

Anticholinergic agents: Excessive anticholinergic effects may occur when tricyclic antidepressants are combined with anticholinergic drugs. Paralytic ileus, urinary retention or acute glaucoma may be precipitated, especially in elderly patients. (see section 4.8)

Sympathomimetic agents: Adrenaline (epinephrine), Noradrenaline (norepinephrine), isoprenaline and phenylephrine: increased risk of hypertension and arrhythmias when given with tricyclics

Antihypertensive: In general, the hypotensive effect of antihypertensives is enhanced by tricyclic antidepressants, but amitriptyline may block the antihypertensive action of guanethidine, and clonidine. Sudden withdrawal of amitriptyline from a patient stabilized on a postganglionic blocking agent may cause serious hypotension. All antihypertensive therapy should be reviewed following withdrawal of a tricyclic antidepressant as well as during treatment.

Anaesthetics, General: increased risk of arrhythmias and hypotension when tricyclics given with general anaesthetics

Anxiolytics & hypnotics: increased sedative effect when tricyclics given with anxiolytics and hypnotics.

Antiarrhythmics (amiodarone, disopyramide, flecainide, procainamide, propafenone, quinidine, sotalol): increased risk of ventricular arrhythmias when tricyclics given concomitantly

Antidepressants: plasma concentration of some tricyclics increased by SSRIsAntiepileptics (barbiturates, carbamazepine, phenytoin, primidone): tricyclics antagonise anticonvulsant effect of antiepileptics (convulsive threshold lowered), also metabolism of tricyclics possibly accelerated (reduced plasma concentration).

Antihistamines: increased antimuscarinic and sedative effects when tricyclics given with antihistamines

Antipsychotics: plasma concentration of tricyclics increased by antipsychotics , possibly increased risk of ventricular arrhythmias

Cimetidine: metabolism of amitriptyline inhibited by cimetidine (increased plasma concentration).

Coumarins: tricyclics may enhance or reduce anticoagulant effect of coumarins

Diltiazem, Verapamil: plasma concentration of tricyclics possibly increased

Disulfiram: concomitant amitriptyline reported to increase disulfiram reaction with alcohol. Delirium has been reported in patients taking Triptafen with disulfiram.

Diuretics: increased risk of postural hypotension when tricyclics given with diuretics

Duloxetine: possible increased serotonergic effects when amitriptyline given with duloxetine

Lithium: risk of toxicity when tricyclics given with lithium

Moxifloxacin: increased risk of ventricular arrhythmias when tricyclics given with moxifloxacin —avoid concomitant use

Nitrates: tricyclics reduce effects of sublingual tablets of nitrates (failure to dissolve under tongue owing to dry mouth)

Pimozide: increased risk of ventricular arrhythmias when tricyclics given with pimozide —avoid concomitant use

Rifampicin: plasma concentration of tricyclics possibly reduced by rifampicin

Ritonavir: Based on the known metabolism of amitriptyline, the protease inhibitor, ritonavir may increase the serum levels of amitriptyline. Therefore careful monitoring of therapeutic and adverse effects is recommended when these drugs are administered concomitantly.

St. John's Wort: plasma concentration of amitriptyline reduced by St John's wort

Selegeline: CNS toxicity reported when tricyclics given with selegiline

Sibutramine: increased risk of CNS toxicity when tricyclics given with sibutramine (manufacturer of sibutramine advises avoid concomitant use)

Thioridazine: increased risk of ventricular arrhythmias when tricyclics given with thioridazine —avoid concomitant use

Thyroid Hormones: effects of amitriptyline enhanced by thyroid hormones Patients should be closely supervised, and the dosage of all medications carefully adjusted when these drugs are administered concomitantly.

Tramadol: increased risk of CNS toxicity when tricyclics given with tramadol.

4.6 Pregnancy And Lactation

Pregnancy;

Unless there are compelling reasons, Triptafen should not be used during pregnancy, particularly during the first and last trimesters, because there is inadequate evidence of its safety during human pregnancy. Although it has been used without apparent ill-effects during pregnancy, there is animal data which indicates harmful effects occur when given at exceptionally high doses.

Lactation:

Breast feeding mothers: Triptafen is detectable in breast milk. Because of the potential for serious adverse reactions in infants from Triptafen, a decision should be made whether to discontinue breast feeding or discontinue the drug.

4.7 Effects On Ability To Drive And Use Machines

Triptafen may cause drowsiness, blurred vision or affect concentration. Patients receiving this medication should not drive or operate machinery unless it has been shown not to interfere with physical or mental capacity.

4.8 Undesirable Effects

Amitriptyline

Cases of suicidal ideation and suicidal behaviours have been reported during Triptafen therapy or early after treatment discontinuation (see section 4.4).

Abrupt withdrawal after prolonged administration has caused nausea, headache and malaise. Reports have associated gradual withdrawal with transient symptoms including irritability, restlessness, as well as dream and sleep disturbances during the first two weeks or dosage reduction.

Frequencies of the ADRs is not known (cannot be estimated from the available data).

System Organ Class	Adverse Reactions
Blood and Lymphatic system disorders	bone marrow depression including agranulocytosis, leucopenia, eosinophilia, purpura, thrombocytopenia
Immune system disorders	skin rash, urticaria, photosensitisation, oedema of face and tongue
Endocrine disorders	testicular swelling, gynaecomastia, breast enlargement, galactorrhoea, increased or decreased libido, impotence, interference with sexual function, elevation or lowering of blood sugar levels, syndrome of inappropriate ADH (antidiuretic hormone) secretion
Psychiatric disorders	confusional states, disturbed concentration, disorientation, delusions, hallucinations, hypomania, excitement, anxiety, restlessness, insomnia, nightmares
Nervous system disorders	peripheral neuropathy, numbness, tingling and paraesthesiae of the extremities, inco-ordination, ataxia, tremors, coma, convulsions, alteration of the EEG, extrapyramidal symptoms including abnormal involuntary movements and tardive dyskinesia, dysarthria and tinnitus. Anticholinergic: dry mouth, blurred vision, disturbance of accommodation, increased intra-ocular pressure, constipation, paralytic ileus, hyperpyrexia, urinary retention, urinary tract dilatation
Cardiovascular disorders	stroke, myocardial infarction, heart block, syncope, postural hypotension, hypertension, palpitations, tachycardia, non-specific ECG changes and changes in AV-conduction. Arrhythmias and severe hypotension are likely to occur with high dosage or overdose
Gastro-intestinal disorders	nausea, epigastric distress, vomiting, anorexia, stomatitis, unpleasant taste, diarrhoea, parotid swelling, black tongue
Hepatobiliary disorders	rarely hepatitis (including altered liver function and jaundice).
Skin and subcutaneous tissue disorders	Increased perspiration and alopecia
Renal and urinary disorders	Urinary frequency
General Disorders	dizziness, headache, weakness, fatigue, weight loss, mydriasis, drowsiness, increased appetite and weight gain (may be a drug reaction or due to relief of the depression)

Class effects

Mania or hypomania has been reported rarely within 2-7 days of stopping chronic therapy with tricyclic antidepressants.

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

Paediatric population

Adverse reactions such as withdrawal symptoms, respiratory depression and agitation have been reported in neonates whose mothers had taken tricyclic antidepressants in the last trimester of pregnancy.

Perphenazine

Frequencies of the ADRs is not known (cannot be estimated from the available data).

System Organ Class	Adverse Reactions
Blood and Lymphatic system disorders	Agranulocytosis; Transient leucopenia
Immune system disorders	Antinuclear antibodies; Systemic lupus erythematous (SLE)
Endocrine disorders	Hyperprolactemia
Psychiatric disorders	Confusional state, Agitation; Excitement; Insomnia.
Nervous system disorders	Choreiform movements of the extremities; Dyskinesias and movement disorders including akathisia, orofacial dyskinesia, extrapyramidal disorder and tardive dyskinesias; Dystonia; Hyperreflexia; Disturbances in consciousness including somnolence, stupor; Dizziness. Parkinsonism; Tremors; Epileptic fits; CSF protein abnormalities; Impaired regulation of body temperature. Neuroleptic malignant syndrome has been reported in patients treated with neuroleptic drugs. It is a relatively uncommon, potentially lethal syndrome, characterized by severe extrapyramidal dysfunction, with rigidity and eventual stupor or coma, hyperthermia and autonomic disturbances, including cardiovascular effects.
Eye Disorders	Oculogyric crisis; Visual disorders including blurring of vision, Corneal and lens deposits; Pigmented retinopathy
Cardiovascular disorders	Sudden unexplained death, cardiac arrest and Torsades de pointes , QT prolongation, Ventricular arrhythmias VF ,VT, Tachycardia, hypotension
Respiratory, thoracic and mediastinal disorders	Nasal stuffiness
Gastro-intestinal disorders	Nausea; Oral dryness and saliva altered, Gastrointestinal atonic and hypomotility disorders including constipation, paralytic ileus
Hepatobiliary disorders	Cholestasis and jaundice, Obstructive jaundice
Skin and subcutaneous tissue disorders	Photosensitivity; Rashes; Hyperhidrosis
Renal and urinary disorders	Urinary hesitancy or urinary retention
Reproductive system and breast disorders	Menstruation with decreased bleeding Amenorrhea; Erectile dysfunction; impaired ejaculation. Gynaecomastia ; Galactorrhoea.
General Disorders	Fatigue; Oedema, weight gain, Headaches
Investigations	Hyperglycemia, false positive pregnancy tests; Raised serum cholesterol

Class effects

With the piperazine group (of which perphenazine is an example), the extrapyramidal symptoms like Opisthotonus, trismus, torticollis, retrocollis, aching and numbness of the limbs, motor restlessness, oculogyric crisis, hyperreflexia, dystonia, including protrusion, slurred speech, dysphagia, akathisia, dyskinesia, parkinsonism and ataxia are more common, and others (e.g., sedation, jaundice, blood dyscrasias) are less frequent.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs- Frequency unknown

4.9 Overdose

Amitriptyline:

Ingestion of 750 mg or more by an adult may result in severe toxicity. The effects in overdose will be potentiated by simultaneous ingestion of alcohol and other psychotropic drugs.

Overdose effects are mainly due to anticholinergic (atropine-like) effects at autonomic nerve endings and in the brain. There is also a quinidine-like effect on the myocardium.

Peripheral symptoms

Commonly include sinus tachycardia, hot dry skin, dry mouth and tongue, dilated pupils and urinary retention.

The most important ECG feature of toxicity is prolongation of the QRS interval, which indicates a high risk of ventricular tachycardia. In very severe poisoning the ECG may be bizarre. Rarely, prolongation of the PR interval or heart block may occur. QT interval prolongation and torsade de pointes has also been reported.

Central symptoms

Commonly include ataxia, nystagmus and drowsiness, which may lead to deep coma and respiratory depression. Increased tone and hyperreflexia may be present with extensor plantar reflexes. In deep coma all reflexes may be abolished. A divergent squint may be present.

Hypotension and hypothermia may occur. Fits occur in >5% of cases.

During recovery confusion, agitation and visual hallucinations may occur.

Management

An ECG should be taken and in particular the QRS interval should be assessed since prolongation signifies an increased risk of arrhythmia and convulsions. Give activated charcoal by mouth or naso-gastric tube if more than 4 mg/kg has been ingested within one hour, provided the airway can be protected. A second dose of charcoal should be considered after two hours in patients with central features of toxicity who are able to swallow.

Tachyarrhythmias are best treated by correction of hypoxia and acidosis. Even in the absence of acidosis 50 millimoles of sodium bicarbonate should be given by intravenous infusion to adults with arrhythmias or clinically significant QRS prolongation on the ECG.

Control convulsions with intravenous diazepam or lorazepam. Give oxygen and correct acid base and metabolic disturbances. Phenytoin is contraindicated in tricyclic overdosage, because, like tricyclic antidepressants, it blocks sodium channels and may increase the risk of cardiac arrhythmias. Glucagon has been used to correct myocardial depression and hypotension.

Perphenazine:

Emergency treatment should be started immediately. Patients should be hospitalised as soon as possible. Concurrent ingestion of alcohol or other drugs or some medical explanation for the patient's condition should be considered.

Symptoms:

Perphenazine overdosage primarily involves the extrapyramidal system. Overdosage symptomatology is generally an extension of the many pharmacologic effects of perphenazine.

CNS depression progressing from drowsiness to stupor or coma with areflexia may occur. Patients with early or mild intoxication may experience restlessness, confusion and excitement. Other symptoms include hypotension, tachycardia, hypothermia, miosis, tremor, muscle twitching, spasm, rigidity or hypotonia, convulsions, difficulty in swallowing and breathing, cyanosis and respiratory and/or vasomotor collapse, possibly with sudden apnea.

Treatment:

Treatment is symptomatic and supportive. There is no specific antidote. The patient should be induced to vomit even if emesis has occurred spontaneously. Pharmacologic vomiting by the administration of ipecac syrup is a preferred method. It should be noted that ipecac has central mode of action in addition to its local gastric irritant properties, and the central mode of action may be blocked by the antiemetic effect of perphenazine products. Vomiting should not be induced in patients with impaired consciousness. The action of ipecac is facilitated by physical activity and by the administration of 240 to 350 ml of water. If emesis does not occur within 15 minutes, the dose of ipecac should be repeated. Precautions against aspiration must be taken, especially in infants and children. Following emesis any drug remaining in the stomach may be adsorbed by activated charcoal administered as a slurry with water. If vomiting is unsuccessful or contraindicated, gastric lavage should be performed. Isotonic and one-half isotonic saline are the lavage solutions of choice. Saline cathartics, such as milk of magnesia, draw water into the bowel by osmosis and therefore may be valuable for their action in rapid dilution of bowel content.

Standard measures (oxygen, i.v. fluids, corticosteroids) should be used to manage circulatory shock or metabolic acidosis. An open airway and adequate fluid intake should be maintained. Body temperature should be regulated. Hypothermia is expected, but severe hyperthermia may occur and must be treated vigorously.

An ECG should be taken and close monitoring of cardiac function instituted for not less than 5 days. Cardiac arrhythmias may be treated with neostigmine, pyridostigmine or propranolol. Digitalis should be considered for cardiac failure.

Vasopressors, such as norepinephrine or phenylephrine, may be used to treat hypotension, but epinephrine should not be used.

Anticonvulsant agents, such as an inhalation anesthetic, diazepam or paraldehyde, are recommended for control of seizures, but not barbiturates, since perphenazine increases the CNS depressant action but not the anticonvulsant action of barbiturates. Since phenothiazines lower the convulsive threshold, convulsant stimulants such as picrotoxin or pentylenetetrazol should not be given.

If acute parkinson-like symptoms result from perphenazine intoxication, benztropine mesylate, trihexyphenidyl or diphenhydramine may be administered.

Arousal may not occur for 48 hours following toxic overdose, despite supportive and contra-active measures. Dialysis is of no value in treatment.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Triptafen contains amitriptyline hydrochloride which is a tricyclic antidepressant, and which does not inhibit monoamine oxidase. The action of amitriptyline hydrochloride is believed to be related to its ability to block the re¬uptake of released monoamines into the pre-synaptic nerve endings. It has anticholinergic effects and sedative properties.

The perphenazine in Triptafen is a depressant which blocks dopamine receptors in the central nervous system.

5.2 Pharmacokinetic Properties

Triptafen is readily absorbed from the gastro-intestinal tract. Both amitriptyline hydrochloride and perphenazine are rapidly taken up by the tissues and widely distributed throughout the body. Amitriptyline hydrochloride may be secreted in breast milk: perphenazine readily crosses the placenta.

Amitriptyline hydrochloride is metabolised by demethylation, hydroxylation, conjugation with glucuronic acid with some N-oxide formation. The metabolites include nortriptyline, and didesmethylamitriptyline, their conjugates and their 10-hydroxy derivatives, and amitriptyline N-oxide.

Perphenazine is metabolised by sulphoxidation, demethylation, hydroxylation, N-oxidation, glucuronic acid conjugation, and possibly ring fission.

About 90% of an intravenous dose of amitriptyline hydrochloride is excreted in the urine, of which 1 to 5% is excreted unchanged. About 8% is excreted in the faeces.

Perphenazine is extensively metabolised by Sulphoxidation, Demethylation, Hydroxylation, N-Oxidation, Glucuronic Acid Conjugation and possibly Ring Fusion.

20% to 70% of perphenazine is excreted in the urine, very little is unchanged. 5% is excreted in the faeces.

5.3 Preclinical Safety Data

No further relevant data

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet Core

Lactose B.P.

Magnesium Stearate B.P.

Maize Starch Special B.P.

Maize starch pregelatinised B.P.

Tablet Coat

Acacia (E414) B.P.

Gelatin B.P.

Butyl hydroxybenzoate B.P.

Calcium phosphate B.P.

Calcium sulphate dihydrate 516

Maize starch B.P.

Tartrazine Ariavit 311840 (E120)

Erytbrosine Ariavit 311807 (E127)

Opaglos aqueous(Purified water EP, Beeswax White BP,Carnauba wax yellow BP,

Polysorbate 20 BP and Sorbic acid.)

Sugar

Mineral water

Opacode black( Shellac glaze, Iron oxide black (E172),N-Butyl alcohol,Purified water, Propylene glycol (E1520),Industrial Methylated Spirit and Isopropyl Alcohol)

6.2 Incompatibilities

None stated.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

No special conditions

6.5 Nature And Contents Of Container

Cardboard carton containing 10 strips of 10 tablets of Triptafen packed in aluminium foil.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Goldshield Pharmaceuticals Limited

NLA Tower

12-16 Addiscombe Road

Croydon

Surry

CR0 0XT

UK

8. Marketing Authorisation Number(S)

PL 12762/0201

9. Date Of First Authorisation/Renewal Of The Authorisation

25.01.1994

10. Date Of Revision Of The Text

19/07/2011

Topiramate 25, 50, 100 and 200 mg film-coated Tablets

1. Name Of The Medicinal Product

Topiramate 25, 50, 100 and 200 mg film-coated Tablets

2. Qualitative And Quantitative Composition

Topiramate 25 mg film-coated Tablets

Each film-coated tablets contains 25 mg of topiramate.

Excipient: 17.8 mg lactose /film-coated tablet.

Topiramate 50 mg film-coated Tablets

Each film-coated tablet contains 50 mg of topiramate.

Excipient: 35.6 mg lactose /film-coated tablet.

Topiramate 100 mg film-coated Tablets

Each film-coated tablet contains 100 mg of topiramate.

Excipient: 71.1 mg lactose /film-coated tablet.

Topiramate 200 mg film-coated Tablets

Each film-coated tablet contains 200 mg of topiramate.

Excipient: 142.2 mg lactose /film-coated tablet.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

Topiramate 25 mg film-coated tablet: White, round shaped, film-coated tablet, plain on both sides.

Topiramate 50 mg film-coated tablet: Yellow, round shaped, film-coated tablet, plain on both sides.

Topiramate 100 mg film-coated tablet: White, round shaped, film-coated tablet, plain on both sides.

Topiramate 200 mg film-coated tablet: Yellow, round shaped, film-coated tablet, plain on both sides.

4. Clinical Particulars

4.1 Therapeutic Indications

Monotherapy in adults, adolescents and children over 6 years of age with partial seizures with or without secondary generalised seizures, and primary generalised tonic-clonic seizures.

Adjunctive therapy in children aged 2 years and above, adolescents and adults with partial onset seizures with or without secondary generalization or primary generalized tonic-clonic seizures and for the treatment of seizures associated with Lennox-Gastaut syndrome

Topiramate is indicated in adults for the prophylaxis of migraine headache after careful evaluation of possible alternative treatment options. Topiramate is not intended for acute treatment.

4.2 Posology And Method Of Administration

General

It is recommended that therapy be initiated at a low dose followed by titration to an effective dose. Dose and titration rate should be guided by clinical response.

Topiramate is available in film-coated tablets and a hard capsule formulation. It is recommended that film-coated tablets not be broken.The hard capsule formulation is provided for those patients who cannot swallow tablets, e.g. paediatric and the elderly.

It is not necessary to monitor topiramate plasma concentrations to optimize therapy with Topiramate. On rare occasions, the addition of topiramate to phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and carbamazepine to adjunctive therapy with topiramate may require adjustment of the dose of Topiramate.

Topiramate can be taken without regard to meals.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs including topiramate should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50-100 mg in adults with epilepsy and by 25-50 mg in adults receiving topiramate at doses up to 100 mg/day for migraine prophylaxis. In paediatric clinical trials, topiramate was gradually withdrawn over a 2-8 week period.

Monotherapy epilepsy

General

When concomitant antiepileptic drugs (AEDs) are withdrawn to achieve monotherapy with topiramate, consideration should be given to the effects this may have on seizure control. Unless safety concerns require an abrupt withdrawal of the concomitant AED, a gradual discontinuation at the rate of approximately one-third of the concomitant AED dose every 2 weeks is recommended.

When enzyme inducing medicinal products are withdrawn, topiramate levels will increase. A decrease in Topiramate dosage may be required if clinically indicated.

Adults

Dose and titration should be guided by clinical response. Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased at 1- or 2-week intervals by increments of 25 or 50 mg/day, administered in two divided doses. If the patient is unable to tolerate the titration regimen, smaller increments or longer intervals between increments can be used.

The recommended initial target dose for topiramate monotherapy in adults is 100 mg/day to 200 mg/day in 2 divided doses. The maximum recommended daily dose is 500 mg/day in 2 divided doses. Some patients with refractory forms of epilepsy have tolerated topiramate monotherapy at doses of 1,000 mg/day. These dosing recommendations apply to all adults including the elderly in the absence of underlying renal disease.

Paediatric population (children over 6 years of age)

Dose and titration rate in children should be guided by clinical outcome. Treatment of children over 6 years of age should begin at 0.5 to 1 mg/kg nightly for the first week. The dosage should then be increased at 1 or 2 week intervals by increments of 0.5 to 1 mg/kg/day, administered in two divided doses. If the child is unable to tolerate the titration regimen, smaller increments or longer intervals between dose increments can be used.

The recommended initial target dose range for topiramate monotherapy in children over 6 years of age is 100 mg/day depending on clinical response, (this is about 2.0mg/kg/day in children 6-16 years).

Adjunctive therapy epilepsy (partial onset seizures with or without secondary generalization, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome)

Adults

Therapy should begin at 25-50 mg nightly for one week. Use of lower initial doses has been reported, but has not been studied systematically. Subsequently, at weekly or bi-weekly intervals, the dose should be increased by 25-50 mg/day and taken in two divided doses. Some patients may achieve efficacy with once-a-day dosing.

In clinical trials as adjunctive therapy, 200 mg was the lowest effective dose. The usual daily dose is 200-400 mg in two divided doses.

These dosing recommendations apply to all adults, including the elderly, in the absence of underlying renal disease (see section 4.4).

Paediatric population (children aged 2 years and above)

The recommended total daily dose of Topiramate (topiramate) as adjunctive therapy is approximately 5 to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical response.

Daily doses up to 30 mg/kg/day have been studied and were generally well tolerated.

Migraine

Adults

The recommended total daily dose of topiramate for prophylaxis of migraine headache is 100 mg/day administered in two divided doses. Titration should begin at 25 mg nightly for 1 week. The dosage should then be increased in increments of 25 mg/day administered at 1-week intervals. If the patient is unable to tolerate the titration regimen, longer intervals between dose adjustments can be used.

Some patients may experience a benefit at a total daily dose of 50 mg/day. . Patients have received a total daily dose up to 200 mg/day. This dose may be benefit in some patients, nevertheless, caution is advised due to an increase incidence of side effects.

Paediatric population

Topiramate (topiramate) is not recommended for treatment or prevention of migraine in children due to insufficient data on safety and efficacy.

General dosing recommendations for Topiramate in special patient populations

Renal impairment

In patients with impaired renal function (CLCR

In patients with end-stage renal failure, since topiramate is removed from plasma by haemodialysis, a supplemental dose of Topiramate equal to approximately one-half the daily dose should be administered on haemodialysis days. The supplemental dose should be administered in divided doses at the beginning and completion of the haemodialysis procedure. The supplemental dose may differ based on the characteristics of the dialysis equipment being used.

Hepatic impairment

In patients with moderate to severe hepatic impairment topiramate should be administered with caution as the clearance of topiramate is decreased.

Elderly

No dose adjustment is required in the elderly population providing renal function is intact.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Migraine prophylaxis in pregnancy and in women of childbearing potential if not using effective methods of contraception.

4.4 Special Warnings And Precautions For Use

In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended (see section 4.2 for further details).

As with other anti-epileptic drugs, some patients may experience an increase in seizure frequency or the onset of new types of seizures with topiramate. These phenomena may be the consequence of an overdose, a decrease in plasma concentrations of concomitantly used anti-epileptics, progress of the disease, or a paradoxical effect.

Adequate hydration while using topiramate is very important. Hydration can reduce the risk of nephrolithiasis (see below). Proper hydration prior to and during activities such as exercise or exposure to warm temperatures may reduce the risk of heat-related adverse reactions (see section 4.8).

Mood disturbances/depression

An increased incidence of mood disturbances and depression has been observed during topiramate treatment.

Suicide/suicide ideation

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic drugs has shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for topiramate.

In double blind clinical trials, suicide related events (SREs) (suicidal ideation, suicide attempts and suicide) occurred at a frequency of 0.5% in topiramate treated patients (46 out of 8,652 patients treated) and at a nearly 3 fold higher incidence than those treated with placebo (0.2%; 8 out of 4,045 patients treated).

Patients therefore should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Nephrolithiasis

Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain.

Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during topiramate treatment. In addition, patients taking other medicinal products associated with nephrolithiasis may be at increased risk.

Decreased hepatic function

In hepatically-impaired patients, topiramate should be administered with caution as the clearance of topiramate may be decreased.

Acute myopia and secondary angle closure glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular hyperaemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in paediatric patients as well as adults. Treatment includes discontinuation of topiramate, as rapidly as possible in the judgment of the treating physician, and appropriate measures to reduce intraocular pressure. These measures generally result in a decrease in intraocular pressure.

Elevated intraocular pressure of any aetiology, if left untreated, can lead to serious sequelae including permanent vision loss.

A determination should be made whether patients with history of eye disorders should be treated with topiramate.

Metabolic acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with topiramate treatment. This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in treatment although it can occur at any time during treatment. These decreases are usually mild to moderate (average decrease of 4 mmol/l at doses of 100 mg/day or above in adults and at approximately 6 mg/kg/day in paediatric patients). Rarely, patients have experienced decreases to values below 10 mmol/l. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or certain medicinal products) may be additive to the bicarbonate lowering effects of topiramate.

Chronic metabolic acidosis increases the risk of renal stone formation and may potentially lead to osteopenia.

Chronic metabolic acidosis in paediatric patients can reduce growth rates. The effect of topiramate on bone-related sequelae has not been systematically investigated in paediatric or adult populations.

Depending on underlying conditions, appropriate evaluation including serum bicarbonate levels is recommended with topiramate therapy. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering).

Topiramate should be used with caution in patients with conditions or treatments that represent a risk factor for the appearance of metabolic acidosis.

Nutritional supplementation

Some patients may experience weight loss whilst on treatment with topiramate. It is recommended that patients on topiramate treatment should be monitored for weight loss. A dietary supplement or increased food intake may be considered if the patient is losing weight while on topiramate.

Topiramat Sandoz contains sucrose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects of topiramate on other antiepileptic medicinal products

The addition of topiramate to other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) has no effect on their steady-state plasma concentrations, except in the occasional patient, where the addition of topiramate to phenytoin may result in an increase of plasma concentrations of phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C19). Consequently, any patient on phenytoin showing clinical signs or symptoms of toxicity should have phenytoin levels monitored.

A pharmacokinetic interaction study of patients with epilepsy indicated the addition of topiramate to lamotrigine had no effect on steady state plasma concentration of lamotrigine at topiramate doses of 100 to 400 mg/day. In addition, there was no change in steady state plasma concentration of topiramate during or after removal of lamotrigine treatment (mean dose of 327 mg/day).

Topiramate inhibits the enzyme CYP 2C19 and may interfere with other substances metabolized via this enzyme (e.g., diazepam, imipramin, moclobemide, proguanil, omeprazol).

Effects of other antiepileptic medicinal products on topiramate

Phenytoin and carbamazepine decrease the plasma concentration of topimarate. The addition or withdrawal of phenytoin or carbamazepine to topiramate therapy may require an adjustment in dosage of the latter. This should be done by titrating to clinical effect. The addition or withdrawal of valproic acid does not produce clinically significant changes in plasma concentrations of topiramate and, therefore, does not warrant dosage adjustment of Topiramate. The results of these interactions are summarized below:

AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	↔**
Carbamazepine (CBZ)	↔
Valproic acid	↔	↔
Lamotrigine	↔	↔
Phenobarbital	↔	NS
Primidone	↔	NS
↔ = No effect on plasma concentration ( ** = Plasma concentrations increase in individual patients NS = Not studied AED = antiepileptic drug

Other medicinal product interactions

Digoxin

In a single-dose study, serum digoxin area under plasma concentration curve (AUC) decreased 12% due to concomitant administration of Topiramate. The clinical relevance of this observation has not been established. When Topiramate is added or withdrawn in patients on digoxin therapy, careful attention should be given to the routine monitoring of serum digoxin.

CNS depressants

Concomitant administration of topiramate and alcohol or other CNS depressant medicinal products has not been evaluated in clinical studies. It is recommended that topiramate not be used concomitantly with alcohol or other CNS depressant medicinal products.

St John's Wort (Hypericum perforatum).

A risk of decreased plasma concentrations resulting in a loss of efficacy could be observed with co-administration of topiramate and St John's Wort. There have been no clinical studies evaluating this potential interaction.

Oral contraceptives

In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 μg ethinyl estradiol (EE), Topiramate given in the absence of other medications at doses of 50 to 200 mg/day was not associated with statistically significant changes in mean exposure (AUC) to either component of the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive therapy in epilepsy patients taking valproic acid. In both studies, topiramate (50-200 mg/day in healthy volunteers and 200-800 mg/day in epilepsy patients) did not significantly affect exposure to NET. Although there was a dose dependent decrease in EE exposure for doses between 200-800 mg/day (in epilepsy patients), there was no significant dose dependent change in EE exposure for doses of 50-200 mg/day (in healthy volunteers). The clinical significance of the changes observed is not known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking combination oral contraceptive products with topiramate. Patients taking estrogen containing contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding.

Lithium

In healthy volunteers, there was an observed reduction (18% for AUC) in systemic exposure for lithium during concomitant administration with topiramate 200 mg/day. In patients with bipolar disorder, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure (26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with topiramate.

Risperidone

Drug-drug interaction studies conducted under single dose conditions in healthy volunteers and multiple dose conditions in patients with bipolar disorder, yielded similar results. When administered concomitantly with topiramate at escalating doses of 100, 250 and 400 mg/day there was a reduction in risperidone (administered at doses ranging from 1 to 6 mg/day) systemic exposure (16% and 33% for steady-state AUC at the 250 and 400 mg/day doses, respectively). However, differences in AUC for the total active moiety between treatment with risperidone alone and combination treatment with topiramate were not statistically significant. Minimal alterations in the pharmacokinetics of the total active moiety (risperidone plus 9-hydroxyrisperidone) and no alterations for 9-hydroxyrisperidone were observed. There were no significant changes in the systemic exposure of the risperidone total active moiety or of topiramate. When topiramate was added to existing risperidone (1-6 mg/day) treatment, adverse events were reported more frequently than prior to topiramate (250-400 mg/day) introduction (90% and 54 % respectively). The most frequently reported AE's when topiramate was added to risperidone treatment were: somnolence (27% and 12%), paraesthesia (22% and 0%) and nausea (18% and 9% respectively).

Hydrochlorothiazide (HCTZ)

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of HCTZ (25 mg q24h) and topiramate (96 mg q12h) when administered alone and concomitantly. The results of this study indicate that topiramate Cmax increased by 27% and AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate were administered in combination.

Metformin

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of metformin and topiramate in plasma when metformin was given alone and when metformin and topiramate were given simultaneously. The results of this study indicated that metformin mean Cmax and mean AUC0-12h increased by 18% and 25%, respectively, while mean CL/F decreased 20% when metformin was co-administered with topiramate. Topiramate did not affect metformin tmax. The clinical significance of the effect of topiramate on metformin pharmacokinetics is unclear. Oral plasma clearance of topiramate appears to be reduced when administered with metformin. The extent of change in the clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unclear.

When Topiramate is added or withdrawn in patients on metformin therapy, careful attention should be given to the routine monitoring for adequate control of their diabetic disease state.

Pioglitazone

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15% decrease in the AUC_,ss of pioglitazone with no alteration in Cmax,ss was observed. This finding was not statistically significant. In addition, a 13% and 16% decrease in Cmax,ss and AUC_,ss respectively, of the active hydroxy-metabolite was noted as well as a 60% decrease in Cmax,ss and AUC_,ss of the active keto-metabolite. The clinical significance of these findings is not known. When Topiramate is added to pioglitazone therapy or pioglitazone is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Glyburide

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 25% reduction in glyburide AUC24 during topiramate administration. Systemic exposure of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis-hydroxyglyburide (M2), were also reduced by 13% and 15%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.

When topiramate is added to glyburide therapy or glyburide is added to topiramate therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

Other forms of interactions

Agents predisposing to nephrolithiasis

Topiramate, when used concomitantly with other agents predisposing to nephrolithiasis, may increase the risk of nephrolithiasis. While using topiramate, agents like these should be avoided since they may create a physiological environment that increases the risk of renal stone formation.

Valproic acid

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either medicinal product alone. In most cases, symptoms and signs abated with discontinuation of either medicinal product. This adverse reaction is not due to a pharmacokinetic interaction. An association of hyperammonemia with topiramate monotherapy or concomitant treatment with other anti-epileptics has not been established.

Additional pharmacokinetic drug interaction studies

Clinical studies have been conducted to assess the potential pharmacokinetic drug interaction between topiramate and other agents. The changes in Cmax or AUC as a result of the interactions are summarized below. The second column (concomitant drug concentration) describes what happens to the concentration of the concomitant drug listed in the first column when topiramate is added. The third column (topiramate concentration) describes how the coadministration of a drug listed in the first column modifies the concentration of topiramate.

Summary of Results from Additional Clinical Pharmacokinetic Drug Interaction Studies
Concomitant Drug	Concomitant Drug Concentrationa	Topiramate Concentrationa
Amitriptyline	↔ 20% increase in Cmax and AUC of nortriptyline metabolite	NS
Dihydroergotamine (Oral and Subcutaneous)	↔	↔
Haloperidol	↔ 31% increase in AUC of the reduced metabolite	NS
Propranolol	↔ 17% increase in Cmax for 4-OH propranolol (TPM 50 mg q12h)	9% and 16% increase in Cmax, 9% and17% increase in AUC (40 and 80 mg propranolol q12h respectively)
Sumatriptan (Oral and Subcutaneous)	↔	NS
Pizotifen	↔	↔
Diltiazem	25% decrease in AUC of diltiazem and 18% decrease in DEA, and ↔ for DEM*	20% increase in AUC
Venlafaxine	↔	↔
Flunarizine	16% increase in AUC (TPM 50 mg q12h)b	↔
a % values are the changes in treatment mean Cmaxor AUC with respect to monotherapy ↔ = No effect on Cmax and AUC ( NS = Not studied *DEA = des acetyl diltiazem, DEM = N-demethyl diltiazem b Flunarizine AUC increased 14% in subjects taking flunarizine alone. Increase in exposure may be attributed to accumulation during achievement of steady state.

4.6 Pregnancy And Lactation

Topiramate was teratogenic in mice, rats and rabbits. In rats, topiramate crosses the placental barrier.

There are no adequate and well-controlled studies with topiramate in pregnant women.

Pregnancy registry data suggest that there may be an association between the use of topiramate during pregnancy and congenital malformations (e.g., craniofacial defects, such as cleft lip/palate, hypospadias, and anomalies involving various body systems). This has been reported with topiramate monotherapy and topiramate as part of a polytherapy regimen. This data should be interpreted with caution, as more data is needed to identify increased risks for malformations.

In addition, data from these registries and other studies suggest that, compared with monotherapy, there may be an increased risk of teratogenic effects associated with the use of anti-epileptic drugs in combination therapy.

It is recommended that women of child bearing potential use adequate contraception.

Animal studies have shown excretion of topiramate in milk. The excretion of topiramate in human milk has not been evaluated in controlled studies. Limited observations in patients suggest an extensive excretion of topiramate into breast milk. Since many medicinal products are excreted into human milk, a decision must be made whether to suspend breast-feeding or to discontinue/ abstain from topiramate therapy taking into account the importance of the medicinal product to the mother (section 4.4).

Indication Epilepsy

During pregnancy, topiramate should be prescribed after fully informing the woman of the known risks of uncontrolled epilepsy to the pregnancy and the potential risks of the medicinal product to the foetus.

Indication Migraine Prophylaxis

Topiramate is contraindicated in pregnancy, and in women of childbearing potential if an effective method of contraception is not used (see section 4.3 and 4.5 Interactions with oral contraceptives).

4.7 Effects On Ability To Drive And Use Machines

Topiramate acts on the central nervous system and may produce drowsiness, dizziness or other related symptoms. It may also cause visual disturbances and/or blurred vision. These adverse reactions could potentially be dangerous in patients driving a vehicle or operating machinery, particularly until such time as the individual patient's experience with the medicinal products established.

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

The safety of topiramate was evaluated from a clinical trial database consisting of 4,111 patients (3,182 on topiramate and 929 on placebo) who participated in 20 double-blind trials and 2,847 patients who participated in 34 open-label trials, respectively, for topiramate as adjunctive treatment of primary generalized tonic-clonic seizures, partial onset seizures, seizures associated with Lennox-Gastaut syndrome, monotherapy for newly or recently diagnosed epilepsy or migraine prophylaxis. The majority of ADRs were mild to moderate in severity. ADRs identified in clinical trials, and during post-marketing experience (as indicated by “*”) are listed by their incidence in clinical trials in Table 1. Assigned frequencies are as follows:

Very common

Common

Uncommon

Rare

Not known cannot be estimated from the available data

The most common ADRs (those with an incidence of >5% and greater than that observed in placebo in at least 1 indication in double-blind controlled studies with topiramate) include: anorexia, decreased appetite, bradyphrenia, depression, expressive language disorder, insomnia, coordination abnormal, disturbance in attention, dizziness, dysarthria, dysgeusia, hypoesthesia, lethargy, memory impairment, nystagmus, paresthesia, somnolence, tremor, diplopia, vision blurred, diarrhoea, nausea, fatigue, irritability, and weight decreased.

Paediatric population

ADRs reported more frequently (

ADRs that were reported in children but not in adults in double-blind controlled studies include: eosinophilia, psychomotor hyperactivity, vertigo, vomiting, hyperthermia, pyrexia, and learning disability.

Table 1: Topiramate Adverse Drug Reactions

System Organ Class	Very common	Common	Uncommon	Rare	Not known
Investigations	Weight decreased	Weight increased*	Crystal urine present, tandem gait test abnormal, white blood cell count decreased	Blood bicarbonate decreased
Cardiac disorders			Bradycardia, sinus bradycardia, palpitations
Blood and lymphatic system disorders		Anaemia	Leucopenia, thrombocytopenia lymphadenopathy, eosinophilia	Neutropenia*
Nervous system disorders	Paraesthesia, somnolence Dizziness	Disturbance in attention, memory impairment, amnesia, cognitive disorder, mental impairment, psychomotor skills impaired, convulsion, coordination abnormal, tremor, lethargy, hypoaesthesia, nystagmus, dysgeusia, balance disorder, dysarthria, intention tremor, sedation ,	Depressed level of consciousness, grand mal convulsion, visual field defect, complex partial seizures, speech disorder, psychomotor hyperactivity, syncope, sensory disturbance, drooling, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, dizziness postural, poor quality sleep, burning sensation, sensory loss, parosmia, cerebellar syndrome, dysaesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, neuropathy peripheral, presyncope, dystonia, formication	Apraxia, circadian rhythm sleep disorder, hyperaesthesia, hyposmia, anosmia, essential tremor, akinesia, unresponsive to stimuli
Eye disorders		Vision blurred, diplopia, visual disturbance	Visual acuity reduced, scotoma, myopia*, abnormal sensation in eye*, dry eye, photophobia, blepharospasm, lacrimation increased, photopsia, mydriasis, presbyopia	Blindness unilateral, blindness transient, glaucoma, accommodation disorder, altered visual depth perception, scintillating scotoma, eyelid oedema*, night blindness, amblyopia	Angle closure glaucoma*, Maculopathy*, eye movement disorder*
Ear and labyrinth disorders		Vertigo, tinnitus, ear pain	Deafness, deafness unilateral, deafness neurosensory, ear discomfort, hearing impaired
Respiratory, thoracic and mediastinal disorders		Dyspnoea, epistaxis, nasal congestion, rhinorrhoea	Dyspnoea exertional, Paranasal sinus hypersecretion, dysphonia
Gastrointestinal disorders	Nausea, diarrhoea	Vomiting, constipation, abdominal pain upper, dyspepsia, abdominal pain, dry mouth, stomach discomfort, paraesthesia oral, gastritis, abdominal discomfort	Pancreatitis, flatulence, gastrooesophageal reflux disease, abdominal pain lower, hypoaesthesia oral, gingival bleeding, abdominal distension, epigastric discomfort, abdominal tenderness, salivary hypersecretion, oral pain, breath odour, glossodynia
Renal and urinary disorders		Nephrolithiasis, pollakisuria, dysuria	Calculus urinary, urinary incontinence, haematuria, incontinence, micturition urgency, renal colic, renal pain	Calculus ureteric, renal tubular acidosis*
Skin and subcutaneous tissue disorders		Alopecia, rash, pruritus	Anhidrosis, hypoaesthesia facial, urticaria, erythema, pruritus generalised, rash macular, skin discolouration, dermatitis allergic, swelling face	Stevens-Johnson syndrome* erythema multiforme*, skin odour abnormal, periorbital oedema*, urticaria localised	Toxic epidermal necrolysis*
Musculoskeletal and connective tissue disorders		Arthralgia, muscle spasms, myalgia, muscle twitching, muscular weakness, musculoskeletal chest pain	Joint swelling*, musculoskeletal stiffness, flank pain, muscle fatigue	Limb discomfort*
Metabolism and nutrition disorders		Anorexia, decreased appetite	Metabolic acidosis, Hypokalaemia, increased appetite, polydipsia	Acidosis hyperchloraemic
Infections and infestations	Nasopharyngitis*
Vascular disorders

Timoptol 0.25% and 0.5% w / v Eye Drops Solution

1. Name Of The Medicinal Product

TIMOPTOL® 0.25% w/v Eye Drops Solution

TIMOPTOL® 0.5% w/v Eye Drops Solution

2. Qualitative And Quantitative Composition

'Timoptol' 0.25% w/v Eye Drops Solution contains timolol maleate equivalent to 0.25% w/v solution of timolol with preservative.

'Timoptol' 0.5% w/v Eye Drops Solution contains timolol maleate equivalent to 0.5% w/v solution of timolol with preservative.

3. Pharmaceutical Form

Eye drops solution.

Clear, colourless to light yellow, sterile eye drops solution.

4. Clinical Particulars

4.1 Therapeutic Indications

'Timoptol' Eye Drops Solution is a beta-adrenoreceptor blocking agent used topically in the reduction of elevated intra-ocular pressure in various conditions including the following: patients with ocular hypertension; patients with chronic open-angle glaucoma including aphakic patients; some patients with secondary glaucoma.

4.2 Posology And Method Of Administration

Recommended therapy is one drop 0.25% solution in the affected eye twice a day.

If clinical response is not adequate, dosage may be changed to one drop 0.5% solution in each affected eye twice a day. If needed, 'Timoptol' may be used with other agent(s) for lowering intra-ocular pressure. The use of two topical beta-adrenergic blocking agents is not recommended (see 4.4 'Special warnings and precautions for use').

Intra-ocular pressure should be reassessed approximately four weeks after starting treatment because response to 'Timoptol' may take a few weeks to stabilise.

Provided that the intra-ocular pressure is maintained at satisfactory levels, many patients can than be placed on once-a-day therapy.

Transfer from other agents

When another topical beta-blocking agent is being used, discontinue its use after a full day of therapy and start treatment with 'Timoptol' the next day with one drop of 0.25% 'Timoptol' in each affected eye twice a day. The dosage may be increased to one drop of 0.5% solution in each affected eye twice a day, if the response is not adequate.

When transferring a patient from a single anti-glaucoma agent other than a topical beta-blocking agent, continue the agent and add one drop of 0.25% 'Timoptol' in each affected eye twice a day. On the following day, discontinue the previous agent completely, and continue with 'Timoptol'. If a higher dosage of 'Timoptol' is required, substitute one drop of 0.5% solution in each affected eye twice a day.

'Timoptol' Eye Drops Solution is also available as 'Timoptol' Unit dose: The Unit-dose Dispenser of 'Timoptol' is free from preservative and should be used for patients who may be sensitive to the preservative benzalkonium chloride, or when use of a preservative-free topical medication is advisable.

Paediatric use: is not currently recommended.

Use in the elderly: there has been wide experience with the use of timolol maleate in elderly patients. The dosage recommendations given above reflect the clinical data derived from this experience.

4.3 Contraindications

Bronchial asthma, history of bronchial asthma or severe chronic obstructive pulmonary disease; sinus bradycardia, second- and third-degree AV block, overt cardiac failure, cardiogenic shock; and hypersensitivity to this product or other beta-blocking agents.

4.4 Special Warnings And Precautions For Use

Like other topically applied ophthalmic drugs, 'Timoptol' may be absorbed systemically and adverse reactions seen with oral beta-blockers may occur.

Cardiac failure should be adequately controlled before beginning therapy with 'Timoptol'. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked.

Respiratory and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death associated with cardiac failure have been reported.

The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be exaggerated when 'Timoptol' is given to the patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended.

There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenoreceptor blocking drugs. The reported incidence is small and in most cases the symptoms have cleared when treatment was withdrawn. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. Cessation of therapy involving beta-blockade should be gradual.

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.

'Timoptol' has been generally well tolerated in glaucoma patients wearing conventional hard contact lenses. 'Timoptol' has not been studied in patients wearing lenses made with material other than polymethylmethacrylate (PMMA), which is used to make hard contact lenses.

The Ocumeter® Dispenser of 'Timoptol' contains benzalkonium chloride as a preservative which may be deposited in soft contact lenses; therefore 'Timoptol' should not be used while wearing these lenses. The lenses should be removed before application of the drops and not reinserted earlier than 15 minutes after use.

In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. 'Timoptol' has little or no effect on the pupil. When 'Timoptol' is used to reduce elevated intra-ocular pressure in angle-closure glaucoma it should be used with a miotic and not alone.

Patients should be advised that if they develop an intercurrent ocular condition (e.g. trauma, ocular surgery or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container (see 6.6 'Special precautions for disposal and other handling').

There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

Risk from anaphylactic reaction: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine (adrenaline) used to treat anaphylactic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Although 'Timoptol' alone has little or no effect on pupil size, mydriasis has occasionally been reported when 'Timoptol' is given with epinephrine (adrenaline).

Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g.quinidine, SSRIs) and timolol.

Oral β-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.

'Timoptol' may potentially add to the effects of oral calcium antagonists, rauwolfia alkaloids or beta-blockers, to induce hypotension and/or marked bradycardia.

Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Oral calcium antagonists may be used in combination with beta-adrenergic blocking agents when heart function is normal, but should be avoided in patients with impaired cardiac function.

The potential exists for hypotension, AV conduction disturbances and left ventricular failure to occur in patients receiving a beta-blocking agent when an oral calcium entry blocker is added to the treatment regimen. The nature of any cardiovascular adverse effect tends to depend on the type of calcium blocker used. Dihydropyridine derivatives, such as nifedipine, may lead to hypotension, whereas verapamil or diltiazem have a greater propensity to lead to AV conduction disturbances or left ventricular failure when used with a beta-blocker.

Intravenous calcium channel blockers should be used with caution in patients receiving beta-adrenergic blocking agents.

The concomitant use of beta-adrenergic blocking agents and digitalis with either diltiazem or verapamil may have additive effects in prolonging AV conduction time.

4.6 Pregnancy And Lactation

Use in pregnancy: 'Timoptol' has not been studied in human pregnancy. The use of 'Timoptol' requires that the anticipated benefit be weighed against possible hazards.

Breast-feeding mothers: Timolol is detectable in human milk. A decision for breast-feeding mothers, either to stop taking 'Timoptol' or stop nursing, should be based on the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

Possible side effects such as dizziness and visual disturbances may affect some patients' ability to drive or operate machinery.

4.8 Undesirable Effects

Side effects

'Timoptol' is usually well tolerated. The following adverse reactions have been reported with ocular administration of this or other timolol maleate formulations, either in clinical trials or since the drug has been marketed. Additional side effects have been reported in clinical experiences with systemic timolol maleate, and may be considered potential effects of ophthalmic timolol maleate:

Special senses:

ocular: signs and symptoms of ocular irritation, including burning and stinging, conjunctivitis, blepharitis, keratitis, dry eyes and decreased corneal sensitivity. Tinnitus, visual disturbances, including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis and choroidal detachment following filtration surgery (see 4.4 'Special warnings and precautions for use').

Cardiovascular:

ocular: bradycardia, arrhythmia, hypotension, syncope, heart block, cerebrovascular accident, cerebral ischaemia, congestive heart failure, palpitation, cardiac arrest, oedema, claudication, Raynaud's phenomenon, cold hands and feet.

systemic: AV block (second- or third-degree), sino-atrial block, pulmonary oedema, worsening of arterial insufficiency, worsening of angina pectoris, vasodilation.

Respiratory:

ocular: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnoea, cough.

systemic: rales

Body as a whole:

ocular: headache, asthenia, fatigue, chest pain.

systemic: extremity pain, decreased exercise tolerance.

Integumentary:

ocular: alopecia, psoriasiform rash or exacerbation of psoriasis.

systemic: pruritus, sweating, exfoliative dermatitis.

Hypersensitivity:

ocular: signs and symptoms of allergic reactions including anaphylaxis, angioedema, urticaria, localised and generalised rash.

Nervous system/psychiatric:

ocular: dizziness, depression, insomnia, nightmares, memory loss, increase in signs and symptoms of myasthenia gravis, paresthesia.

systemic: vertigo, local weakness, diminished concentration, increased dreaming.

Digestive:

ocular: nausea, diarrhoea, dyspepsia, dry mouth.

systemic: vomiting

Urogenital:

ocular: decreased libido, Peyronie's disease.

systemic: impotence, micturition difficulties.

Immunologic:

ocular: systemic lupus erythematosus

Endocrine:

systemic: hyperglycaemia, hypoglycaemia.

Musculoskeletal:

systemic: arthralgia.

Haematologic:

systemic: non-thrombocytopenic purpura.

4.9 Overdose

There have been reports of inadvertent overdosage with 'Timoptol' resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest (see 'Side effects').

If overdosage occurs, the following measures should be considered:

1. Gastric lavage, if ingested. Studies have shown that timolol does not dialyse readily.

2. Symptomatic bradycardia: atropine sulphate, 0.25 to 2 mg intravenously, should be used to induce vagal blockade. If bradycardia persists, intravenous isoprenaline hydrochloride should be administered cautiously. In refractory cases, the use of a cardiac pacemaker may be considered.

3. Hypotension: a sympathomimetic pressor agent such as dopamine, dobutamine or noradrenaline should be used. In refractory cases, the use of glucagon has been reported to be useful.

4. Bronchospasm: isoprenaline hydrochloride should be used. Additional therapy with aminophylline may be considered.

5. Acute cardiac failure: conventional therapy with digitalis, diuretics, and oxygen should be instituted immediately. In refractory cases, the use of intravenous aminophylline is suggested. This may be followed, if necessary, by glucagon, which has been reported useful.

6. Heart block (second- or third-degree): isoprenaline hydrochloride or a pacemaker should be used.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Timolol maleate is a non-selective beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic activity. Timolol maleate combines reversibly with the beta-adrenergic receptor, and this inhibits the usual biologic response that would occur with stimulation of that receptor. This specific competitive antagonism blocks stimulation of the beta-adrenergic stimulating (agonist) activity, whether these originate from an endogenous or exogenous source. Reversal of this blockade can be accomplished by increasing the concentration of the agonist which will restore the usual biological response.

Unlike miotics, 'Timoptol' reduces IOP with little or no effect on accommodation or pupil size. In patients with cataracts, the inability to see around lenticular opacities when the pupil is constricted is avoided. When changing patients from miotics to 'Timoptol' a refraction might be necessary when the effects of the miotic have passed.

Diminished response after prolonged therapy with 'Timoptol' has been reported in some patients.

5.2 Pharmacokinetic Properties

The onset of reduction in intra-ocular pressure can be detected within one-half hour after a single dose. The maximum effect occurs in one or two hours; significant lowering of IOP can be maintained for as long as 24 hours with a single dose.

5.3 Preclinical Safety Data

No adverse ocular effects were observed in rabbits and dogs administered 'Timoptol' topically in studies lasting one and two years, respectively. The oral LD₅₀ of the drug is 1,190 and 900 mg/kg in female mice and female rats, respectively.

Carcinogenesis, mutagenesis, impairment of fertility

In a two-year oral study of timolol maleate in rats there was a statistically significant (p

In a lifetime oral study in mice, there were statistically significant (p

The increased occurrence of mammary adenocarcinoma was associated with elevations in serum prolactin which occurred in female mice administered timolol at 500 mg/kg/day, but not at doses of 5 or 50 mg/kg/day. An increased incidence of mammary adenocarcinomas in rodents has been associated with administration of several other therapeutic agents which elevate serum prolactin, but no correlation between serum prolactin levels and mammary tumours has been established in man. Furthermore, in adult human female subjects who received oral dosages of up to 60 mg of timolol maleate, the maximum recommended human oral dosage, there were no clinically meaningful changes in serum prolactin.

Timolol maleate was devoid of mutagenic potential when evaluated in vivo (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 100 mcg/ml). In Ames tests the highest concentrations of timolol employed, 5,000 or 10,000 mcg/plate, were associated with statistically significant (p

Reproduction and fertility studies in rats showed no adverse effect on male or female fertility at doses up to 150 times the maximum recommended human oral dose.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Disodium phosphate dodecahydrate (may be replaced by equivalent amounts of the dihydrate or anhydrous )

Sodium dihydrogen phosphate dihydrate (may be replaced by equivalent amounts of monohydrate)

Sodium hydroxide

Benzalkonium chloride

Water for injections

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months

Discard 'Timoptol' Eye Drops Solution 28 days after opening the bottle.

6.4 Special Precautions For Storage

Do not store above 25°C. Store the bottle in the outer carton.

6.5 Nature And Contents Of Container

The OCUMETER Plus ophthalmic dispenser consists of a translucent high-density polyethylene container with a sealed dropper tip, a flexible fluted side area, which is depressed to dispense the drops, and a two-piece cap assembly. The two-piece cap mechanism punctures the sealed dropper tip upon initial use, then locks together to provide a single cap during the usage period. Tamper evidence is provided by two perforated tabs on the container label extending on to the cap. The OCUMETER Plus ophthalmic dispenser contains 5 ml of solution.

6.6 Special Precautions For Disposal And Other Handling

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

Patients should also be instructed that ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

7. Marketing Authorisation Holder

Merck Sharp & Dohme Limited

Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK

8. Marketing Authorisation Number(S)

0.25% w/v Eye Drops Solution PL0025/0134

0.5% w/v Eye Drops Solution PL0025/0135

9. Date Of First Authorisation/Renewal Of The Authorisation

Granted: 5 January 1979

Last renewed: 12 February 2002

10. Date Of Revision Of The Text

February 2008

LEGAL CATEGORY

POM

® denotes registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

© Merck Sharp & Dohme Limited 2008 All rights reserved

SPC.TOTOS.06.UK.2345 F.T. 020608