Topiramate

Registered South African indications: 

• Epilepsy

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• The safety and efficacy of topiramate in children under 2 years has not yet been established
• Pregnancy
• Lactation
• Women of childbearing potential with epilepsy not using highly effective contraception
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Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Migraine prophylaxis in pregnancy and in women of childbearing potential if not using a highly effective method of contraception

• Pregnancy (for the indication of epilepsy) (Recommendations in other jurisdictions)
• Breastfeeding (Recommendations in other jurisdictions)
• Moderate to severe renal impairment
• Hepatic impairment
• Nephrolithiasis
• Acute myopia associated with secondary closed angle glaucoma
• Metabolic acidosis
• Cognitive impairment
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• Signs of suicidal ideation and behaviour
• Visual field defects
• Weight loss
• Concomitant use with valproic acid (risk of Hperammonemia)

Forms avail. in SA and covered in this monograph: cap, fct, tab

South African registered indications and dosages

Epilepsy - monotherapy
- In patients with newly diagnosed epilepsy or for conversion to monotherapy in patients with epilepsy

• Oral (cap, fct, tab): Initial: 25mg, dly at night for 1 week; Titrate by 25-50mg/day at intervals of 1-2 weeks, administered in 2 divided doses; Maintenance: 100-500mg/day, in 2 divided doses; Max: 1000mg/24hrs

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When concomitant anti-epileptic medicines are withdrawn to achieve monotherapy with topiramate, consideration should be given to the effects this may have on seizure control.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 anti-epileptic medicine, a gradual discontinuation at the rate of approximately one-third of the concomitant anti-epileptic medicine dose every 2 weeks is recommended

Adjust dose if enzyme-inducing medicines are withdrawn. If patient is unable to tolerate the titration regimen, use smaller increments or longer intervals

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Epilepsy - adjunctive therapy
- In patients who are inadequately controlled on conventional first line anti-epileptic medicines for partial onset seizures with or without secondary generalised seizures, seizures associated with Lennox-Gastaut syndrome, or primary generalized tonic-clonic seizures

• Oral (cap, fct, tab): Initial: 25-50mg, dly at night for 1 week; Titrate by 25-50mg/day at 1 week intervals administered in 2 divided doses (some patients may achieve efficacy with once-a-day dosing); Maintenance: 200-400mg/day, in 2 divided doses; Max: 800mg/24hrs

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For optimal control, it is recommended that therapy be initiated at a low dose, followed by titration to an effective dose guided by clinical outcome

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Method of administration
Tablets and film-coated tablets should not be broken
The sprinkle formulation is provided for those patients who cannot swallow tablets. The sprinkle capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This medicine/food mixture should be swallowed immediately and not chewed. It should not be stored for future use
Topiramate can be taken without regard to meals

Paed. forms avail. in SA and covered in this monograph: cap, fct, tab

South African registered indications and dosages

Epilepsy - monotherapy
- In patients with newly diagnosed epilepsy or for conversion to monotherapy in patients with epilepsy

Younger than 2 years

• Contraindicated

Older than 2 years

• Oral (cap, fct, tab): Initial: 0.5-1mg/kg, dly at night for the 1st week; Titrate by increments of 0.5-1mg/kg/day at 1-2 week intervals administered in 2 divided doses; Maintenance: 100-400mg/day, in 2 divided doses; Children with recently diagnosed partial onset seizures have received doses of up to 500mg/day

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If the child is unable to tolerate the titration regimen, smaller increments or longer intervals between dose increments can be used. Dose and dose titration rate should be guided by clinical outcome

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When concomitant anti-epileptic medicines 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 anti-epileptic medicine, a gradual discontinuation at the rate of approximately one-third of the concomitant anti-epileptic medicine dose every 2 weeks is recommended

Adjust dose if enzyme-inducing medicines are withdrawn.

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Epilepsy - adjunctive therapy
- In patients who are inadequately controlled on conventional first line anti-epileptic medicines for partial onset seizures with or without secondary generalized seizures, seizures associated with Lennox-Gastaut syndrome, or primary generalized tonic-clonic seizures

Younger than 4 years

• Not established for use

Older than 4 years

• Oral (cap, fct, tab): Initial:1-3mg/kg/day (up to 25mg/24hrs), at night for the 1st week; Titrate by 1-3mg/kg/day at 1-2 week intervals, administered in 2 divided doses; Maintenance: 5-9mg/kg/day, in 2 divided doses

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For optimal control, it is recommended that therapy be initiated at a low dose, followed by titration to an effective dose guided by clinical outcome

---

Method of administration
Tablets and film-coated tablets should not be broken
The sprinkle formulation is provided for those patients who cannot swallow tablets. The sprinkle capsules may be swallowed whole or may be administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This medicine/food mixture should be swallowed immediately and not chewed. It should not be stored for future use
Topiramate can be taken without regard to meals

Pregnancy

South African recommendations

• Contraindicated
• Topiramate is also contraindicated in women of childbearing potential with epilepsy not using highly effective contraception
• Topiramate can cause major congenital malformations and foetal growth restriction when used during pregnancy. Recent data also suggests that topiramate use during pregnancy may increase the risk of neurodevelopmental disorders (NDD) including autism spectrum disorders, intellectual disability and attention deficit hyperactivity disorder (ADHD)
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• Topiramate is teratogenic in animals. Studies in animals and humans have shown reproductive toxicity. In humans, topiramate crosses the placenta and similar concentrations have been reported in the umbilical cord and maternal blood. There are no adequate and well-controlled studies using topiramate in pregnant women
• Topiramate may cause foetal harm when administered to a pregnant woman. There is an increased risk of pre-term labour and premature delivery associated with the use of anti-epileptic medicines including topiramate. Compared with a reference group not taking anti-epileptic medicines, registry data for topiramate as monotherapy showed a higher prevalence of low birth weight (<2500 grams)
• Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk of 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
• In addition, data from other studies indicate that, compared with monotherapy, there is an increased risk of teratogenic effects associated with the use anti-epileptic medicines in combination therapy. The risk has been observed in all doses and effects were reported to be dose-dependent. In women treated with topiramate who have had a child with congenital malformation, there appears to be an increased risk of malformations in subsequent pregnancies when exposed to topiramate
• One pregnancy registry reported an increased frequency of infants who were small for gestational age (SGA; defined as birth weight below the 10th percentile corrected for their gestational age, stratified by sex) among those exposed to topiramate monotherapy in utero
• Specialist advice should be given to women who are of childbearing potential. The need for treatment with anti-epileptic medicines should be reviewed when a woman is planning to become pregnant. In women being treated for epilepsy, sudden discontinuation of anti-epileptic therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child
• It is recommended to consider alternative therapeutic options in women of child-bearing potential. If topiramate is used in women of childbearing potential, it is recommended that highly effective contraception be used, and that the woman is fully informed of the known risks of uncontrolled epilepsy to the pregnancy and the potential risks of topiramate to the foetus. If a woman plans a pregnancy, a pre-conceptional visit is recommended in order to reassess the treatment, and to consider other therapeutic options

Recommendations in other jurisdictions

• Contraindicated (for the indication of migraine prophylaxis)
• Caution; positive evidence of risk (for the indication of epilepsy)
• Risk related to epilepsy and anti-epileptic drugs (AEDs) in general
  • Specialist advice should be given to women who are of childbearing potential. The need for treatment with AEDs should be reviewed when a woman is planning to become pregnant. In women being treated for epilepsy, sudden discontinuation of therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child
  • Monotherapy should be preferred whenever possible because therapy with multiple AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics
• Risk related to topiramate
  • Topiramate was teratogenic in mice, rats and rabbits. In rats, topiramate crosses the placental barrier
  • In humans, topiramate crosses the placenta and similar concentrations have been reported in the umbilical cord and maternal blood
  • Clinical data from pregnancy registries indicate that infants exposed to topiramate monotherapy have an increased risk of congenital malformations (particularly cleft lip/palate, hypospadias, and anomalies involving various body systems) following exposure during the first trimester
  • The North American Antiepileptic Drug pregnancy registry data for topiramate monotherapy showed an approximate 3-fold higher prevalence of major congenital malformations (4.3%), compared with a reference group not taking AEDs (1.4%). In addition, data from other studies indicate that, compared with monotherapy, there is an increased risk of teratogenic effects associated with the use of AEDs in combination therapy. The risk has been reported to be dose dependent; effects were observed in all doses. In women treated with topiramate who have had a child with a congenital malformation, there appears to be an increased risk of malformations in subsequent pregnancies when exposed to topiramate
  • A higher prevalence of low birth weight (<2500 grams) compared with a reference group
  • An increased prevalence of being small for gestational age (SGA; defined as birth weight below the 10^th percentile corrected for their gestational age, stratified by sex). The long term consequences of the SGA findings could not be determined
• Indication epilepsy
  • It is recommended to consider alternative therapeutic options in women of child bearing potential. If topiramate is used in women of child bearing potential, it is recommended that highly effective contraception be used, and that the woman is fully informed of the known risks of uncontrolled epilepsy to the pregnancy and the potential risks of the medicinal product to the foetus. If a woman plans a pregnancy, a preconceptional visit is recommended in order to reassess the treatment, and to consider other therapeutic options. In case of administration during the first trimester, careful prenatal monitoring should be performed
• Indication migraine prophylaxis
  • Topiramate is contraindicated in pregnancy and in women of childbearing potential if a highly effective method of contraception is not used

Breastfeeding

South African recommendations

• Contraindicated
• 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. Diarrhoea and somnolence have been reported in breastfed infants whose mothers receive topiramate treatment

Recommendations in other jurisdictions

• Caution; not recommended
• 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. Effects that have been observed in breastfed newborns/infants of treated mothers include diarrhoea, drowsiness, irritability and inadequate weight gain. Therefore a decision must be made whether to suspend breastfeeding or to discontinue/ abstain from topiramate therapy taking into account the importance of the medicinal product to the mother

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• Animal studies did not reveal impairment of fertility by topiramate. The effect of topiramate on human fertility has not been established

• Moderate to severe: Caution; dose adjustment recommended
• CrCl<70 ml/min: Reduce dose by 50%

• Caution; no dose adjustment recommended

• No dose adjustment recommended

Central Nervous System Disorders

• Depression
• Bradyphrenia
• Insomnia
• Expressive language disorder
• Anxiety
• Disorientation
• Aggression
• Agitation
• Mood swings
• Abnormal behaviour
• Suicidal ideation
• Suicide attempt
• Hallucination
• Psychotic disorder
• Apathy
• Lack of spontaneous speech
• Sleep disorder
• Affect lability
• Restlessness
• Dysphemia
• Euphoric mood
• Paranoia
• Perseveration
• Reading disorder
• Initial insomnia
• Loss of libido
• Listless
• Distractibility
• Panic disorder
• Hypomania
• Paraesthesia
• Somnolence 
• Dizziness
• Disturbance in attention
• Memory impairment
• Amnesia
• Cognitive disorder
• Mental impairment
• Psychomotor skills impaired
• Convulsion
• Coordination abnormal
• Tremor
• Lethargy
• Hypoaesthesia
• Nystagmus
• Dysgeusia
• 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
• Aphasia
• Repetitive speech
• Hypokinesia
• Dyskinesia
• 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

Cardiovascular Disorders

• Bradycardia
• Palpitations
• Hypotension
• Orthostatic hypotension
• Flushing
• Hot flush
• Raynaud's phenomenon
• Gait abnormality
• Malaise
• Aesthenia

Respiratory Disorders

• Dyspnoea 
• Epistaxis
• Nasal congestion
• Rhinorrhoea
• Cough
• Dyspnoea exertional
• Paranasal sinus hypersecretion
• Dysphonia

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation
• Abdominal pain
• Dyspepsia
• Dry mouth
• Paraesthesia oral
• Gastritis
• Pancreatitis
• Flatulence
• Gastrooesophageal reflux disease
• Hypoaesthesia oral
• Gingival bleeding
• Abdominal distension
• Salivary hypersecretion
• Oral pain
• Breath odour
• Glossodynia

Hepatobiliary Disorders

• Hepatitis
• Hepatic failure

Genitourinary Disorders

• Nephrolithiasis
• Pollakiuria
• Dysuria
• Calculus urinary
• Urinary incontinence
• Haematuria
• Incontinence
• Micturition urgency
• Renal colic
• Renal pain
• Calculus ureteric
• Renal tubular acidosis
• Erectile dysfunction
• Sexual dysfunction

Endocrine and Metabolic Disorders

• Anorexia
• Decreased appetite
• Metabolic acidosis
• Hypokalaemia
• Increased appetite
• Polydipsia
• Acidosis hyperchloraemic
• Thirst

Musculoskeletal Disorders

• Arthralgia
• Muscle spasms
• Myalgia
• Muscle twitching
• Muscular weakness
• Musculoskeletal chest pain
• Joint swelling
• Musculoskeletal stiffness
• Flank pain
• Muscle fatigue
• Limb discomfort

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

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Leucopenia
• Thrombocytopenia lymphadenopathy
• Eosinophilia
• Neutropenia
• Hypersensitivity
• Allergic oedema
• Nasopharyngitis
• Pyrexia
• Influenza like illness

Sensory Disorders

• Diplopia
• Visual disturbance
• Reduced visual acuity
• Scotoma
• Myopia
• Abnormal sensation in eye
• Dry eye
• Photophobia
• Blepharospasm
• Increased lacrimation 
• Photopsia
• Mydriasis
• Presbyopia
• Unilateral blindness
• Transient blindness
• Glaucoma
• Accommodation disorder
• Altered visual depth perception
• Scintillating scotoma
• Eyelid oedema
• Night blindness
• Amblyopia
• Closed angle glaucoma
• Maculopathy
• Eye movement disorder
• Conjunctival oedema
• Vertigo
• Tinnitus
• Ear pain
• Deafness

Others

• Sluggishness
• Peripheral coldness
• Facial oedema
• Calcinosis

• CYP2C19 substrates
• Phenytoin 
• Carbamazepine
• Digoxin
• Central nervous system depressants
• St. John's Wort 
• Oral contraceptives
• Lithium
• Risperidone
• Hydrochlorothiazide
• Metformin
• Pioglitazone
• Glyburide
• Agents predisposing to nephrolithiasis
• Valproic acid
• Propranolol
• Diltiazem
• Flunarazine
• Warfarin

None routine. Specific cases may require

• Weight
• Mental status
• Bicarbonate levels
• Intraocular pressure

Topiramate is a sulfamate-substituted monosaccharide. The precise mechanism is unknown. It blocks the action potentials elicited repetitively by a sustained depolarization of the neurons in a time-dependent manner, suggesting a state-dependent sodium channel blocking action. Topiramate also potentiates the activity of the inhibitory neurotransmitter gamma-aminobutyrate (GABA). It also demonstrates antagonism of the AMPA/kainate subtype of the glutamate excitatory amino acid receptor.  

Capsule sprinkles 15mg

• Topamax SC (Janssen) originator

Capsule sprinkles 25mg

• Topamax SC (Janssen) originator

Capsule sprinkles 50mg

• Topamax SC (Janssen) originator

Tablet 25mg

• Adco Topiramate(Adcock)
• Epimate (Litha)
• Epitoz (Zydus)
• Pamiram (Akacia)
• Piramax (Cipla Medpro)
• Sandoz topiramate (Sandoz)
• Topalex (Janssen)
• Topamax (Janssen) originator
• Topirol (Sun Pharm)
• Toplep (Ranbaxy)

Tablet 50mg

• Adco Topiramate (Adcock)
• Epimate (Litha)
• Epitoz (Zydus)
• Pamiram  (Akacia)
• Sandoz topiramate (Sandoz)
• Topalex (Janssen)
• Topamax (Janssen) originator
• Topirol (Pharmaplan)
• Toplep (Ranbaxy)

Tablet 100mg

• Adco Topiramate (Adcock)
• Epimate (Litha)
• Epitoz (Zydus)
• Pamiram (Akacia)
• Piramax (Cipla Medpro)
• Sandoz topiramate (Sandoz)
• Topalex (Janssen)
• Topamax (Janssen) originator
• Topirol (Sun Pharm)
• Toplep (Ranbaxy)

Tablet 200mg

• Adco Topiramate (Adcock)
• Epimate (Litha)
• Pamiram (Akacia)
• Piramax (Cipla Medpro)
• Sandoz topiramate (Sandoz)
• Topamax (Janssen) originator
• Toplep (Ranbaxy)