Tiramat

Overdose

Signs and symptoms

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbances, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses with multiple medicinal products including topiramate.

Topiramate overdose can result in severe metabolic acidosis.

Treatment

In acute topiramate 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 adsorb topiramate in vitro. Treatment should be appropriately supportive and the patient should be well hydrated. Haemodialysis has been shown to be an effective means of removing topiramate from the body.

Signs and symptoms

Overdoses of Tiramat have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbances, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after overdoses with multiple medicinal products including Tiramat.

Tiramat overdose can result in severe metabolic acidosis.

Treatment

In acute Tiramat 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 adsorb Tiramat in vitro. Treatment should be appropriately supportive and the patient should be well hydrated. Haemodialysis has been shown to be an effective means of removing Tiramat from the body.

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness, speech disturbance, blurred vision, diplopia, mentation impaired, lethargy, abnormal coordination, stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences were not severe in most cases, but deaths have been reported after polydrug overdoses involving topiramate.

Topiramate overdose has resulted in severe metabolic acidosis.

A patient who ingested a dose between 96 g and 110 g of topiramate was admitted to hospital with coma lasting 20 to 24 hours followed by full recovery after 3 to 4 days.

Similar signs, symptoms, and clinical consequences are expected to occur with overdosage of QUDEXY XR. Therefore, in acute QUDEXY XR 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 adsorb topiramate in vitro. Treatment should be appropriately supportive. Hemodialysis is an effective means of removing topiramate from the body.

Tiramat price

Contraindications

Migraine prophylaxis in pregnancy and in women of childbearing potential if not using a highly effective method of contraception.

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

QUDEXY XR is contraindicated in patients with metabolic acidosis who are taking concomitant metformin.

Incompatibilities

Not applicable.

Not applicable.

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 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:

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, paresthesia, somnolence, tremor, diplopia, vision blurred, diarrhoea, nausea, fatigue, irritability, and weight decreased.

Congenital malformations and fetal growth restrictions.

Paediatric population

Adverse reactions reported more frequently (>2-fold) in children than in adults in double-blind controlled studies include:

- Decreased appetite

- Increased appetite

- Hyperchloraemic acidosis

- Hypokalaemia

- Abnormal behaviour

- Aggression

- Apathy

- Initial insomnia

- Suicidal ideation

- Disturbance in attention

- Lethargy

- Circadian rhythm sleep disorder

- Poor quality sleep

- Lacrimation increased

- Sinus bradycardia

- Feeling abnormal

- Gait disturbance.

Adverse reactions that were reported in children but not in adults in double-blind controlled studies include:

- Eosinophilia

- Psychomotor hyperactivity

- Vertigo

- Vomiting

- Hyperthermia

- Pyrexia

- Learning disability.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

The safety of Tiramat was evaluated from a clinical trial database consisting of 4,111 patients (3,182 on Tiramat and 929 on placebo) who participated in 20 double-blind trials and 2,847 patients who participated in 34 open-label trials, respectively, for Tiramat 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:

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 Tiramat) 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 (>2-fold) in children than in adults in double-blind controlled studies include:

- Decreased appetite

- Increased appetite

- Hyperchloraemic acidosis

- Hypokalaemia

- Abnormal behaviour

- Aggression

- Apathy

- Initial insomnia

- Suicidal ideation

- Disturbance in attention

- Lethargy

- Circadian rhythm sleep disorder

- Poor quality sleep

- Lacrimation increased

- Sinus bradycardia

- Feeling abnormal

- Gait disturbance

ADRs that were reported in children but not in adults in double-blind controlled studies include:

- Eosinophilia

- Psychomotor hyperactivity

- Vertigo

- Vomiting

- Hyperthermia

- Pyrexia

- Learning disability

Table 1: Tiramat Adverse Drug Reactions

* identified as an ADR from postmarketing spontaneous reports. Its frequency was calculated based on clinical trial data.

The following serious adverse reactions are discussed in more detail in other sections of the labeling:

• Acute Myopia and Secondary Angle Closure Glaucoma
• Visual Field Defects
• Oligohydrosis and Hyperthermia
• Metabolic Acidosis
• Suicidal Behavior and Ideation
• Cognitive/Neuropsychiatric Adverse Reactions
• Fetal Toxicity
• Hyperammonemia and Encephalopathy
• Kidney Stones
• Hypothermia with Concomitant Valproic Acid Use
• Paresthesia

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. 19

Topiramate treatment is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled studies of approved and unapproved indications, bleeding was more frequently reported as an adverse event for topiramate than for placebo (4.5% versus 3.0% in adult patients, and 4.4% versus 2.3% in pediatric patients). In this analysis, the incidence of serious bleeding events for topiramate and placebo was 0.3% versus 0.2% for adult patients, and 0.4% versus 0% for pediatric patients.

Adverse bleeding reactions reported with topiramate ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhages. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulants).

Adult Patients 16 Years of Age and Older

The adverse reactions in the monotherapy controlled trial (Study 1) that occurred most commonly in adults in the 400 mg per day topiramate group and at an incidence ≥ 5% higher than the 50 mg per day group were paresthesia, weight decrease, somnolence, anorexia, and difficulty with memory (see Table 5).

Approximately 21% of the 159 adult patients in the 400 mg per day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common ( ≥ 2% more frequent than for topiramate 50 mg per day) adverse reactions causing discontinuation in this trial were difficulty with memory, fatigue, asthenia, insomnia, somnolence, and paresthesia.

Pediatric Patients 6 to less than 16 Years of Age

The adverse reactions in Study 1 that occurred most commonly in pediatric patients in the 400 mg per day topiramate group and at an incidence ≥ 5% higher than in the 50 mg per day group were fever, weight decrease, mood problems, cognitive problems, infection, flushing, and paresthesia (see Table 5).

Approximately 14% of the 77 pediatric patients in the 400 mg per day group who received topiramate as monotherapy in Study 1 discontinued therapy due to adverse reactions. The most common ( ≥ 2% more frequent than for topiramate 50 mg per day) adverse reactions resulting in discontinuation in this trial were difficulty with concentration/attention, fever, flushing, and confusion. 20

Table 5: Adverse Reactions in the Immediate-Release Topiramate Monotherapy Trial with Incidence ≥ 2% in Any Topiramate Group and Incidence in the 400 mg per Day Group Greater Than in the 50 mg per Day Group

The most commonly observed adverse reactions associated with the use of topiramate at dosages of 200 to 400 mg per day (recommended dose range) in controlled trials in adults with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at an incidence of higher ( ≥ 5%) than in the placebo group were: somnolence, weight decrease, anorexia, dizziness, ataxia, speech disorders and related speech problems, language problems, psychomotor slowing, confusion, abnormal vision, difficulty with memory, paresthesia, diplopia, nervousness, and asthenia (see Table 6). Dose-related adverse reactions at dosages of 200 mg to 1,000 mg per day are shown in Table 8.

The most commonly observed adverse reactions associated with the use of topiramate at dosages of 5 mg/kg/day to 9 mg/kg/day in controlled trials in pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome, that were seen at an incidence higher ( ≥ 5%) than in the placebo group were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease (see Table 9). Table 9 also presents the incidence of adverse reactions occurring in at least 1% of pediatric patients treated with topiramate and occurring with greater incidence than placebo.

In controlled clinical trials in adults, 11% of patients receiving topiramate 200 to 400 mg per day as adjunctive therapy discontinued due to adverse reactions. This rate appeared to increase at dosages above 400mg per day. Adverse events associated with discontinuing therapy included somnolence, dizziness, anxiety, difficulty with concentration or attention, fatigue, and paresthesia and increased at dosages above 400 mg per day. None of the pediatric patients who received topiramate adjunctive therapy at 5 mg/kg/day to 9 mg/kg/day in controlled clinical trials discontinued due to adverse reactions.

Approximately 28% of the 1757 adults with epilepsy who received topiramate at dosages of 200 mg to 1,600 mg per day in clinical studies discontinued treatment because of adverse reactions; an individual patient could have reported more than one adverse reaction. These adverse reactions were: psychomotor slowing (4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence (3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression (2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia (2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse reactions. Adverse reactions associated with discontinuing therapy included aggravated convulsions (2.3%), difficulty with concentration/attention (1.6%), language problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).

Table 6 lists the incidence of adverse reactions that occurred in at least 1% of adults treated with 200 to 400 mg per day topiramate (and also higher daily dosing of 600 mg to 1,000 mg) in controlled trials that was numerically greater with topiramate than with placebo. In general, most patients who experienced adverse reactions during the first eight weeks of these trials no longer experienced them by their last visit. Table 9 lists the incidence of adverse reactions that occurred in at least 1% of pediatric patients treated with 5 to 9 mg/kg topiramate in controlled trials and that was numerically greater than the incidence in patients treated with placebo.

Other adverse reactions that occurred in more than 1% of adults treated with 200 mg to 400 mg of topiramate in placebo-controlled epilepsy trials but with equal or greater frequency in the placebo group were headache, injury, anxiety, rash, pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness, insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection, and eye pain.

Table 6: Incidence of Adverse Reactions in Placebo-Controlled, Adjunctive Epilepsy Trials in Adultsa,b,c

Study 7 was a randomized, double-blind, adjunctive, placebo-controlled, parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200 mg per day with a 25 mg per day starting dose, increased by 25 mg per day each week for 8 weeks until the 200 mg per day maintenance dose was reached; and 3) topiramate 200 mg per day with a 50 mg per day starting dose, increased by 50 mg per day each week for 4 weeks until the 200 mg per day maintenance dose was reached. All patients were maintained on concomitant carbamazepine with or without another concomitant antiepileptic drug.

The most commonly observed adverse reactions associated with the use of topiramate that were seen at an incidence higher ( ≥ 5%) than in the placebo group were: paresthesia, nervousness, somnolence, difficulty with concentration/attention, and fatigue (see Table 7). Because these topiramate treatment difference incidence (topiramate % - Placebo %) of many adverse reactions reported in this study were markedly lower than those reported in the previous epilepsy studies, they cannot be directly compared with data obtained in other studies.

Table 7: Incidence of Adverse Reactions in Study 7a,b,c

Preclinical safety data

In nonclinical studies of fertility, despite maternal and paternal toxicity as low as 8 mg/kg/day, no effects on fertility were observed, in male or female rats with doses up to 100 mg/kg/day.

In preclinical studies, topiramate has been shown to have teratogenic effects in the species studied (mice, rats and rabbits). In mice, fetal weights and skeletal ossification were reduced at 500 mg/kg/day in conjunction with maternal toxicity. Overall numbers of fetal malformations in mice were increased for all drug-treated groups (20, 100 and 500 mg/kg/day).

In rats, dosage-related maternal and embryo/fetal toxicity (reduced fetal weights and/or skeletal ossification) were observed down to 20 mg/kg/day with teratogenic effects (limb and digit defects) at 400 mg/kg/day and above. In rabbits, dosage-related maternal toxicity was noted down to 10 mg/kg/day with embryo/fetal toxicity (increased lethality) down to 35 mg/kg/day, and teratogenic effects (rib and vertebral malformations) at 120 mg/kg/day.

The teratogenic effects seen in rats and rabbits were similar to those seen with carbonic anhydrase inhibitors, which have not been associated with malformations in humans. Effects on growth were also indicated by lower weights at birth and during lactation for pups from female rats treated with 20 or 100 mg/kg/day during gestation and lactation. In rats, topiramate crosses the placental barrier.

In juvenile rats, daily oral administration of topiramate at doses up to 300 mg/kg/day during the period of development corresponding to infancy, childhood, and adolescence resulted in toxicities similar to those in adult animals (decreased food consumption with decreased body weight gain, centrolobullar hepatocellular hypertrophy). There were no relevant effects on long bone (tibia) growth or bone (femur) mineral density, preweaning and reproductive development, neurological development (including assessments on memory and learning), mating and fertility or hysterotomy parameters.

In a battery of in vitro and in vivo mutagenicity assays, topiramate did not show genotoxic potential.

In nonclinical studies of fertility, despite maternal and paternal toxicity as low as 8 mg/kg/day, no effects on fertility were observed, in male or female rats with doses up to 100 mg/kg/day.

In preclinical studies, Tiramat has been shown to have teratogenic effects in the species studied (mice, rats and rabbits). In mice, fetal weights and skeletal ossification were reduced at 500 mg/kg/day in conjunction with maternal toxicity. Overall numbers of fetal malformations in mice were increased for all drug-treated groups (20, 100 and 500 mg/kg/day).

In rats, dosage-related maternal and embryo/fetal toxicity (reduced fetal weights and/or skeletal ossification) were observed down to 20 mg/kg/day with teratogenic effects (limb and digit defects) at 400 mg/kg/day and above. In rabbits, dosage-related maternal toxicity was noted down to 10 mg/kg/day with embryo/fetal toxicity (increased lethality) down to 35 mg/kg/day, and teratogenic effects (rib and vertebral malformations) at 120 mg/kg/day.

The teratogenic effects seen in rats and rabbits were similar to those seen with carbonic anhydrase inhibitors, which have not been associated with malformations in humans. Effects on growth were also indicated by lower weights at birth and during lactation for pups from female rats treated with 20 or 100 mg/kg/day during gestation and lactation. In rats, Tiramat crosses the placental barrier.

In juvenile rats, daily oral administration of Tiramat at doses up to 300 mg/kg/day during the period of development corresponding to infancy, childhood, and adolescence resulted in toxicities similar to those in adult animals (decreased food consumption with decreased body weight gain, centrolobullar hepatocellular hypertrophy). There were no relevant effects on long bone (tibia) growth or bone (femur) mineral density, preweaning and reproductive development, neurological development (including assessments on memory and learning), mating and fertility or hysterotomy parameters.

In a battery of in vitro and in vivo mutagenicity assays, Tiramat did not show genotoxic potential.

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.

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.

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

QUDEXY XR extended-release capsules are indicated as initial monotherapy in patients 2 years of age and older with partial onset or primary generalized tonic-clonic seizures and adjunctive therapy in patients 2 years of age and older with partial onset or primary generalized tonic-clonic seizures. Safety and effectiveness in patients who were converted to monotherapy from a previous regimen of other anticonvulsant drugs have not been established in controlled trials.

QUDEXY XR extended-release capsules are indicated as adjunctive therapy in patients 2 years of age and older with seizures associated with Lennox-Gastaut syndrome.

QUDEXY XR extended-release capsules are indicated for the prophylaxis of migraine headache in adults and adolescents 12 years of age and older. The usefulness of QUDEXY XR in the acute treatment of migraine headache has not been studied.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptics, other antiepileptics, antimigraine preparations, ATC code: N03AX11

Topiramate is classified as a sulfamate-substituted monosaccharide. The precise mechanism by which topiramate exerts its antiseizure and migraine prophylaxis effects are unknown. Electrophysiological and biochemical studies on cultured neurons have identified three properties that may contribute to the antiepileptic efficacy of topiramate.

Action potentials elicited repetitively by a sustained depolarization of the neurons were blocked by topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel blocking action. Topiramate increased the frequency at which γ-aminobutyrate (GABA) activated GABAA receptors, and enhanced the ability of GABA to induce a flux of chloride ions into neurons, suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter.

This effect was not blocked by flumazenil, a benzodiazepine antagonist, nor did topiramate increase the duration of the channel open time, differentiating topiramate from barbiturates that modulate GABAA receptors.

Because the antiepileptic profile of topiramate differs markedly from that of the benzodiazepines, it may modulate a benzodiazepine-insensitive subtype of GABAA receptor. Topiramate antagonized the ability of kainate to activate the kainate/AMPA (α -amino-3-hydroxy-5-methylisoxazole-4-propionic acid) subtype of excitatory amino acid (glutamate) receptor, but had no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate were concentration-dependent over a range of 1 µM to 200 µM, with minimum activity observed at 1 µM to 10 µM.

In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. This pharmacologic effect is much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to be a major component of topiramate's antiepileptic activity.

In animal studies, topiramate exhibits anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests and is effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Topiramate is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole.

Studies in mice receiving concomitant administration of topiramate and carbamazepine or phenobarbital showed synergistic anticonvulsant activity, while combination with phenytoin showed additive anticonvulsant activity. In well-controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations of topiramate and its clinical efficacy. No evidence of tolerance has been demonstrated in man.

Absence seizures

Two small one arm studies were carried out with children aged 4-11 years old (CAPSS-326 and TOPAMAT-ABS-001). One included 5 children and the other included 12 children before it was terminated early due to lack of therapeutic response. The doses used in these studies were up to approximately 12 mg/kg in study TOPAMAT-ABS-001 and a maximum of the lesser of 9 mg/kg/day or 400 mg/day in study CAPSS-326. These studies do not provide sufficient evidence to reach conclusion regarding efficacy or safety in the paediatric population.

Pharmacotherapeutic group: antiepileptics, other antiepileptics, antimigraine preparations, ATC code: N03AX11

Tiramat is classified as a sulfamate-substituted monosaccharide. The precise mechanism by which Tiramat exerts its antiseizure and migraine prophylaxis effects are unknown. Electrophysiological and biochemical studies on cultured neurons have identified three properties that may contribute to the antiepileptic efficacy of Tiramat.

Action potentials elicited repetitively by a sustained depolarization of the neurons were blocked by Tiramat in a time-dependent manner, suggestive of a state-dependent sodium channel blocking action. Tiramat increased the frequency at which γ-aminobutyrate (GABA) activated GABAA receptors, and enhanced the ability of GABA to induce a flux of chloride ions into neurons, suggesting that Tiramat potentiates the activity of this inhibitory neurotransmitter.

This effect was not blocked by flumazenil, a benzodiazepine antagonist, nor did Tiramat increase the duration of the channel open time, differentiating Tiramat from barbiturates that modulate GABAA receptors.

Because the antiepileptic profile of Tiramat differs markedly from that of the benzodiazepines, it may modulate a benzodiazepine-insensitive subtype of GABAA receptor. Tiramat antagonized the ability of kainate to activate the kainate/AMPA (α -amino-3-hydroxy-5 methylisoxazole-4-propionic acid) subtype of excitatory amino acid (glutamate) receptor, but had no apparent effect on the activity of N-methyl-Daspartate (NMDA) at the NMDA receptor subtype. These effects of Tiramat were concentration dependent over a range of 1 μM to 200 μM, with minimum activity observed at 1 μM to 10 μM.

In addition, Tiramat inhibits some isoenzymes of carbonic anhydrase. This pharmacologic effect is much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to be a major component of Tiramat's antiepileptic activity.

In animal studies, Tiramat exhibits anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests and is effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia. Tiramat is only weakly effective in blocking clonic seizures induced by the GABAA receptor antagonist, pentylenetetrazole.

Studies in mice receiving concomitant administration of Tiramat and carbamazepine or Phenobarbital showed synergistic anticonvulsant activity, while combination with phenytoin showed additive anticonvulsant activity. In well-controlled add-on trials, no correlation has been demonstrated between trough plasma concentrations of Tiramat and its clinical efficacy. No evidence of tolerance has been demonstrated in man.

Absence seizures

The results of two studies (CAPSS-326 and TOPMAT-ABS-001) on absences showed that Tiramat treatment did not reduce the frequency of absence seizures.

Topiramate has anticonvulsant activity in rat and mouse maximal electroshock seizure (MES) tests. Topiramate is only weakly effective in blocking clonic seizures induced by the GABA-A receptor antagonist, pentylenetetrazole. Topiramate is also effective in rodent models of epilepsy, which include tonic and absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in rats by kindling of the amygdala or by global ischemia.

Changes (increases and decreases) from baseline in vital signs (systolic blood pressure-SBP, diastolic blood pressure-DBP, pulse) occurred more frequently in pediatric patients (6 to 17 years) treated with various daily doses of topiramate (50 mg, 100 mg, 200 mg, 2 to 3 mg/kg) than in patients treated with placebo in controlled trials for migraine prophylaxis. The most notable changes were SBP < 90 mm Hg, DBP < 50 mm Hg, SBP or DBP increases or decreases ≥ 20 mm Hg, and pulse increases or decreases ≥ 30 beats per minute. These changes were often dose-related, and were most frequently associated with the greatest treatment difference at the 200 mg dose level. When a position was specified for measurement of vital signs in a trial, measurements were made in a sitting position. Systematic collection of orthostatic vital signs has not been conducted. The clinical significance of these various changes in vital signs has not been clearly established.

Pharmacokinetic properties

The film-coated tablet and hard capsule formulations are bioequivalent.

The pharmacokinetic profile of topiramate compared to other AEDs shows a long plasma half-life, linear pharmacokinetics, predominantly renal clearance, absence of significant protein binding, and lack of clinically relevant active metabolites.

Topiramate is not a potent inducer of drug metabolizing enzymes, can be administered without regard to meals, and routine monitoring of plasma topiramate concentrations is not necessary. In clinical studies, there was no consistent relationship between plasma concentrations and efficacy or adverse events.

Absorption

Topiramate is rapidly and well absorbed. Following oral administration of 100 mg topiramate to healthy subjects, a mean peak plasma concentration (Cmax) of 1.5 µg/ml was achieved within 2 to 3 hours (Tmax).

Based on the recovery of radioactivity from the urine the mean extent of absorption of a 100 mg oral dose of 14C-topiramate was at least 81%. There was no clinically significant effect of food on the bioavailability of topiramate.

Distribution

Generally, 13 to 17% of topiramate is bound to plasma protein. A low capacity binding site for topiramate in/on erythrocytes that is saturable above plasma concentrations of 4 µg/ml has been observed. The volume of distribution varied inversely with the dose. The mean apparent volume of distribution was 0.80 to 0.55 l/kg for a single dose range of 100 to 1200 mg. An effect of gender on the volume of distribution was detected, with values for females circa 50% of those for males. This was attributed to the higher percent body fat in female patients and is of no clinical consequence.

Biotransformation

Topiramate is not extensively metabolized (~20%) in healthy volunteers. It is metabolized up to 50% in patients receiving concomitant antiepileptic therapy with known inducers of drug metabolizing enzymes. Six metabolites, formed through hydroxylation, hydrolysis and glucuronidation, have been isolated, characterized and identified from plasma, urine and faeces of humans. Each metabolite represents less than 3% of the total radioactivity excreted following administration of 14C-topiramate. Two metabolites, which retained most of the structure of topiramate, were tested and found to have little or no anticonvulsant activity.

Elimination

In humans, the major route of elimination of unchanged topiramate and its metabolites is via the kidney (at least 81% of the dose). Approximately 66% of a dose of 14C-topiramate was excreted unchanged in the urine within four days. Following twice a day dosing with 50 mg and 100 mg of topiramate the mean renal clearance was approximately 18 ml/min and 17 ml/min, respectively. There is evidence of renal tubular reabsorption of topiramate. This is supported by studies in rats where topiramate was co-administered with probenecid, and a significant increase in renal clearance of topiramate was observed. Overall, plasma clearance is approximately 20 to 30 ml/min in humans following oral administration.

Linearity/non-linearity

Topiramate exhibits low intersubject variability in plasma concentrations and, therefore, has predictable pharmacokinetics. The pharmacokinetics of topiramate are linear with plasma clearance remaining constant and area under the plasma concentration curve increasing in a dose-proportional manner over a 100 to 400 mg single oral dose range in healthy subjects. Patients with normal renal function may take 4 to 8 days to reach steady-state plasma concentrations. The mean Cmax following multiple, twice a day oral doses of 100 mg to healthy subjects was 6.76 µg/ml. Following administration of multiple doses of 50 mg and 100 mg of topiramate twice a day, the mean plasma elimination half-life was approximately 21 hours.

Use with other AEDs

Concomitant multiple-dose administration of topiramate, 100 to 400 mg twice a day, with phenytoin or carbamazepine shows dose proportional increases in plasma concentrations of topiramate.

Renal impairment

The plasma and renal clearance of topiramate are decreased in patients with moderate and severe impaired renal function (CLCR ≤ 70 ml/min). As a result, higher steady-state topiramate plasma concentrations are expected for a given dose in renal-impaired patients as compared to those with normal renal function. In addition, patients with renal impairment will require a longer time to reach steady-state at each dose. In patients with moderate and severe renal impairment, half of the usual starting and maintenance dose is recommended.

Topiramate is effectively removed from plasma by haemodialysis. A prolonged period of hemodialysis may cause topiramate concentration to fall below levels that are required to maintain an anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of topiramate in the patient being dialyzed.

Hepatic impairment

Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic impairment. Therefore, topiramate should be administered with caution in patients with hepatic impairment.

Elderly population

Plasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal disease.

Paediatric population (pharmacokinetics, up to 12 years of age)

The pharmacokinetics of topiramate in children, as in adults receiving add-on therapy, are linear, with clearance independent of dose and steady-state plasma concentrations increasing in proportion to dose. Children, however, have a higher clearance and a shorter elimination half-life. Consequently, the plasma concentrations of topiramate for the same mg/kg dose may be lower in children compared to adults. As in adults, hepatic enzyme inducing AEDs decrease the steady-state plasma concentrations.

The pharmacokinetic profile of Tiramat compared to other antiepileptic drugs shows a long plasma halflife, linear pharmacokinetics, predominantly renal clearance, absence of significant protein binding, and lack of clinically relevant active metabolites.

Tiramat is not a potent inducer of drug metabolizing enzymes, can be administered without regard to meals, and routine monitoring of plasma Tiramat concentrations is not necessary. In clinical studies, there was no consistent relationship between plasma concentrations and efficacy or adverse events.

Absorption

Tiramat is rapidly and well absorbed. Following oral administration of 100 mg Tiramat to healthy subjects, a mean peak plasma concentration (Cmax) of 1.5 μg/ml was achieved within 2 to 3 hours (Tmax).

Based on the recovery of radioactivity from the urine the mean extent of absorption of a 100 mg oral dose of 14C-Tiramat was at least 81%. There was no clinically significant effect of food on the bioavailability of Tiramat.

Distribution

Generally, 13 to 17% of Tiramat is bound to plasma protein. A low capacity binding site for Tiramat in/on erythrocytes that is saturable above plasma concentrations of 4 μg/ml has been observed. The volume of distribution varied inversely with the dose. The mean apparent volume of distribution was 0.80 to 0.55 l/kg for a single dose range of 100 to 1200 mg. An effect of gender on the volume of distribution was detected, with values for females circa 50% of those for males. This was attributed to the higher percent body fat in female patients and is of no clinical consequence.

Metabolism

Tiramat is not extensively metabolized (~20%) in healthy volunteers. It is metabolized up to 50% in patients receiving concomitant antiepileptic therapy with known inducers of drug metabolizing enzymes. Six metabolites, formed through hydroxylation, hydrolysis and glucuronidation, have been isolated, characterized and identified from plasma, urine and faeces of humans. Each metabolite represents less than 3% of the total radioactivity excreted following administration of 14C-Tiramat. Two metabolites, which retained most of the structure of Tiramat, were tested and found to have little or no anticonvulsant activity.

Elimination

In humans, the major route of elimination of unchanged Tiramat and its metabolites is via the kidney (at least 81% of the dose). Approximately 66% of a dose of 14C-Tiramat was excreted unchanged in the urine within four days. Following twice a day dosing with 50 mg and 100 mg of Tiramat the mean renal clearance was approximately 18 ml/min and 17 ml/min, respectively. There is evidence of renal tubular reabsorption of Tiramat. This is supported by studies in rats where Tiramat was co-administered with probenecid, and a significant increase in renal clearance of Tiramat was observed. Overall, plasma clearance is approximately 20 to 30 ml/min in humans following oral administration.

Tiramat exhibits low intersubject variability in plasma concentrations and, therefore, has predictable pharmacokinetics. The pharmacokinetics of Tiramat are linear with plasma clearance remaining constant and area under the plasma concentration curve increasing in a dose-proportional manner over a 100 to 400 mg single oral dose range in healthy subjects. Patients with normal renal function may take 4 to 8 days to reach steady-state plasma concentrations. The mean Cmax following multiple, twice a day oral doses of 100 mg to healthy subjects was 6.76 μg/ml. Following administration of multiple doses of 50 mg and 100 mg of Tiramat twice a day, the mean plasma elimination half-life was approximately 21 hours.

Concomitant multiple-dose administration of Tiramat, 100 to 400 mg twice a day, with phenytoin or carbamazepine shows dose proportional increases in plasma concentrations of Tiramat.

The plasma and renal clearance of Tiramat are decreased in patients with moderate and severe impaired renal function (CLCR ≤ 70 ml/min). As a result, higher steady-state Tiramat plasma concentrations are expected for a given dose in renal-impaired patients as compared to those with normal renal function.

In addition, patients with renal impairment will require a longer time to reach steady-state at each dose. In patients with moderate and severe renal impairment, half of the usual starting and maintenance dose is recommended.

Tiramat is effectively removed from plasma by haemodialysis. A prolonged period of hemodialysis may cause Tiramat concentration to fall below levels that are required to maintain an anti-seizure effect. To avoid rapid drops in Tiramat plasma concentration during hemodialysis, a supplemental dose of Tiramat may be required. The actual adjustment should take into account 1) the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the effective renal clearance of Tiramat in the patient being dialyzed.

Plasma clearance of Tiramat decreased a mean of 26% in patients with moderate to severe hepatic impairment. Therefore, Tiramat should be administered with caution in patients with hepatic impairment.

Plasma clearance of Tiramat is unchanged in elderly subjects in the absence of underlying renal disease.

Paediatric population (pharmacokinetics, up to 12 years of age)

The pharmacokinetics of Tiramat in children, as in adults receiving add-on therapy, are linear, with clearance independent of dose and steady-state plasma concentrations increasing in proportion to dose. Children, however, have a higher clearance and a shorter elimination half-life. Consequently, the plasma concentrations of Tiramat for the same mg/kg dose may be lower in children compared to adults. As in adults, hepatic enzyme inducing anti-epileptic drugs decrease the steady-state plasma concentrations.

The pharmacokinetics of QUDEXY XR are linear with dose proportional increases in plasma concentration when administered as a single oral dose over the range of 50 mg to 1,400 mg. At 25 mg, the pharmacokinetics of QUDEXY XR are nonlinear, possibly due to the binding of topiramate to carbonic anhydrase in red blood cells.

QUDEXY XR sprinkled on a spoonful of soft food is bioequivalent to the intact capsule formulation.

Following a single 200 mg oral dose of QUDEXY XR, peak plasma concentrations (Tmax) occurred approximately 20 hours after dosing. Steady-state was reached in about 5 days following daily dosing of QUDEXY XR in subjects with normal renal function, with a Tmax of approximately 6 hours.

At steady-state, the plasma exposure (AUC0-24hr, Cmax, and Cmin) of topiramate from QUDEXY XR administered once daily and the immediate-release topiramate tablets administered twice-daily were shown to be bioequivalent. Fluctuation of topiramate plasma concentrations at steady-state for QUDEXY XR administered once daily was approximately 40% in healthy subjects, compared to approximately 53% for immediate-release topiramate.

Compared to the fasted state, high-fat meal had no effect on bioavailability (AUC and Cmax) but delayed the Tmax by approximately 4 hours following a single dose of QUDEXY XR. QUDEXY XR can be taken without regard to meals.

Topiramate is 15% to 41% bound to human plasma proteins over the blood concentration range of 0.5 mcg/mL to 250 mcg/mL. The fraction bound decreased as blood concentration increased.

Carbamazepine and phenytoin do not alter the binding of immediate-release topiramate. Sodium valproate, at 500 mcg/mL (a concentration 5 to 10 times higher than considered therapeutic for valproate) decreased the protein binding of immediate-release topiramate from 23% to 13%. Immediate-release topiramate does not influence the binding of sodium valproate.

Topiramate is not extensively metabolized and is primarily eliminated unchanged in the urine (approximately 70% of an administered dose). Six metabolites have been identified in humans, none of which constitutes more than 5% of an administered dose. The metabolites are formed via hydroxylation, hydrolysis, and glucuronidation. There is evidence of renal tubular reabsorption of topiramate. In rats, given probenecid to inhibit tubular reabsorption, along with topiramate, a significant increase in renal clearance of topiramate was observed. This interaction has not been evaluated in humans. Overall, oral plasma clearance (CL/F) is approximately 20 mL/min to 30 mL/min in adults following oral administration. The mean effective half-life of QUDEXY XR is approximately 56 hours. Steady-state is reached in about 5 days after QUDEXY XR dosing in subjects with normal renal function.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is recommended.

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). Proper hydration prior to and during activities such as exercise or exposure to warm temperatures may reduce the risk of heat-related adverse reactions.

Women of childbearing potential

Topiramate may cause fetal harm and fetal growth restriction (small for gestational age and low birth weight) when administered to a pregnant woman. 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.

Before the initiation of treatment with topiramate in a woman of childbearing potential, pregnancy testing should be performed and a highly effective contraceptive method advised. The patient should be fully informed of the risks related to the use of topiramate during pregnancy.

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.

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 AEDs 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 renal function

In patients with impaired renal function (CLCR ≤ 70 mL/min) topiramate should be administered with caution as the plasma and renal clearance of topiramate are decreased.

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.

Visual field defects

Visual field defects have been reported in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual field defects occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.

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 signs or symptoms are present (e.g. Kussmaul's deep breathing, dyspnoea, anorexia, nausea, vomiting, excessive tiredness, tachycardia or arrhythmia), indicative of metabolic acidosis, measurement of serum bicarbonate is recommended. 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.

Impairment of cognitive function

Cognitive impairment in epilepsy is multifactorial and may be due to the underlying aetiology, due to the epilepsy or due to the anti-epileptic treatment. There have been reports in the literature of impairment of cognitive function in adults on topiramate therapy which required reduction in dosage or discontinuation of treatment. However, studies regarding cognitive outcomes in children treated with topiramate are insufficient and its effect in this regard still needs to be elucidated.

Hyperammonemia and encephalopathy

Hyperammonemia with or without encephalopathy has been reported with topiramate treatment. The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia has been reported more frequently when topiramate is used concomitantly with valproic acid.

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.

Lactose intolerance

Tiramat tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.

In situations where rapid withdrawal of Tiramat is medically required, appropriate monitoring is recommended.

As with other anti-epileptic drugs, some patients may experience an increase in seizure frequency or the onset of new types of seizures with Tiramat. 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 Tiramat 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.

Oligohydrosis (decreased sweating) has been reported in association with the use of Tiramat. Decreased sweating and 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 Tiramat 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 Tiramat.

In double blind clinical trials, suicide related events (SREs) (suicidal ideation, suicide attempts and suicide) occurred at a frequency of 0.5% in Tiramat 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 Tiramat treatment.

In addition, patients taking other medicinal products associated with nephrolithiasis may be at increased risk.

Decreased hepatic function

In hepatically-impaired patients, Tiramat should be administered with caution as the clearance of Tiramat 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 Tiramat. 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 Tiramat therapy. In contrast to primary narrow angle glaucoma, which is rare under 40 years of age, secondary angle closure glaucoma associated with Tiramat has been reported in paediatric patients as well as adults. Treatment includes discontinuation of Tiramat, 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 Tiramat.

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 Tiramat treatment. This decrease in serum bicarbonate is due to the inhibitory effect of Tiramat 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 Tiramat.

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 Tiramat on bonerelated sequelae has not been systematically investigated in paediatric or adult populations.

Depending on underlying conditions, appropriate evaluation including serum bicarbonate levels is recommended with Tiramat therapy. If signs or symptoms are present (e.g. Kussmaul's deep breathing, dyspnoea, anorexia, nausea, vomiting, excessive tiredness, tachycardia or arrhythmia), indicative of metabolic acidosis, measurement of serum bicarbonate is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing Tiramat (using dose tapering).

Tiramat 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 Tiramat. It is recommended that patients on Tiramat 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 Tiramat.

Impairment of cognitive function

Cognitive impairment in epilepsy is multifactorial and may be due to the underlying aetiology, due to the epilepsy or due to the anti epileptic treatment. There have been reports in the literature of impairment of cognitive function in adults on Tiramat therapy which required reduction in dosage or discontinuation of treatment. However, studies regarding cognitive outcomes in children treated with Tiramat are insufficient and its effect in this regard still needs to be elucidated.

Sucrose intolerance

Tiramat Capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Included as part of the PRECAUTIONS section.

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 hyperemia (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 pediatric patients as well as adults. The primary treatment to reverse symptoms is discontinuation of QUDEXY XR as rapidly as possible, according to the judgment of the treating physician. Other measures, in conjunction with discontinuation of QUDEXY XR, may be helpful.

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

Visual field defects have been reported in patients receiving topiramate independent of elevated intraocular pressure. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during treatment with QUDEXY XR, consideration should be given to discontinuing the drug.

Oligohydrosis (decreased sweating), resulting in hospitalization in some cases, has been reported in association with topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases were reported after exposure to elevated environmental temperatures.

The majority of the reports have been in pediatric patients. Patients, especially pediatric patients, treated with QUDEXY XR should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when QUDEXY XR is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with topiramate treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of topiramate in placebo-controlled clinical trials and in the post-marketing period. Generally, topiramate-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. Bicarbonate decrements are usually mild-moderate (average decrease of 4 mEq/L at daily doses of 400 mg in adults and at approximately 6 mg/kg/day in pediatric patients); rarely, patients can experience severe decrements to values below 10 mEq/L. Conditions or therapies that predispose patients to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet or specific drugs) may be additive to the bicarbonate lowering effects of topiramate.

Some manifestations of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis, and may also result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fractures. Chronic metabolic acidosis in pediatric patients may also reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of topiramate on growth and bone-related sequelae has not been systematically investigated in long-term, placebo-controlled trials. Long-term, open-label treatment of infants/toddlers, with intractable partial epilepsy, for up to 1 year, showed reductions from baseline in Z SCORES for length, weight, and head circumference compared to age and sex-matched normative data, although these patients are likely to have different growth rates than normal infants. Reductions in Z SCORES for length and weight were correlated to the degree of acidosis. Topiramate treatment that causes metabolic acidosis during pregnancy can possibly produce adverse effects on the fetus and might also cause metabolic acidosis in the neonate from possible transfer of topiramate to the fetus.

Adult Patients

In adults, the incidence of persistent decreases in serum bicarbonate (levels of less than 20 mEq/L at two consecutive visits or at the final visit) in controlled clinical trials for adjunctive treatment of epilepsy was 32% for 400 mg per day, and 1% for placebo. Metabolic acidosis has been observed at doses as low as 50 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in the adjunctive therapy trials was 3% for 400 mg per day and 0% for placebo. The incidence of persistent decreases in serum bicarbonate in adult patients ( ≥ 16 years of age) in the epilepsy controlled clinical trial for monotherapy was 14% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in this trial for adults was 1% for 50 mg per day and 6% for 400 mg per day. Serum bicarbonate levels have not been systematically evaluated at daily doses greater than 400 mg per day.

Pediatric Patients (2 years to 16 years of age)

The incidence of persistent decreases in serum bicarbonate in placebo-controlled trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures in patients age 2 years to 16 years was 67% for topiramate (at approximately 6 mg/kg/day), and 10% for placebo. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in these trials was 11% for topiramate and 0% for placebo. Cases of moderately severe metabolic acidosis have been reported in patients as young as 5 months old, especially at daily doses above 5 mg/kg/day.

In pediatric patients (6 years to 15 years of age), the incidence of persistent decreases in serum bicarbonate in the epilepsy controlled clinical trial for monotherapy performed with topiramate was 9% for 50 mg per day and 25% for 400 mg per day. The incidence of a markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in this trial was 1% for 50 mg per day and 6% for 400 mg per day.

Pediatric Patients (under 2 years of age)

Although QUDEXY XR is not approved for use in patients less than 2 years of age, a study of topiramate as adjunctive use in patients under 2 years of age with partial onset seizures revealed that topiramate produced a metabolic acidosis that is notably greater in magnitude than that observed in controlled trials in older children and adults. The mean treatment difference (25 mg/kg/day topiramate-placebo) was -5.9 mEq/L for bicarbonate. The incidence of metabolic acidosis (defined by a serum bicarbonate less than 20 mEq/L) was 0% for placebo, 30% for 5 mg/kg/day, 50% for 15 mg/kg/day, and 45% for 25 mg/kg/day. The incidence of markedly abnormal changes (i.e., less than 17 mEq/L and greater than 5 mEq/L decrease from baseline of greater than or equal to 20 mEq/L) was 0% for placebo, 4% for 5 mg/kg/day, 5% for 15 mg/kg/day and 5% for 25 mg/kg/day.

Adult Patients

The incidence of persistent decreases in serum bicarbonate in placebo-controlled trials in adults for the prophylaxis of migraine was 44% for 200 mg/day, 39% for 100 mg/day, 23% for 50 mg/day, and 7% for placebo. The incidence of markedly abnormally low serum bicarbonate (i.e., absolute value less than 17 mEq/L and greater than 5 mEq/L decrease from pretreatment) in these trials was 11% for 200 mg/day, 9% for 100 mg/day, 2% for 50 mg/day, and < 1% for placebo.

Adolescent Patients

In pooled, double-blind migraine prophylaxis studies in adolescent patients (12 to 17 years of age), the incidence of persistent decreases in serum bicarbonate was 77% for 200 mg/day, 27% for 100 mg/day, 30% for 50 mg/day, and 9% for placebo. The incidence of markedly low serum bicarbonate (i.e., absolute value < 17 mEq/L and > 5 mEq/L decrease from pretreatment) was 6% for 100 mg/day, 2% for 50 mg/day, and 2% for placebo. This bicarbonate criterion was not met by any patients in the 200 mg/day group, which had a low number of subjects (n=13).

Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, alkali treatment should be considered.

Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED, including QUDEXY XR, for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 4 shows absolute and relative risk by indication for all evaluated AEDs.

Table 4: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing QUDEXY XR or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Adverse reactions most often associated with the use of topiramate, and therefore expected to be associated with the use of QUDEXY XR, were related to the central nervous system and were observed in both the epilepsy and migraine populations. In adults, the most frequent of these can be classified into three general categories: 1) Cognitive-related dysfunction (e.g. confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems, particularly word-finding difficulties), 2) Psychiatric/behavioral disturbances (e.g. depression or mood problems), and 3) Somnolence or fatigue.

Cognitive Related Dysfunction

The majority of cognitive-related adverse reactions were mild to moderate in severity, and they frequently occurred in isolation. Rapid titration rate and higher initial dose were associated with higher incidences of these reactions. Many of these reactions contributed to withdrawal from treatment.

In the adjunctive epilepsy controlled trials conducted with topiramate (using rapid titration such as 100 mg per day to 200 mg per day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 42% for 200 mg per day, 41% for 400 mg per day, 52% for 600 mg per day, 56% for 800 and 1,000 mg per day, and 14% for placebo. These dose-related adverse reactions began with a similar frequency in the titration or in the maintenance phase, although in some patients the events began during titration and persisted into the maintenance phase. Some patients who experienced one or more cognitive-related adverse reactions in the titration phase had a dose-related recurrence of these reactions in the maintenance phase.

In the monotherapy epilepsy controlled trial conducted with topiramate, the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg per day and 26% for 400 mg per day.

In the 6-month migraine prophylaxis controlled trials using a slower titration regimen (25 mg/day weekly increments), the proportion of patients who experienced one or more cognitive-related adverse reactions was 19% for topiramate 50 mg/day, 22% for 100 mg/day (the recommended dose), 28% for 200 mg/day, and 10% for placebo. These dose-related adverse reactions typically began in the titration phase and often persisted into the maintenance phase, but infrequently began in the maintenance phase. Some patients experienced a recurrence of one or more of these cognitive adverse reactions and this recurrence was typically in the titration phase. A relatively small proportion of topiramate-treated patients experienced more than one concurrent cognitive adverse reaction. The most common cognitive adverse reactions occurring together included difficulty with memory along with difficulty with concentration/attention, difficulty with memory along with language problems, and difficulty with concentration/attention along with language problems. Rarely, topiramate-treated patients experienced three concurrent cognitive reactions.

Psychiatric/Behavioral Disturbances

Psychiatric/behavioral disturbances (depression or mood) were dose-related for both the epilepsy and migraine populations treated with topiramate.

Somnolence/Fatigue

Somnolence and fatigue were the adverse reactions most frequently reported during clinical trials of topiramate for adjunctive epilepsy. For the adjunctive epilepsy population, the incidence of somnolence did not differ substantially between 200 mg per day and 1,000 mg per day, but the incidence of fatigue was dose-related and increased at dosages above 400 mg per day. For the monotherapy epilepsy population in the 50 mg per day and 400 mg per day groups, the incidence of somnolence was dose-related (9% for the 50 mg per day group and 15% for the 400 mg per day group) and the incidence of fatigue was comparable in both treatment groups (14% each). For the migraine population, somnolence and fatigue were dose-related and more common in the titration phase.

Additional nonspecific CNS events commonly observed with topiramate in the adjunctive epilepsy population include dizziness or ataxia.

Epilepsy

In double-blind adjunctive therapy and monotherapy epilepsy clinical studies conducted with topiramate, the incidences of cognitive/neuropsychiatric adverse reactions in pediatric patients were generally lower than observed in adults. These reactions included psychomotor slowing, difficulty with concentration/attention, speech disorders/related speech problems and language problems. The most frequently reported neuropsychiatric reactions in pediatric patients during adjunctive therapy double-blind studies were somnolence and fatigue. The most frequently reported neuropsychiatric reactions in pediatric patients in the 50 mg per day and 400 mg per day groups during the monotherapy double-blind study were headache, dizziness, anorexia, and somnolence.

No patients discontinued treatment due to any adverse reactions in the adjunctive epilepsy double-blind trials. In the monotherapy epilepsy double-blind trial conducted with immediate-release topiramate product, 1 pediatric patient (2%) in the 50 mg per day group and 7 pediatric patients (12%) in the 400 mg per day group discontinued treatment due to any adverse reactions. The most common adverse reaction associated with discontinuation of therapy was difficulty with concentration/attention; all occurred in the 400 mg per day group.

Migraine

The incidence of cognitive adverse reactions was increased in topiramate-treated patients (7%) versus placebo (4%) in pooled, double-blind placebo-controlled studies in which adolescent patients (12 to 17 years) were randomized to placebo or one of several fixed daily doses of topiramate (50 mg, 100 mg, 200 mg).

The incidence of cognitive adverse reactions was also increased in a placebo-controlled study of pediatric patients (6 to 16 years) treated with 2 to 3 mg/kg/day of topiramate (10%) versus placebo treatment (2%). QUDEXY XR is not approved for prophylaxis of migraine in pediatric patients under 12 years of age.

The risk for cognitive adverse reactions was dose-dependent, and was particularly evident at the 200 mg dose. This risk for cognitive adverse reactions was also greater in younger patients (6 to 11 years) than in older patients (12 to 17 years). The most common cognitive adverse reaction in these trials was difficulty with concentration/attention. Cognitive adverse reactions most commonly developed in the titration period and sometimes persisted into the maintenance period. These adverse reactions typically occurred in isolation as single type of cognitive adverse reaction. Cognitive adverse reactions that led to study discontinuation occurred in one patient (difficulty with concentration/attention and language problems). The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to adolescents (12 to 17 years) to assess the effects of topiramate on cognitive function at baseline and at the end of the Study 3. Mean change from baseline in certain CANTAB tests suggests that topiramate treatment may result in psychomotor slowing and decreased verbal fluency.

Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts) and for being small for gestational age. In multiple species, oral administration of topiramate to pregnant animals at clinically relevant doses resulted in structural malformations, including craniofacial defects, and reduced body weights in offspring.

Consider the benefits and risks of QUDEXY XR when administering the drug in women of childbearing potential, particularly when QUDEXY XR is considered for a condition not usually associated with permanent injury or death. QUDEXY XR should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs including QUDEXY XR, should be gradually withdrawn to minimize the potential for seizures or increased seizure frequency. In situations where rapid withdrawal of QUDEXY XR is medically required, appropriate monitoring is recommended.

Topiramate treatment has produced hyperammonemia (in some instances dose-related) in a clinical investigational program in adolescent patients (12 to 17 years) who were treated with topiramate for migraine prophylaxis. The incidence of hyperammonia (above the upper limit of normal reference) at any time in the trial was 9% for placebo, 14% for 50 mg, and 26% for 100 mg topiramate daily. In some patients, hyperammonemia was observed at the end of the trial at the final visit. The incidence of markedly increased hyperammonemia (at least 50% or higher above upper limit of normal) at any time in the trial in adolescent patients was also increased at 100 mg/day (9%) compared to 50 mg topiramate (0%) or placebo (3%). During this trial, markedly increased ammonia levels returned to normal in all but one patient (in whom the ammonia level fell to high instead of markedly abnormal).

Topiramate treatment has produced hyperammonemia in a clinical investigational program in very young pediatric patients (1 month to 24 months) who were treated with adjunctive topiramate for partial onset epilepsy (8% for placebo, 10% for 5 mg/kg/day, 0% for 15 mg/kg/day, 9% for 25 mg/kg/day). QUDEXY XR is not approved as adjunctive treatment of partial onset seizures in pediatric patients less than 2 years old. In some patients, ammonia was markedly increased (greater than 50% above upper limit of normal). The hyperammonemia associated with topiramate treatment occurred with and without encephalopathy in placebo-controlled trials, and in an open-label, extension trial of infants with refractory epilepsy. Dose-related hyperammonemia was also observed in the extension trial in pediatric patients up to 2 years old. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting.

Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients who were taking topiramate without concomitant valproic acid (VPA).

Concomitant administration of topiramate and valproic acid (VPA) has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone based upon post-marketing reports. Although hyperammonemia may be asymptomatic, clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction.

Although QUDEXY XR is not indicated for use in infants/toddlers (1 month to 24 months), topiramate with concomitant VPA clearly produced a dose-related increase in the incidence of hyperammonemia (above the upper limit of normal, 0% for placebo, 12% for 5 mg/kg/day, 7% for 15 mg/kg/day, 17% for 25 mg/kg/day) in an investigational program using topiramate. Markedly increased, dose-related hyperammonemia (0% for placebo and 5 mg/kg/day, 7% for 15 mg/kg/day, and 8% for 25 mg/kg/day) also occurred in these infants/toddlers. Dose-related hyperammonemia was similarly observed in a long-term, extension trial utilizing topiramate in these very young, pediatric patients.

Hyperammonemia with and without encephalopathy has also been observed in post-marketing reports in patients taking topiramate with valproic acid (VPA).

The hyperammonemia associated with topiramate treatment appears to be more common when used concomitantly with VPA.

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate or QUDEXY XR treatment or an interaction of concomitant topiramate-based product and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons.

In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

A total of 32/2086 (1.5%) of adults exposed to topiramate during its adjunctive epilepsy therapy development reported the occurrence of kidney stones, an incidence about 2 to 4 times greater than expected in a similar, untreated population. In the double-blind monotherapy epilepsy study, a total of 4/319 (1.3%) of adults exposed to topiramate reported the occurrence of kidney stones. As in the general population, the incidence of stone formation among topiramate-treated patients was higher in men. Kidney stones have also been reported in pediatric patients taking topiramate for epilepsy or migraine.

During long-term (up to 1 year) topiramate treatment in an open-label extension study of 284 pediatric patients 1 month to 24 months old with epilepsy, 7% developed kidney or bladder stones that were diagnosed clinically or by sonogram. QUDEXY XR is not approved for pediatric patients less than 2 years old.

Kidney stones have also been reported in pediatric patients taking topiramate for migraine prophylaxis. For the double-blind migraine prophylaxis studies, one adverse event (renal calculus) occurred in a topiramate-treated subject in the age 12 to 17 years group. The overall experience with open-label, long-term, topiramate treatment for migraine prophylaxis is limited in pediatric patients.

QUDEXY XR would be expected to have the same effect as topiramate on the formation of kidney stones. An explanation for the association of topiramate and kidney stones may lay in the fact that topiramate is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) can promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. The concomitant use of QUDEXY XR with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.

Increased fluid intake increases the urinary output, lowering the concentration of substances involved in stone formation. Hydration is recommended to reduce new stone formation.

Hypothermia, defined as an unintentional drop in body core temperature to less than 35°C (95°F) has been reported in association with topiramate use with concomitant valproic acid (VPA) both in the presence and in the absence of hyperammonemia. This adverse reaction in patients using concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing the daily dose of topiramate. Consideration should be given to stopping topiramate or valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels.

Paresthesia (usually tingling of the extremities), an effect associated with the use of other carbonic anhydrase inhibitors, appears to be a common effect of topiramate in adult and pediatric patients. Paresthesia was more frequently reported in the monotherapy epilepsy trials and migraine prophylaxis trials conducted with immediate-release topiramate than in the adjunctive therapy epilepsy trials conducted with the same product. In the majority of instances, paresthesia did not lead to treatment discontinuation.

Topiramate is a CNS depressant. Concomitant administration of topiramate with other CNS depressant drugs or alcohol can result in significant CNS depression. Patients should be watched carefully when QUDEXY XR is co-administered with other CNS depressant drugs.

Advise patients and caregivers to read the FDA-approved patient labeling (Medication Guide).

Counsel patients to swallow QUDEXY XR capsules whole or carefully open and sprinkle the entire contents on a spoonful of soft food. This drug/food mixture should be swallowed immediately and not chewed. Do not store drug/food mixture for future use.

Instruct patients taking QUDEXY XR to seek immediate medical attention if they experience blurred vision, visual disturbances or periorbital pain.

Effects on ability to drive and use machines

Tiramat has minor or moderate influence on the 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.

Tiramat 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.

Dosage (Posology) and method of administration

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 optimize therapy with Tiramat. 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 Tiramat may require adjustment of the dose of Tiramat.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs (AEDs) 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 concomitantAEDs 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 Tiramat (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.

Paediatric population (children aged 2 years and above)

The recommended total daily dose of Tiramat (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

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

General dosing recommendations for Tiramat in special patient populations

Renal impairment

In patients with impaired renal function (CLCR ≤ 70 mL/min) topiramate should be administered with caution as the plasma and renal clearance of topiramate are decreased. Subjects with known renal impairment may require a longer time to reach steady-state at each dose. Half of the usual starting and maintenance dose is recommended.

In patients with end-stage renal failure, since topiramate is removed from plasma by haemodialysis, a supplemental dose of Tiramat 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.

Method of administration

Tiramat is available in film-coated tablets and a hard capsule formulation, for oral administration. 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.

Tiramat can be taken without regard to meals.

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.

Tiramat is available in film-coated tablet and a hard capsule formulations. 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.

Tiramat 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 medicinal product/food mixture is to be swallowed immediately and not chewed. It must not be stored for future use.

It is not necessary to monitor Tiramat plasma concentrations to optimize therapy with Tiramat. On rare occasions, the addition of Tiramat 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 Tiramat may require adjustment of the dose of Tiramat.

Tiramat can be taken without regard to meals.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs including Tiramat 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 Tiramat at doses up to 100 mg/day for migraine prophylaxis. In paediatric clinical trials, Tiramat was gradually withdrawn over a 2-8 week period.

Monotherapy epilepsy

General

When concomitant antiepileptic drugs (AEDs) are withdrawn to achieve monotherapy with Tiramat, 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, Tiramat levels will increase. A decrease in Tiramat 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 Tiramat 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 Tiramat 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 Tiramat 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.

Paediatric population (children aged 2 years and above)

The recommended total daily dose of Tiramat 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 Tiramat 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

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

General dosing recommendations for Tiramat in special patient populations

Renal impairment

In patients with impaired renal function (CLCR ≤ 70 mL/min) Tiramat should be administered with caution as the plasma and renal clearance of Tiramat are decreased. Subjects with known renal impairment may require a longer time to reach steady-state at each dose. Half of the usual starting and maintenance dose is recommended.

In patients with end-stage renal failure, since Tiramat is removed from plasma by haemodialysis, a supplemental dose of Tiramat 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 Tiramat should be administered with caution as the clearance of Tiramat is decreased.

Elderly

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

Adults and Pediatric Patients 10 Years and Older with Partial Onset or Primary Generalized Tonic-Clonic Seizures

The recommended dose for QUDEXY XR monotherapy in adults and pediatric patients 10 years of age and older is 400 mg orally once daily. Titrate QUDEXY XR according to the following schedule (Table 1):

Table 1: Monotherapy Titration Schedule for Adults and Pediatric Patients 10 years and older

Pediatric Patients 2 to less than 10 Years with Partial Onset or Primary Generalized Tonic-Clonic Seizures

Dosing in patients 2 to less than 10 years is based on weight. During the titration period, the initial dose of QUDEXY XR should be 25 mg once daily given at nighttime for the first week. Based upon tolerability, the dosage can be increased to 50 mg once daily in the second week. Dosage can be increased by 25 mg to 50 mg once daily each subsequent week, as tolerated. Titration to the minimum maintenance dose should be attempted over 5 to 7 weeks. Based upon tolerability and clinical response, additional titration to a higher dose (up to the maximum maintenance dose) can be attempted in weekly increments by 25 mg to 50 mg once daily, up to the maximum recommended maintenance dose for each range of body weight (see Table 2).

Table 2: Monotherapy Target Once Daily Maintenance Dosing for Patients 2 to Less Than 10 Years

Adults (17 Years of Age and Older) - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of QUDEXY XR as adjunctive therapy in adults with partial onset seizures or Lennox-Gastaut Syndrome is 200 mg to 400 mg orally once daily. The recommended total dose for adults with primary generalized tonic-clonic seizures is 400 mg orally once daily.

Initiate therapy at 25 mg to 50 mg once daily followed by titration to an effective dose in increments of 25 mg to 50 mg every week. Daily topiramate doses above 1,600 mg have not been studied.

In the study of primary generalized tonic-clonic seizures using topiramate, the assigned dose was reached at the end of 8 weeks.

Pediatric Patients (Ages 2 Years to 16 Years) - Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, or Lennox-Gastaut Syndrome

The recommended total daily dose of QUDEXY XR as adjunctive therapy for pediatric patients with partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome is approximately 5 mg/kg to 9 mg/kg orally once daily. Begin titration at 25 mg once daily (based on a range of 1 mg/kg/day to 3 mg/kg/day) given nightly for the first week. Subsequently, increase the dosage at 1 or 2 week intervals by increments of 1 mg/kg to 3 mg/kg to achieve optimal clinical response. Dose titration should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.

In the study of primary generalized tonic-clonic seizures, the assigned dose of 6 mg/kg once daily was reached at the end of 8 weeks.

The recommended total daily dose of QUDEXY XR as treatment for prophylaxis of migraine headache in adults and adolescents 12 years of age and older is 100 mg once daily. The recommended titration rate for QUDEXY XR for migraine prophylaxis to 100 mg/day is:

Table 3: Migraine Prophylaxis Titration Schedule for Adults and Adolescents 12 years of Age and Older

Dose and titration rate should be guided by clinical outcome. If required, longer intervals between dose adjustments can be used.

In patients with renal impairment (creatinine clearance less than 70 mL/min/1.73 m²), one-half of the usual adult dose is recommended. Such patients will require a longer time to reach steady-state at each dose.

Prior to dosing, obtain an estimated creatinine clearance (CrCl) in patients at high risk for renal insufficiency (e.g., older patients, or those with diabetes mellitus, hypertension, or autoimmune disease). CrCl can be estimated using the following equation (multiply by 0.85 for women):

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than in patients with normal renal function. Accordingly, a prolonged period of dialysis may cause topiramate concentration to fall below that required to maintain an anti-seizure effect. To avoid rapid drops rin topiramate plasma concentration during hemodialysis, a supplemental dose of topiramate may be required. The actual adjustment should take into account the:

• duration of dialysis period
• clearance rate of the dialysis system being used
• effective renal clearance of topiramate in the patient being dialyzed.

Measurement of baseline and periodic serum bicarbonate during QUDEXY XR treatment is recommended.

The co-administration of QUDEXY XR with phenytoin may require an adjustment of the dose of phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and/or carbamazepine during adjunctive therapy with QUDEXY XR may require adjustment of the dose of QUDEXY XR.

It is not necessary to monitor topiramate plasma concentrations to optimize QUDEXY XR therapy.

QUDEXY XR 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 drug/food mixture should be swallowed immediately and not chewed or crushed. Do not store drug/food mixture for further use. QUDEXY XR can be taken without regard to meals.

Special precautions for disposal and other handling

No special requirements.