Topsaver (Tablets, Capsules) Instructions for Use

ATC Code

N03AX11 (Topiramate)

Active Substance

Topiramate (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Anticonvulsant agent

Pharmacological Action

Antiepileptic drug. Topiramate is a sulfamate-substituted monosaccharide. It blocks sodium channels and suppresses the generation of repetitive action potentials during prolonged depolarization of the neuronal membrane. It enhances GABA activity at some GABA receptor subtypes. It prevents the activation by kainate of the kainate/AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subtype sensitivity to glutamate, without affecting NMDA activity at NMDA receptors. These effects are dose-dependent.

In addition, Topiramate inhibits the activity of some carbonic anhydrase isoenzymes. This effect is significantly weaker than that of the carbonic anhydrase inhibitor acetazolamide and is not the main component of topiramate’s antiepileptic activity.

Pharmacokinetics

Absorption

Topiramate is rapidly and well absorbed. Food intake has no clinically significant effect on its bioavailability, which is about 80%. The mean C_max after multiple oral administration of a 100 mg dose twice daily is 6.76 µg/ml.

Distribution

Plasma protein binding is 13-17%. The mean V_d is 0.55-0.8 L/kg for a single dose up to 1.2 g. V_d is gender-dependent: in women, these values are 50% of those observed in men, which is associated with a higher fat tissue content in women. After a single dose, the pharmacokinetics are linear, plasma clearance is constant, and AUC increases proportionally to the dose in the range from 100 mg to 400 mg. With normal renal function, it may take 4-8 days to reach C_ss.

Topiramate is presumed to be excreted in breast milk.

Metabolism

Approximately 20% of topiramate is metabolized. Up to 50% of topiramate is metabolized in patients concurrently taking other antiepileptic drugs (AEDs) that induce metabolizing enzymes. Six virtually inactive metabolites of topiramate have been isolated from human plasma, urine, and feces.

Excretion

Unchanged Topiramate and its metabolites are primarily excreted by the kidneys. Plasma clearance is about 20-30 ml/min.

T_1/2 after multiple administration of 50 mg and 100 mg twice daily is 21 hours.

Pharmacokinetics in Special Clinical Cases

V_d is gender-dependent: in women, these values are 50% of those observed in men, which is associated with a higher fat tissue content in women.

In patients with impaired renal function (CrCl < 60 ml/min), the plasma and renal clearance of topiramate is reduced; in patients with end-stage renal disease, the plasma clearance of topiramate is reduced.

Topiramate is effectively removed from plasma by hemodialysis.

Plasma clearance of topiramate does not change in elderly patients without impaired renal function.

Plasma clearance of topiramate is reduced in patients with moderate and severe hepatic impairment.

The pharmacokinetics of topiramate in children, as in adults, is linear. The drug clearance is dose-independent, and the steady-state plasma concentration increases proportionally to the dose. However, children are characterized by higher clearance values and a shorter T_1/2. Consequently, the plasma concentration of topiramate at the same doses per kg of body weight may be lower in children compared to adults.

Indications

• Monotherapy of epilepsy in children from 7 years of age and adults (including patients with newly diagnosed epilepsy);
• Adjunctive therapy in children from 3 years of age and adults with insufficient efficacy of first-choice AEDs for partial or generalized tonic-clonic seizures, as well as for seizures associated with Lennox-Gastaut syndrome.

ICD codes

Dosage Regimen

Tablets

The drug is administered orally. The tablet should be swallowed whole, without chewing, and can be taken with or without food. For optimal seizure control, it is recommended to start treatment with low doses followed by an increase to an effective dose.

As part of combination therapy

For adults, the minimum effective dose is 200 mg/day. The usual daily dose is 200-400 mg (in 2 divided doses). The maximum daily dose is 1.6 g. Treatment is started with 25-50 mg daily at bedtime for 1 week. Then the dose is increased by 25-50 mg/day over 1-2 weeks, with a frequency of administration of twice daily. If this dosing regimen is not tolerated, the dose is increased by a smaller amount or at longer intervals. The dose and frequency of administration are selected depending on the clinical effect.

For children over 3 years old, the recommended daily dose is 5-9 mg/kg of body weight, divided into 2 doses. Treatment is started with a dose of 25 mg at bedtime for 1 week. Then the dose is increased by 1-3 mg/kg/day over 1-2 weeks, with a frequency of administration of twice daily, until the optimal clinical effect is achieved.

Monotherapy

In adults, treatment is started with 25 mg at bedtime for 1 week. Then the dose is increased by 25-50 mg/day over 1-2 weeks, with a frequency of administration of twice daily. If this dosing regimen is not tolerated, the dose is increased by a smaller amount or taken at longer intervals. The dose and frequency of administration are selected depending on the clinical effect. The recommended initial dose of topiramate for monotherapy in adults with newly diagnosed epilepsy is 100 mg/day, the maximum recommended dose is 500 mg/day. These doses are recommended for all adults, including elderly patients with normal renal function.

In children aged 7 years and older, treatment is started with a dose of 0.5-1 mg/kg of body weight at bedtime for 1 week. Then the dose is increased by 0.5-1 mg/kg/day over 1-2 weeks, with a frequency of administration of twice daily. If this dosing regimen is not tolerated, the dose is increased by a smaller amount or at longer intervals. The dose and frequency of administration are selected depending on the clinical effect. The recommended dose range is 3-6 mg/kg of body weight. Children with recently diagnosed partial seizures can be prescribed up to 500 mg/day.

Capsules

Individual, depending on the indications, patient’s age, renal function, and the effectiveness of the therapy.

Adverse Reactions

Definition of adverse reaction frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated cases.

Infections: very rare – nasopharyngitis.

Blood and lymphatic system disorders: common – anemia; uncommon – leukopenia, thrombocytopenia, lymphadenopathy, thrombocytopenia, in children – eosinophilia; very rare – neutropenia.

Nervous system disorders: very common – somnolence, dizziness, paresthesia, in children – apathy, attention disturbance; common – coordination abnormal, nystagmus, lethargy, memory impairment, concentration impaired, tremor, amnesia, hypoaesthesia, taste perversion, thinking abnormal, speech disorder, cognitive disorder, apathy, mental impairment, psychomotor disturbances, convulsions, intention tremor, sedative effect; uncommon – ageusia, anosmia, aphasia, burning sensation (mainly on the face and limbs), cerebellar syndrome, clumsiness, postural dizziness, hypersalivation, dysesthesia, dysgraphia, dyskinesia, dysphasia, formication, hypogeusia, hypokinesia, peripheral neuropathy, parosmia, presyncope, repetitive speech, tactile disturbance, stupor, syncope, in children – psychomotor hyperactivity; rare – apraxia, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, unresponsiveness to stimuli, in children – sleep circadian rhythm disturbance.

Psychiatric disorders: very common – depression; common – slowed thinking, confusion, insomnia, agitation, anxiety, irritability, disorientation, emotional lability, anger, erectile dysfunction, in children – abnormal behavior, aggressive reactions; uncommon – sexual dysfunction, disturbance in sexual arousal, dysphemia, early morning awakening, euphoric mood, auditory and visual hallucinations, hypomanic states, decreased libido, panic attacks, paranoid states, perseveration of thinking, reading disorder, restlessness, sleep disorders, suicidal thoughts, suicide attempts, tearfulness; rare – mania, anorgasmia, feeling of despair, decreased sensations during orgasm, in children – apathy, crying.

Eye disorders: common – vision blurred, diplopia, visual disturbance; uncommon – accommodation disorder, amblyopia, blepharospasm, myopia, photopsia, presbyopia, scotoma, including scintillating, visual acuity reduced; rare – unilateral blindness, transient blindness, dry eye, lacrimation increased, mydriasis, night blindness; very rare – angle-closure glaucoma, eye movement disorder, maculopathy, eyelid edema, conjunctival edema.

Ear and labyrinth disorders: common – ear pain, tinnitus, in children – vertigo; uncommon – deafness, including neurosensory and unilateral, ear discomfort, hearing impaired.

Cardiac disorders: uncommon – bradycardia, palpitations, flushing, orthostatic hypotension; rare – Raynaud’s phenomenon.

Respiratory, thoracic and mediastinal disorders: common – dyspnea, nasal congestion, epistaxis, in children – rhinorrhea; uncommon – hoarseness, exertional dyspnea, sinus hyper secretion.

Gastrointestinal disorders: very common – nausea, diarrhea; common – decreased appetite, anorexia, constipation, upper abdominal pain, dry mouth, dyspepsia, abdominal discomfort, oral paresthesia, gastritis, in children – vomiting; uncommon – pancreatitis, flatulence, gastroesophageal reflux, lower abdominal pain, oral hypoaesthesia, gingival bleeding, halitosis, flatulence, glossodynia, oral pain, polydipsia, increased appetite, salivary hypersecretion, epigastric discomfort.

Musculoskeletal and connective tissue disorders: common – myalgia, muscle spasms, muscle twitching, muscle weakness, arthralgia, musculoskeletal chest pain; uncommon – musculoskeletal stiffness, flank pain, muscle weakness, muscle fatigue; rare – joint swelling, limb discomfort, lumbar discomfort.

Renal and urinary disorders: common – nephrolithiasis, dysuria, pollakiuria; uncommon – urinary calculus, hematuria, urinary incontinence, urinary frequency, renal colic, renal pain; rare – ureteric calculus, renal tubular acidosis.

Skin and subcutaneous tissue disorders: common – skin rash, alopecia, pruritus; uncommon – anhidrosis, oligohidrosis (mainly in children), facial skin hypoaesthesia, erythema, generalized pruritus, macular rash, skin pigmentation disorder, skin eruption, face edema; rare – erythema multiforme, periorbital edema, skin odor abnormal, Stevens-Johnson syndrome; very rare – generalized edema; in isolated cases – toxic epidermal necrolysis.

Allergic reactions uncommon – urticaria, allergic dermatitis.

Metabolism and nutrition disorders very common – weight decreased; uncommon – blood bicarbonate decreased, crystalluria, metabolic acidosis, in children – hypokalemia, hyperchloremic acidosis; very rare – weight increased.

General disorders and administration site conditions: very common – fatigue; common – asthenia, in children – pyrexia; uncommon – feeling cold in extremities; very rare – influenza-like illness.

Contraindications

• Children under 3 years of age;
• Pregnancy;
• Lactation period (breastfeeding);
• Hypersensitivity to any component of the drug.

With caution the drug should be prescribed for renal or hepatic insufficiency, nephrourolithiasis (including history), hypercalciuria.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Use with caution in hepatic insufficiency.

In patients with impaired liver function, the clearance of topiramate is reduced.

Use in Renal Impairment

Use with caution in renal insufficiency.

Patients with moderate or severe renal impairment may require 10-15 days to reach steady-state plasma concentration, unlike 4-8 days for patients with normal renal function. As with all patients, gradual dose increases should be made in accordance with clinical outcomes (such as seizure control, side effect frequency), bearing in mind that patients with moderate or severe renal impairment may require more time to reach steady state after each dose.

Pediatric Use

Contraindicated: children under 3 years of age.

Geriatric Use

Doses recommended for adults are also suitable for elderly patients with normal renal function.

Special Precautions

Antiepileptic drugs, including Topsaver, should be withdrawn gradually to minimize the possibility of increased seizure frequency. In clinical studies, topiramate doses were reduced by 50-100 mg at weekly intervals for adults in epilepsy therapy; in children, Topiramate was gradually withdrawn over 2-8 weeks. If rapid withdrawal of Topsaver is medically necessary, it is recommended to be carried out under medical supervision.

Patients with moderate and severe renal impairment may require 10-15 days to reach C_ss in plasma, unlike 4-8 days for patients with normal renal function. As with all patients, gradual dose increases should be made in accordance with clinical outcomes (such as seizure control, side effect frequency), bearing in mind that patients with moderate and severe renal impairment may require more time to reach steady state after each dose.

During therapy with Topsaver, adequate increase in fluid intake is very important to reduce the risk of nephrolithiasis, as well as side effects that may occur under the influence of physical exertion or elevated temperature.

Risk factors for nephrolithiasis include a history of nephrolithiasis (including family history), hypercalciuria, concomitant therapy with drugs that promote the development of nephrolithiasis.

Oligohidrosis and increased body temperature during treatment with Topsaver may develop in children exposed to high environmental temperatures.

Treatment with Topsaver may be accompanied by mood changes and depression.

A meta-analysis of randomized placebo-controlled studies of topiramate showed a small increase in the risk of suicidal thoughts and suicidal behavior, the mechanism of which is unknown. Available data do not rule out an association with the use of topiramate.

In double-blind clinical studies using topiramate for approved and investigational indications, suicide attempts occurred in 0.5% of patients (46 out of 8652 patients), which is almost 3 times higher than in patients in the placebo group (0.2% (8 out of 4045 patients)).

Patients, as well as their caregivers and educators, should be warned to closely monitor for the emergence of signs of suicidal thoughts and to immediately report these conditions to a doctor.

In patients with impaired liver function, Topsaver should be used with caution due to a possible decrease in topiramate clearance.

During the use of Topsaver, acute myopia with concomitant secondary angle-closure glaucoma may develop. Symptoms may be accompanied by decreased visual acuity and/or eye pain. Ophthalmological examination may reveal myopia, flattening of the anterior chamber, ocular hyperemia (redness), increased intraocular pressure, and mydriasis may also be observed. This symptom complex may be accompanied by fluid secretion, leading to forward displacement of the lens and iris with the development of secondary angle-closure glaucoma. Symptoms may appear within 1 month after starting treatment. Unlike primary open-angle glaucoma, which is rare in patients under 40 years of age, secondary angle-closure glaucoma is observed with the use of topiramate in both adults and children. If a symptom complex including myopia associated with angle-closure glaucoma occurs, the treating physician should, if possible, discontinue Topiramate and take appropriate measures aimed at reducing intraocular pressure. This is usually sufficient for the intraocular pressure to normalize. Increased intraocular pressure of any etiology, if not adequately treated, can lead to serious complications, including vision loss.

During the use of Topsaver, hyperchloremic, non-anion gap, metabolic acidosis may occur (e.g., a decrease in plasma bicarbonate concentration below normal in the absence of respiratory alkalosis). Such a decrease in serum bicarbonate concentration is a consequence of the inhibitory effect of topiramate on renal carbonic anhydrase. In most cases, the decrease in bicarbonate concentration occurred at the beginning of treatment, although this effect may appear at any time during treatment. When using the drug in adults at doses greater than 100 mg/day and in children at doses of about 6 mg/kg/day, the decrease in bicarbonate concentration is usually mild or moderate (mean value is 4 mmol/L). In rare cases, patients have a bicarbonate concentration of less than 10 mmol/L. Some diseases or treatments that predispose to the development of acidosis (e.g., renal disease, severe respiratory diseases, status epilepticus, diarrhea, surgery, ketogenic diet, use of certain drugs) may be additional factors that enhance the bicarbonate-lowering effect of topiramate.

In children, chronic metabolic acidosis can lead to growth retardation. The effect of topiramate on growth and possible complications associated with the skeletal system has not been systematically studied in children and adults.

When treating with Topsaver, it is recommended to monitor serum bicarbonate concentrations. If signs of metabolic acidosis occur, such as Kussmaul breathing, shortness of breath, loss of appetite, nausea, vomiting, rapid fatigue, tachycardia, or arrhythmia, a dose reduction or discontinuation of topiramate treatment should be considered.

Topsaver should be used with caution in patients with risk factors for developing metabolic acidosis.

If weight loss is observed during treatment with Topsaver, the advisability of prescribing additional nutrition should be considered.

The cause of cognitive impairment in epilepsy can be both the disease itself and the ongoing AED therapy. Cases of worsening cognitive impairment in adults have been described, requiring a reduction in dose or discontinuation of topiramate treatment. The effect of topiramate on cognitive functions in children has been insufficiently studied.

Effect on the ability to drive vehicles and machinery

Patients should exercise caution when driving vehicles and engaging in other activities requiring high concentration and rapid psychomotor functions, as Topsaver affects the CNS and can cause drowsiness, dizziness, and visual disturbances.

Overdose

Symptoms: convulsions, drowsiness, speech disorders, visual impairment, diplopia, thinking disorders, coordination disorders, lethargy, stupor, decreased BP, abdominal pain, dizziness, agitation, and depression. In most cases, the clinical consequences were not severe, but fatalities have been reported following overdose with a combination of several drugs, including Topiramate. Topiramate overdose can cause severe metabolic acidosis, and in children, hyperchloremic acidosis.

Treatment: if the patient has eaten shortly before the overdose, gastric lavage should be performed immediately or vomiting should be induced. In vitro studies have shown that activated charcoal adsorbs Topiramate. Symptomatic therapy should be carried out if necessary. Hemodialysis is an effective method for removing topiramate from the body. Patients are advised to adequately increase their fluid intake.

Drug Interactions

Effect of topiramate on other AEDs

Concomitant administration of topiramate with other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect their plasma concentrations, except for individual patients in whom the addition of topiramate to phenytoin may cause an increase in phenytoin plasma concentration. This may be because Topiramate inhibits the specific polymorphic isoenzyme CYP2C19. Therefore, in any patient taking phenytoin who develops clinical signs or symptoms of toxicity, phenytoin plasma concentrations should be monitored.

In a pharmacokinetic study in patients with epilepsy, the addition of topiramate to lamotrigine did not affect the C_ss of the latter at topiramate doses of 100-400 mg/day. During treatment and after discontinuation of lamotrigine (mean dose 327 mg/day), the C_ss of topiramate did not change.

Effect of other AEDs on Topiramate

Phenytoin and carbamazepine reduce topiramate plasma concentrations. The addition or withdrawal of phenytoin or carbamazepine during topiramate treatment may require an adjustment of the latter’s dose. The dose should be adjusted based on achieving the desired clinical effect. The addition or withdrawal of valproic acid does not cause clinically significant changes in topiramate plasma concentration and, therefore, does not require a dose adjustment. The results of this interaction are presented in Table 1.

Table 1. Effect of other AEDs on topiramate plasma concentration

“-” – no effect;
NI – not investigated.

Other interactions

When co-administered with topiramate, the AUC of digoxin after a single dose decreased by 12%. The clinical significance of this observation is unclear.

There are no data on the simultaneous use of topiramate and alcohol or other CNS depressant drugs. The combination of topiramate and CNS depressants is not recommended.

In a drug interaction study of topiramate with an oral contraceptive containing norethisterone (1 mg) and ethinyl estradiol (35 mcg), Topiramate at doses of 50-800 mg/day did not significantly affect the efficacy of norethisterone and at doses of 50-200 mg/day – the efficacy of ethinyl estradiol. A significant dose-dependent decrease in the efficacy of ethinyl estradiol was observed at topiramate doses of 200-800 mg/day. The clinical significance of the described changes is unclear. A possible decrease in the effectiveness of oral contraceptives and an increased risk of breakthrough uterine bleeding should be considered in patients receiving Topiramate.

Women taking estrogen-containing contraceptives should be warned to report any changes in the timing and nature of menstruation to their doctor.

In healthy volunteers, a decrease in the AUC of lithium by 18% was observed with simultaneous administration of topiramate at a dose of 200 mg/day. In patients with bipolar affective disorder, the use of topiramate at doses up to 200 mg/day did not affect the pharmacokinetics of lithium, however, at higher doses (up to 600 mg/day), the AUC of lithium was increased by 26%. When topiramate and lithium are used concomitantly, the plasma concentration of the latter should be monitored.

Concomitant use of risperidone with single and multiple doses of topiramate in healthy volunteers and patients with bipolar affective disorder yielded similar results. With concomitant use of topiramate at doses of 250 mg/day or 400 mg/day, the AUC of risperidone, taken at doses of 1-6 mg/day, decreased by 16% and 33%, respectively. At the same time, the pharmacokinetics of 9-hydroxyrisperidone did not change, and the total pharmacokinetics of the active substances (risperidone and 9-hydroxyrisperidone) changed insignificantly. The change in systemic exposure to risperidone/9-hydroxyrisperidone and topiramate was not clinically significant, and this interaction does not have a significant clinical effect.

The drug interaction of hydrochlorothiazide (25 mg) and topiramate (96 mg) was evaluated in healthy volunteers.
The study results showed that in this case, the C_max of topiramate increases by 27% and the AUC of topiramate by 29%. The clinical significance of these studies has not been identified.

The pharmacokinetic parameters of hydrochlorothiazide were not significantly altered by concomitant therapy with topiramate.

When topiramate and metformin are taken concomitantly, the C_max and AUC of metformin increase by 18% and 25%, respectively, while the clearance of metformin decreases by 20%. Topiramate did not affect the time to reach C_max of metformin in plasma. The clearance of topiramate decreases when used concomitantly with metformin. The extent of the identified changes in clearance has not been studied. The clinical significance of the effect of metformin on the pharmacokinetics of topiramate is unclear.

When pioglitazone and topiramate were used concomitantly, a 15% decrease in the AUC of pioglitazone was detected, without a change in the C_max of pioglitazone. These changes were not statistically significant. Also, for the active hydroxymetabolite of pioglitazone, a decrease in C_max and AUC by 13% and 16%, respectively, was detected, and for the active ketometabolite, a decrease in both C_max and AUC by 60% was detected. The clinical significance of these data has not been determined.

When glibenclamide (5 mg/day) was used alone or concomitantly with topiramate (150 mg/day) in patients with type 2 diabetes, the AUC of glibenclamide decreased by 25%. The systemic exposure to 4-trans-hydroxyglibenclamide and 3-cis-hydroxyglibenclamide was also reduced by 13% and 15%, respectively. Glibenclamide did not affect the pharmacokinetics of topiramate at steady state.

Concomitant use of topiramate with other drugs that predispose to nephrolithiasis may increase the risk of kidney stone formation.

Concomitant use of topiramate and valproic acid in patients who tolerate each drug separately is accompanied by hyperammonemia with or without encephalopathy. In most cases, the symptoms and signs disappear after discontinuation of one of the drugs. This adverse event is not caused by a pharmacokinetic interaction. A relationship between hyperammonemia and the use of topiramate as monotherapy or in combination with other drugs has not been established.

Additional drug interaction studies are presented in Table 2.

Table 2. Results of additional interaction studies between topiramate and various drugs.

^a expressed as % of C_max and AUC values during monotherapy;

“-“- no change in C_max and AUC (up to 15% from baseline data);

^b with multiple doses of flunarizine alone, an increase in AUC by 14% was observed, which may be associated with its accumulation during the achievement of steady state;

NI – not investigated.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.