Sencresus 25/50/100/200 mg FC tablets

SENCRESUS is indicated as monotherapy in patients with newly diagnosed epilepsy or for conversion to monotherapy in patients with epilepsy. SENCRESUS is indicated as adjunctive therapy for adults and children aged 12 years and above who are inadequately controlled on conventional first-line anti-epileptic medicines for:

• Partial onset seizures with or without secondary generalised seizures.
• Primary generalised tonic-clonic seizures.

Posology

For optimal control in both adults and children, it is recommended that therapy be initiated at a low dose, followed by titration to an effective dose. It is recommended that tablets not be broken and can be taken with or without meals.

MONOTHERAPY: When concomitant anti-epileptic medicines (AEMs) are withdrawn to achieve monotherapy with SENCRESUS, consideration should be given to the effects this may have on seizure control. Unless safety concerns require an abrupt withdrawal of the concomitant AEM, a gradual discontinuation at the rate of approximately one-third of the concomitant AEM dose every 2 weeks is recommended. When enzyme inducing medicines are withdrawn, topiramate levels will increase. A decrease in SENCRESUS dosage may be required if clinically indicated.

Adults: 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 to 50 mg/day, administered in two divided doses. If the patient is unable to tolerate the titration regimen, small increments or longer intervals between increments can be used. Dose and titration rate should be guided by clinical outcome. The recommended initial target dose for SENCRESUS monotherapy in adults is 100 mg/day and the maximum recommended daily dose is 400 mg. Some patients with refractory forms of epilepsy have tolerated SENCRESUS monotherapy at doses of 1 000 mg/day, administered in two divided doses. These dosing recommendations apply to all adults including the elderly in the absence of underlying renal disease.

Children: Treatment of children aged 12 years and above 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. Dose and dose titration should be guided by clinical outcome. The recommended initial target dose range for SENCRESUS monotherapy in children aged twelve years and above is 3 to 6 mg/kg/day. Children with recently diagnosed partial onset seizures have received doses of up to 500 mg/day.

ADJUNCTIVE THERAPY: Adults: Therapy should begin at 25 - 50 mg nightly for one week. Subsequently, at weekly intervals, the dose should be increased by 25 u2013 50 mg/day and the dose should be taken in two divided doses. Dose titration should be guided by clinical outcome. Some patients may achieve efficacy with once-a-day dosing. In clinical trials, 200 mg was effective and was the lowest dosage studied. This is therefore considered the minimal effective dose. The usual total daily dose is 200 mg to 400 mg in two divided doses. Some patients may require doses up to 800 mg per day, which is the maximum dose. It is recommended that therapy be initiated at a low dose, followed by titration to an effective dose.

Since SENCRESUS is removed from plasma by haemodialysis, a supplemental dosage of SENCRESUS 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. These dosing recommendations apply to all adults, including the elderly, in the absence of underlying renal disease. (See Section 4.4) This formulation is not suitable for children younger than 12 years.

Method of administration

For oral administration.

• Hypersensitivity to any component in SENCRESUS.
• The safety and efficacy of topiramate in children under 2 years have not been established.
• Pregnancy and lactation, as topiramate is teratogenic in animals.
• In women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled (see sections 4.4 and 4.6).

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 SENCRESUS. 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 SENCRESUS therapy. Secondary angle closure glaucoma associated with SENCRESUS has been reported in paediatric patients as well as adults. Treatment includes discontinuation of SENCRESUS as rapidly as possible and appropriate measures applied to reduce intraocular pressure.

Oral contraceptives: Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding (see Section 4.5).

Hepatic impairment: In hepatically impaired patients, SENCRESUS should be administered with caution as the clearance of topiramate may be decreased. Anti-epileptic medicines, including SENCRESUS, should be withdrawn gradually to minimise the potential of increased seizure frequency.

Renal elimination is dependent on renal function and is independent of age. Patients with moderate or severe renal impairment may take 10 to 15 days to reach steady-state plasma concentrations as compared to 4 to 8 days in patients with normal renal function. The titration schedule should be guided by clinical outcome (i.e. seizure control, avoidance of side-effects) with the knowledge that subjects with known renal impairment may require a longer time to reach steady-state at each dose. 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 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 medication associated with nephrolithiasis may be at increased risk. Adequate hydration while using SENCRESUS is very important. Hydration can reduce the risk of nephrolithiasis (renal stone formation). Proper hydration prior to and during activities such as exercise or exposure to warm temperatures may reduce the risk of heat-related adverse events.

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

Metabolic acidosis: Hypocloraemic metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of respiratory alkalosis) is associated with SENCRESUS treatment. This decrease in serum bicarbonate is due to the inhibitory effect of SENCRESUS on renal carbonic anhydrase and consequently renal bicarbonate wasting. 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; however, 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 medicines) may be additive to the bicarbonate lowering effects of SENCRESUS. Chronic metabolic acidosis can lead to nephrolithiasis and increased risk of fractures. Appropriate evaluation of patients including serum bicarbonate levels is recommended with SENCRESUS therapy. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing SENCRESUS (using dose tapering).

Pregnancy prevention programme: Topiramate can cause major congenital malformations and fetal growth restriction when administered to a pregnant woman. Some data suggest an increased risk of neurodevelopmental disorders in children exposed to topiramate in utero, while other data do not suggest an increased risk (see section 4.6). Topiramate is contraindicated in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled (see section 4.3 and 4.6).

The conditions of the Pregnancy Prevention Programme are that the prescriber must ensure that:

• a pregnancy test before starting treatment;
• counselling about the risks of topiramate treatment and the need for highly effective contraception throughout treatment;
• a review of ongoing treatment at least annually by completion of a risk awareness form.
• To confirm that appropriate measures have been taken, patients and prescribers will go through this form at the beginning of treatment and at each annual review and if the patient is planning a pregnancy or has become pregnant. It should be ensured that the patient is fully informed and has understood the risks and measures to be taken.

Women of childbearing potential: Pregnancy testing should be performed before initiating treatment with topiramate in a woman of childbearing potential. The patient must be fully informed and understand the risks related to the use of topiramate during pregnancy (see sections 4.3 and 4.6). This includes the need to consult her doctor if the woman is planning a pregnancy to discuss switching to alternative treatments prior to discontinuation of contraception, and for prompt contact with a doctor if she becomes pregnant or thinks she may be pregnant.

This includes the need to consult her doctor as soon as she is planning for pregnancy, and for prompt contact with her doctor if she becomes pregnant or thinks she may be pregnant and is taking topiramate.

Oligohydrosis: Oligohydrosis (decreased sweating) has been reported in association with the use of topiramate. Decreased sweating and hyperthermia (rise in body temperature) may occur especially in young children exposed to high ambient temperature.

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

Hyperammonemia and encephalopathy: Hyperammonemia with or without encephalopathy has been reported with topiramate treatment (see section 4.8). The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid (see section 4.5).

In patients who develop unexplained lethargy or changes in mental status associated with topiramate monotherapy or adjunctive therapy, it is recommended to consider hyperammonemic encephalopathy and measuring ammonia levels.

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.

Excipients with known effect: SENCRESUS contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially sodium-free.

Effects of SENCRESUS on other anti-epileptic medicines: The addition of SENCRESUS to other anti-epileptic agents (phenytoin, carbamazepine, valproic acid, phenobarbital, primodone) has no effect on their steady-state plasma concentrations, except in the occasional patient, where the addition of SENCRESUS to phenytoin may result in an increase of plasma concentrations of phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C meph). Consequently any patient on phenytoin should have phenytoin levels monitored. A pharmacokinetic interaction study of patients with epilepsy indicated the addition of SENCRESUS to lamotrigine had no effect on steady state plasma concentration of lamotrigine at SENCRESUS doses of 100 to 400 mg/day. In addition, there was no change in steady state plasma concentration of SENCRESUS during or after removal of lamotrigine. However, the incidence of adverse effects was meaningfully increased with the combination.

Effects of other anti-epileptic medicines on SENCRESUS: Phenytoin and carbamazepine decrease the plasma concentration of SENCRESUS. The addition or withdrawal of phenytoin or carbamazepine to SENCRESUS 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 SENCRESUS and therefore, does not warrant dosage adjustment of SENCRESUS. The above interactions are summarised in the following table:

AEM Co - administered AEM Concentration SENCRESUS Concentration

Phenytoin u2194 ** u2193

Carbamazepine (CBZ) u2194 u2193

Valproic acid u2194 u2194

Lamotrigine u2194 u2194

Phenobarbital u2194 NS

Primidone u2194 NS

u2194 = No effect on plasma concentration (< 15 % change)

** = Plasma concentrations increase in individual patients

u2193 = Plasma concentrations decrease

NS = Not studied

AEM = Anti-epileptic medicine

Other medicine interactions: Digoxin: Concomitant administration has shown a decrease in serum digoxin. When SENCRESUS is added or withdrawn in patients on digoxin therapy, careful attention should be given to the monitoring of serum digoxin.

Oral contraceptives: SENCRESUS increases plasma clearance of the oestrogenic component significantly and efficacy of the oral contraceptive may be compromised. The possibility of increased breakthrough bleeding should be therefore considered in patients taking combination oral contraceptive products with SENCRESUS. Patients taking oestrogen-containing contraceptives should be asked to report any change in their bleeding patterns. Patients should use an alternative non-hormonal method of contraception or patients should, bearing in mind the potential risk of teratogenicity, receive a preparation containing not less than 50 micrograms of oestrogen.

Hydrochlorothiazide (HCTZ): The concomitant use of hydrochlorothiazide and SENCRESUS may increase the peak concentration and AUC of topiramate. Dosage reduction of SENCRESUS may be required.

Metformin: The concomitant use of metformin and SENCRESUS may increase the peak concentration and AUC of metformin. When SENCRESUS 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: When SENCRESUS is added to pioglitazone therapy or pioglitazone is added to SENCRESUS therapy, careful attention should be given to the routine monitoring of patients for adequate control of their diabetic disease state.

CNS depressants: Concomitant use of SENCRESUS with alcohol or other central nervous system (CNS) depressant medicines should be avoided.

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

Summary of results from additional clinical pharmacokinetic substance interaction studies:

Concomitant substance Concomitant substance concentration a Topiramate concentration a

Amitriptyline u2194 20 % increase in C max and AUC of nortriptyline metabolite NS

Dihydroergotamine (Oral and subcutaneous) u2194 u2194

Haloperidol u2194 31 % increase in AUC of the reduced metabolite NS

Propranolol u2194 17 % increase in C max for 4-OH propranolol (TPM 50 mg q12h) 16 % increase in C max 17 % increase in AUC (80 mg propranolol q12h)

Sumatriptan (Oral and subcutaneous) u2194 NS

Pizotifen u2194 u2194

a % values are the changes in treatment mean Cmax or AUC with respect to monotherapy

u2194 = No effect on Cmax and AUC (u226415 % change) of the parent compound

NS = No studies

Other interactions: St Johnu2019s Wort (Hypericum perforatum): A risk of decreased plasma concentrations resulting in a loss of efficacy could be observed with co-administration of SENCRESUS and St Johnu2019s Wort.

Lithium: There was an observed reduction in systemic exposure for lithium during concomitant administration with SENCRESUS. Lithium levels should be monitored when co-administered with SENCRESUS.

Risperidone: When administered concomitantly with MYLAN TOPIRAMATE SENCRESUS there was a reduction in risperidone.

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

Agents predisposing to nephrolithiasis: Concomitant use of SENCRESUS with agents predisposing to nephrolithiasis (renal stone formation) should be avoided.

Valproic acid: Concomitant administration of SENCRESUS and valproic acid has been associated with hyperammonaemia with or without encephalopathy in patients who had tolerated either medicinal product alone.

Warfarin: Decreased Prothrombin Time/International Normalized Ratio (PT/INR) has been reported in patients treated with topiramate in combination with warfarin. Therefore, INR should be carefully monitored in patients concomitantly treated with topiramate and warfarin.

Pregnancy

Risk related to epilepsy and anti-epileptic drugs (AEDs) in general: Specialist advice regarding the potential risks to a fetus caused by both seizures and antiepileptic treatment should be given to women of childbearing potential, and especially to women planning for pregnancy and women who are pregnant. 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 AED therapy should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the fetus. 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 is 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. Cases of hypospadias have been reported in male infants exposed in utero to topiramate, with or without other anticonvulsants; however, a causal relationship with topiramate has not been established. It is recommended that women of child bearing potential use adequate contraception. Topiramate is contraindicated in women of childbearing potential unless the conditions of the Pregnancy Prevention Programme are fulfilled (see section 4.3 and 4.4 4.6). Alternative therapeutic options should be considered in women of childbearing potential. Pregnancy testing should be performed before initiating treatment with topiramate in a woman of childbearing potential.

Breastfeeding: Animal studies have shown the excretion of topiramate in milk. 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 diarrhea, 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 benefit of breastfeeding for the child and the benefit of topiramate therapy for the women. Safety has not been demonstrated (see section 4.3).

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

SENCRESUS may produce central nervous system related events such as: drowsiness, dizziness or other related symptoms. Caution is advised when driving or operating machinery. SENCRESUS may be more sedating than other anti-epileptic medicines.

b. Tabulated summary of adverse reactions

MedDRA system organ class Frequency Adverse reactions

Blood and lymphatic system disorders Less frequent Neutropenia, thromboembolic events, leucopenia, thrombocytopenia, Eosinophilia Frequent Anaemia, purpura

Immune system disorders Frequent Hypersensitivity

Metabolism and nutrition disorders Frequent Weight loss, Anorexia Decreased appetite Less frequent Metabolic acidosis, Hypokalaemia, Increased appetite, hyperammonemic, hyperchloraemic

Psychiatric disorders Frequent Confusion and psychomotor slowing, depression, concentration disturbances, anxiety, apathy, euphoria, emotional lability, agitation, cognitive problems, decreased libido, aggressive reactions, personality disorders Less frequent Hallucinations, suicidal ideation, suicidal attempts, suicide, psychosis or psychotic symptoms, Mania, Panic disorder

Nervous system disorders Frequent Ataxia, paraesthesia, speech disorders, aphasia, tremor, asthenia, fatigue, dizziness, headache, somnolence, insomnia, Difficulty with memory Less frequent Hypokinesia, hyperkinesias, stupor, coordination problems, abnormal gait

Eye disorders Frequent Diplopia, abnormal vision, nystagmus Less frequent Acute myopia and secondary angle closure glaucoma, conjunctivitis, eye pain, blurred vision, Visual acuity, reduced, Scotoma, Dry eye, Photophobia, Blepharospasm, Lacrimation increased, Photopsia, Mydriasis, Presbyopia, Accommodation disorder, Blindness unilateral

Ear and labyrinth disorders Frequent Tinnitus, Ear pain, Vertigo Less frequent Deafness, Deafness unilateral, Deafness neurosensory, Ear discomfort, Hearing impaired

Cardiac disorders Less frequent Bradycardia, Sinus bradycardia, Palpitations

Vascular disorders Less frequent Hypotension, postural hypotension, Flushing, Hot flush, Raynaudu2019s phenomenon

Respiratory thoracic and mediastinal disorders Frequent Epistaxis, rhinitis, pharyngitis, pneumonia, Rhinorrhoea Less frequent Dyspnoea, Hypersecretion, Dysphonia Frequency unknown Cough

Gastrointestinal disorders Frequent Constipation, nausea, abdominal pain, dyspepsia, increased saliva, taste perversion Less frequent Diarrhoea, vomiting and dry mouth, pancreatitis, Flatulence, Gastrooesophageal reflux disease, Hypoaesthesia oral, Gingival bleeding, Abdominal distention, Epigastric discomfort, Abdominal tenderness, Salivary hypersecretion, Oral pain, Breath odour, Glossodynia

Hepato-biliary disorders Less frequent Hepatitis, hepatic failure

Skin and subcutaneous tissue disorders Frequent Alopecia, increased sweating, Rash, Pruritus Less frequent Folliculitis, pruritus, decreased sweating, bullous skin and mucosal reactions (including erythema multiforme, pemphigus, Stevens-Johnson syndrome and toxic epidermal necrolysis), Anhidrosis, Hypoaesthesia facial, Urticaria, Skin discolouration, Dermatitis allergic, Swelling face

Musculoskeletal and connective tissue disorders Frequent Skeletal pain, Muscle spasms, Myalgia, Muscle twitching, Muscular weakness, Musculoskeletal chest pain Less frequent Musculoskeletal stiffness, Flank pain, Muscle fatigue

Renal and urinary disorders Frequent Urinary frequency, urinary incontinence, dysuria, haematuria, renal failure, Pollakiuria Less frequent Nephrolithiasis, Calculus urinary

Reproductive system and breast disorders Frequent Menstrual disturbances, impotence

General disorders and administration site conditions Frequent Allergic reaction, Hyperthermia, Thirst, Sluggishness Less frequent Malaise, Feeling abnormal

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

Signs and symptoms: Convulsions, drowsiness, speech disturbances, blurred vision, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression.

Treatment: In acute SENCRESUS overdose, if the ingestion is recent, the stomach should be emptied immediately by lavage or by induction of emesis. Activated charcoal has been shown to absorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis has been shown to be an effective means of removing topiramate from the body. The patient should be well hydrated.