TOPIRAMATE MILPHARM

Posology 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. It is not necessary to monitor topiramate plasma concentrations to optimise therapy with Topiramate Milpharm.

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 Milpharm may require adjustment of the dose of topiramate.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs (AEDs) including topiramate should be gradually withdrawn to minimise the potential for seizures or increased seizure frequency.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In paediatric clinical trials, topiramate was gradually withdrawn over a 2-8 week period. Monotherapy epilepsy General When concomitant AEDs are withdrawn to achieve monotherapy with topiramate, consideration should be given to the effects this may have on seizure control.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 When enzyme inducing medicinal products are withdrawn, topiramate levels will increase.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 Milpharm (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.

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 generalised 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 adverse reactions were mild to moderate in severity. Adverse reactions 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 ≥1/10 Common ≥1/100 to <1/10 Uncommon ≥1/1,000 to <1/100 Rare ≥1/10,000 to <1/1,000 Not known cannot be estimated from the available data The most common adverse reactions (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, paraesthesia, somnolence, tremor, diplopia, vision blurred, diarrhoea, nausea, fatigue, irritability, and weight decreased.

Table 1:

Topiramate Milpharm Adverse Reactions System Organ Class Very common Common Uncommon Rare Not known Infections and infestations nasopharyn gitis* Blood and lymphatic system disorders anaemia leucopenia, thrombocyto penia lymphadeno pathy, eosinophilia neutropenia* Immune system disorders hypersensiti vity allergic oedema* Metabolis m and nutrition disorders anorexia, decreased appetite metabolic acidosis, hypokalaemi a, increased appetite, polydipsia acidosis hyperchlorae mic, hyperammon emia*, hyperammon emic encephalopat hy* Psychiatric disorders depression bradyphreni a, insomnia, expressive language disorder, anxiety, confusional state, disorientatio n, aggression, mood altered, agitation, mood swings, depressed mood, suicidal ideation, suicide attempt, hallucination , psychotic disorder, hallucination auditory, hallucination visual, apathy, lack of spontaneous speech, sleep disorder, affect lability, mania, panic disorder, feeling of despair*, hypomania anger, abnormal behaviour libido decreased, restlessness, crying, dysphemia, euphoric mood, paranoia, perseveratio n, panic attack, tearfulness, reading disorder, initial insomnia, flat affect, thinking abnormal, loss of libido, listless, middle insomnia, distractibilit y, early morning awakening, panic reaction, elevated mood Nervous system disorders paraesthesi a, somnolence dizziness disturbance in attention, memory impairment, amnesia, cognitive disorder, mental impairment, psychomoto r skills impaired, convulsion, coordination abnormal, tremor, lethargy, depressed level of consciousnes s, grand mal convulsion, visual field defect, complex partial seizures, speech disorder, psychomotor hyperactivity , syncope, sensory disturbance, apraxia, circadian rhythm sleep disorder, hyperaesthesi a, hyposmia, anosmia, essential tremor, akinesia, unresponsive to stimuli hypoaesthes ia, nystagmus, dysgeusia, balance disorder, dysarthria, intention tremor, sedation 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 Eye disorders vision blurred, diplopia, visual disturbance visual acuity reduced, scotoma, myopia*, abnormal sensation in eye*, dry eye, photophobia, blepharospas m, lacrimation increased, photopsia, mydriasis, presbyopia blindness unilateral, blindness transient, glaucoma, accommodati on disorder, altered visual depth perception, scintillating scotoma, eyelid oedema*, night blindness, amblyopia angle closure glaucoma *, maculopat hy*, eye movemen t disorder*, conjuncti val oedema*, uveitis Ear and labyrinth disorders vertigo, tinnitus, ear pain deafness, deafness unilateral, deafness neurosensor y, ear discomfort, hearing impaired Cardiac disorders bradycardia, sinus bradycardia, palpitations Vascular disorders hypotension, orthostatic hypotension, flushing, hot flush Raynaud's phenomenon Respiratory , thoracic and mediastinal disorders dyspnoea , epistaxis, nasal congestion, rhinorrhoea, cough* dyspnoea exertional, paranasal sinus hypersecreti on, dysphonia Gastrointes tinal disorders nausea, diarrhoea vomiting, constipation, abdominal pain upper, dyspepsia, abdominal pain, dry mouth, stomach discomfort, paraesthesia oral, gastritis, abdominal discomfort pancreatitis, flatulence, gastrooesoph ageal reflux disease, abdominal pain lower, hypoaesthesi a oral, gingival bleeding, abdominal distension, epigastric discomfort, abdominal tenderness, salivary hypersecreti on, oral pain, breath odour, glossodynia Hepatobilia ry disorders hepatitis, hepatic failure Skin and subcutaneo us tissue disorders alopecia, rash, pruritus anhidrosis, hypoaesthesi a facial, urticaria, erythema, pruritus generalised, rash macular, skin discolouratio n, dermatitis allergic, swelling face Stevens- Johnson syndrome* erythema multiforme*, skin odour abnormal, periorbital oedema*, urticaria localised toxic epidermal necrolysis * Musculosk eletal and connective tissue disorders arthralgia, muscle spasms, myalgia, muscle twitching, muscular weakness, musculoskel etal chest pain joint swelling*, musculoskel etal stiffness, flank pain, muscle fatigue limb discomfort* Renal and urinary disorders nephrolithia sis, pollakiuria, dysuria, nephrocalci nosis* calculus urinary, urinary incontinence , haematuria, incontinence , micturition urgency, renal […]

2). As with other AEDs, 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 AEDs, 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). 8). Pregnancy prevention programme Topiramate Milpharm can cause major congenital malformations and fetal growth restriction when administered to a pregnant woman.

6). 6). The conditions of the Pregnancy Prevention Programme are that the prescriber must ensure that: • Individual circumstances should be evaluated in each case. Involving the patient in the discussion to support her engagement, discuss therapeutic options and ensure her understanding of the risks and the measures needed to minimise the risks.

• The potential for pregnancy is assessed for all female patients. • The patient has understood and acknowledged the risks of congenital malformations, neuro-developmental disorders and fetal growth restriction in children exposed to topiramate in utero.

• The patient understands the need to undergo pregnancy testing prior to initiation of topiramate and during treatment, as needed. • The patient is counselled regarding contraception, and that the patient is capable of complying with the need to use effective contraception without interruption during the entire duration of treatment with topiramate and for at least 4 weeks after stopping treatment.

• The patient understands the need for regular (at least annual) review of treatment. • The patient understands the need to consult her physician as soon as she is planning pregnancy to ensure timely discussion and switching to alternative treatment options prior to conception and before contraception is discontinued.

1. 6). 6). 6). 6).