Components:
Method of action:
Treatment option:
Medically reviewed by Militian Inessa Mesropovna, PharmD. Last updated on 13.03.2022
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Epilepsy
Normatol is indicated as adjunctive therapy in the treatment of partial seizures with and without secondary generalization in adults and children aged 6 years and above.
Normatol is indicated as monotherapy in the treatment of partial seizures with and without secondary generalization in adults and adolescents aged 12 years and above.
Treatment of peripheral neuropathic pain
Normatol is indicated for the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia in adults.
Posology
For all indications a titration scheme for the initiation of therapy is described in Table 1, which is recommended for adults and adolescents aged 12 years and above. Dosing instructions for children under 12 years of age are provided under a separate sub-heading later in this section.
| Table 1 | ||
| DOSING CHART - INITIAL TITRATION | ||
| Day 1 | Day 2 | Day 3 |
| 300 mg once a day | 300 mg two times a day | 300 mg three times a day |
Discontinuation of gabapentin
In accordance with current clinical practice, if gabapentin has to be discontinued it is recommended this should be done gradually over a minimum of 1 week independent of the indication.
Epilepsy
Epilepsy typically requires long-term therapy. Dosage is determined by the treating physician according to individual tolerance and efficacy.
Adults and adolescents
In clinical trials, the effective dosing range was 900 to 3600 mg/day. Therapy may be initiated by titrating the dose as described in Table 1 or by administering 300 mg three times a day (TID) on Day 1. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300 mg/day increments every 2-3 days up to a maximum dose of 3600 mg/day. Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800 mg/day is one week, to reach 2400 mg/day is a total of 2 weeks, and to reach 3600 mg/day is a total of 3 weeks. Dosages up to 4800 mg/day have been well tolerated in long-term open-label clinical studies. The total daily dose should be divided in three single doses, the maximum time interval between the doses should not exceed 12 hours to prevent breakthrough convulsions.
Children aged 6 years and above
The starting dose should range from 10 to 15 mg/kg/day and the effective dose is reached by upward titration over a period of approximately three days. The effective dose of gabapentin in children aged 6 years and older is 25 to 35 mg/kg/day. Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. The total daily dose should be divided in three single doses, the maximum time interval between doses should not exceed 12 hours.
It is not necessary to monitor gabapentin plasma concentrations to optimize gabapentin therapy. Further, gabapentin may be used in combination with other antiepileptic medicinal products without concern for alteration of the plasma concentrations of gabapentin or serum concentrations of other antiepileptic medicinal products.
Peripheral neuropathic pain
Adults
The therapy may be initiated by titrating the dose as described in Table 1. Alternatively, the starting dose is 900 mg/day given as three equally divided doses. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300 mg/day increments every 2-3 days up to a maximum dose of 3600 mg/day. Slower titration of gabapentin dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800 mg/day is one week, to reach 2400 mg/day is a total of 2 weeks, and to reach 3600 mg/day is a total of 3 weeks.
In the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia, efficacy and safety have not been examined in clinical studies for treatment periods longer than 5 months. If a patient requires dosing longer than 5 months for the treatment of peripheral neuropathic pain, the treating physician should assess the patient's clinical status and determine the need for additional therapy.
Instruction for all areas of indication
In patients with poor general health, i.e., low body weight, after organ transplantation etc., the dose should be titrated more slowly, either by using smaller dosage strengths or longer intervals between dosage increases.
Elderly (over 65 years of age)
Elderly patients may require dosage adjustment because of declining renal function with age (see Table 2). Somnolence, peripheral oedema and asthenia may be more frequent in elderly patients.
Renal impairment
Dosage adjustment is recommended in patients with compromised renal function as described in Table 2 and/or those undergoing haemodialysis. Gabapentin 100 mg capsules can be used to follow dosing recommendations for patients with renal insufficiency.
| Table 2 | |
| DOSAGE OF GABAPENTIN IN ADULTS BASED ON RENAL FUNCTION | |
| Creatinine Clearance (mL/min) | Total Daily Dosea (mg/day) |
| >80 | 900-3600 |
| 50-79 | 600-1800 |
| 30-49 | 300-900 |
| 15-29 | 150b-600 |
| <15c | 150b-300 |
a Total daily dose should be administered as three divided doses. Reduced dosages are for patients with renal impairment (creatinine clearance < 79 mL/min).
b To be administered as 300 mg every other day.
c For patients with creatinine clearance <15 mL/min, the daily dose should be reduced in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive).
Use in patients undergoing haemodialysis
For anuric patients undergoing haemodialysis who have never received gabapentin, a loading dose of 300 to 400 mg, then 200 to 300 mg of gabapentin following each 4 hours of haemodialysis, is recommended. On dialysis-free days, there should be no treatment with gabapentin.
For renally impaired patients undergoing haemodialysis, the maintenance dose of gabapentin should be based on the dosing recommendations found in Table 2. In addition to the maintenance dose, an additional 200 to 300 mg dose following each 4-hour haemodialysis treatment is recommended.
Method of administration
For oral use.
Gabapentin can be given with or without food and should be swallowed whole with sufficient fluid-intake (e.g. a glass of water).
Posology
For all indications a titration scheme for the initiation of therapy is described in Table 1, which is recommended for adults and adolescents aged 12 years and above. Dosing instructions for children under 12 years of age are provided under a separate sub-heading later in this section.
| Table 1 | ||
| DOSING CHART - INITIAL TITRATION | ||
| Day 1 | Day 2 | Day 3 |
| 300 mg once a day | 300 mg two times a day | 300 mg three times a day |
Discontinuation of Normatol
In accordance with current clinical practice, if Normatol has to be discontinued it is recommended this should be done gradually over a minimum of 1 week independent of the indication.
Epilepsy
Epilepsy typically requires long-term therapy. Dosage is determined by the treating physician according to individual tolerance and efficacy.
Adults and adolescents
In clinical trials, the effective dosing range was 900 to 3600 mg/day. Therapy may be initiated by titrating the dose as described in Table 1 or by administering 300 mg three times a day (TID) on Day 1. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300 mg/day increments every 2-3 days up to a maximum dose of 3600 mg/day. Slower titration of Normatol dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800 mg/day is one week, to reach 2400 mg/day is a total of 2 weeks, and to reach 3600 mg/day is a total of 3 weeks.
Dosages up to 4800 mg/day have been well tolerated in long-term open-label clinical studies. The total daily dose should be divided in three single doses, the maximum time interval between the doses should not exceed 12 hours to prevent breakthrough convulsions.
Children aged 6 years and above
The starting dose should range from 10 to 15 mg/kg/day and the effective dose is reached by upward titration over a period of approximately three days. The effective dose of Normatol in children aged 6 years and older is 25 to 35 mg/kg/day. Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. The total daily dose should be divided in three single doses, the maximum time interval between doses should not exceed 12 hours.
It is not necessary to monitor Normatol plasma concentrations to optimize Normatol therapy. Further, Normatol may be used in combination with other antiepileptic medicinal products without concern for alteration of the plasma concentrations of Normatol or serum concentrations of other antiepileptic medicinal products.
Peripheral neuropathic pain
Adults
The therapy may be initiated by titrating the dose as described in Table 1. Alternatively, the starting dose is 900 mg/day given as three equally divided doses. Thereafter, based on individual patient response and tolerability, the dose can be further increased in 300 mg/day increments every 2-3 days up to a maximum dose of 3600 mg/day. Slower titration of Normatol dosage may be appropriate for individual patients. The minimum time to reach a dose of 1800 mg/day is one week, to reach 2400 mg/day is a total of 2 weeks, and to reach 3600 mg/day is a total of 3 weeks.
In the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia, efficacy and safety have not been examined in clinical studies for treatment periods longer than 5 months. If a patient requires dosing longer than 5 months for the treatment of peripheral neuropathic pain, the treating physician should assess the patient's clinical status and determine the need for additional therapy.
Instruction for all areas of indication
In patients with poor general health, i.e., low body weight, after organ transplantation etc., the dose should be titrated more slowly, either by using smaller dosage strengths or longer intervals between dosage increases.
Elderly (over 65 years of age)
Elderly patients may require dosage adjustment because of declining renal function with age (see Table 2). Somnolence, peripheral oedema and asthenia may be more frequent in elderly patients.
Renal impairment
Dosage adjustment is recommended in patients with compromised renal function as described in Table 2 and/or those undergoing haemodialysis. Normatol 100 mg capsules can be used to follow dosing recommendations for patients with renal insufficiency.
| Table 2 | |
| DOSAGE OF Normatol IN ADULTS BASED ON RENAL FUNCTION | |
| Creatinine Clearance (mL/min) | Total Daily Dosea (mg/day) |
| > 80 | 900-3600 |
| 50-79 | 600-1800 |
| 30-49 | 300-900 |
| 15-29 | 150b-600 |
| < 15c | 150b-300 |
a Total daily dose should be administered as three divided doses. Reduced dosages are for patients with renal impairment (creatinine clearance < 79 mL/min).
b To be administered as 300 mg every other day.
c For patients with creatinine clearance < 15 mL/min, the daily dose should be reduced in proportion to creatinine clearance (e.g., patients with a creatinine clearance of 7.5 mL/min should receive one-half the daily dose that patients with a creatinine clearance of 15 mL/min receive).
Use in patients undergoing haemodialysis
For anuric patients undergoing haemodialysis who have never received Normatol, a loading dose of 300 to 400 mg, then 200 to 300 mg of Normatol following each 4 hours of haemodialysis, is recommended. On dialysis-free days, there should be no treatment with Normatol.
For renally impaired patients undergoing haemodialysis, the maintenance dose of Normatol should be based on the dosing recommendations found in Table 2. In addition to the maintenance dose, an additional 200 to 300 mg dose following each 4-hour haemodialysis treatment is recommended.
Method of administration
For oral use.
Normatol can be given with or without food and should be swallowed whole with sufficient fluid- intake (e.g. a glass of water).
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)
Severe, life-threatening, systemic hypersensitivity reactions such as Drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking antiepileptic drugs including gabapentin.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Gabapentin should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Anaphylaxis
Gabapentin can cause anaphylaxis. Signs and symptoms in reported cases have included difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment. Patients should be instructed to discontinue gabapentin and seek immediate medical care should they experience signs or symptoms of anaphylaxis.
Suicidal ideation and behaviour
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 also 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 gabapentin.
Therefore patients should be monitored for signs of suicidal ideation and behaviours 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.
Acute pancreatitis
If a patient develops acute pancreatitis under treatment with gabapentin, discontinuation of gabapentin should be considered.
Seizures
Although there is no evidence of rebound seizures with gabapentin, abrupt withdrawal of anticonvulsants in epileptic patients may precipitate status epilepticus.
As with other antiepileptic medicinal products, some patients may experience an increase in seizure frequency or the onset of new types of seizures with gabapentin.
As with other anti-epileptics, attempts to withdraw concomitant anti-epileptics in treatment refractive patients on more than one anti-epileptic, in order to reach gabapentin monotherapy have a low success rate.
Gabapentin is not considered effective against primary generalized seizures such as absences and may aggravate these seizures in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizures including absences.
Gabapentin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall). There have also been post-marketing reports of confusion, loss of consciousness and mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.
Concomitant use with opioids
Patients who require concomitant treatment with opioids should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence, sedation and respiratory depression. Patients who use gabapentin and morphine concomitantly may experience increases in gabapentin concentrations. The dose of gabapentin or opioids should be reduced appropriately.
Respiratory depression
Gabapentin has been associated with severe respiratory depression. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants and the elderly might be at higher risk of experiencing this severe adverse reaction. Dose adjustments might be necessary in these patients.
Elderly (over 65 years of age)
No systematic studies in patients 65 years or older have been conducted with gabapentin. In one double blind study in patients with neuropathic pain, somnolence, peripheral oedema and asthenia occurred in a somewhat higher percentage in patients aged 65 years or above, than in younger patients. Apart from these findings, clinical investigations in this age group do not indicate an adverse event profile different from that observed in younger patients.
Paediatric population
The effects of long-term (greater than 36 weeks) gabapentin therapy on learning, intelligence, and development in children and adolescents have not been adequately studied. The benefits of prolonged therapy must therefore be weighed against the potential risks of such therapy.
Abuse and dependence
Cases of abuse and dependence have been reported in the post-marketing database. Carefully evaluate patients for a history of drug abuse and observe them for possible signs of gabapentin abuse e.g. drug-seeking behaviour, dose escalation, development of tolerance.
Laboratory tests
False positive readings may be obtained in the semi-quantitative determination of total urine protein by dipstick tests. It is therefore recommended to verify such a positive dipstick test result by methods based on a different analytical principle such as the Biuret method, turbidimetric or dye-binding methods, or to use these alternative methods from the beginning.
Normatol hard capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)
Severe, life-threatening, systemic hypersensitivity reactions such as Drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in patients taking antiepileptic drugs including Normatol.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Normatol should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Anaphylaxis
Normatol can cause anaphylaxis. Signs and symptoms in reported cases have included difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment. Patients should be instructed to discontinue Normatol and seek immediate medical care should they experience signs or symptoms of anaphylaxis.
Suicidal ideation and behaviour
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 also 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 Normatol.
Therefore patients should be monitored for signs of suicidal ideation and behaviours 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.
Acute pancreatitis
If a patient develops acute pancreatitis under treatment with Normatol, discontinuation of Normatol should be considered.
Seizures
Although there is no evidence of rebound seizures with Normatol, abrupt withdrawal of anticonvulsants in epileptic patients may precipitate status epilepticus.
As with other antiepileptic medicinal products, some patients may experience an increase in seizure frequency or the onset of new types of seizures with Normatol.
As with other anti-epileptics, attempts to withdraw concomitant anti-epileptics in treatment refractive patients on more than one anti-epileptic, in order to reach Normatol monotherapy have a low success rate.
Normatol is not considered effective against primary generalized seizures such as absences and may aggravate these seizures in some patients. Therefore, Normatol should be used with caution in patients with mixed seizures including absences.
Normatol treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall). There have also been post-marketing reports of confusion, loss of consciousness and mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.
Concomitant use with opioids
Patients who require concomitant treatment with opioids should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence, sedation and respiratory depression. Patients who use Normatol and morphine concomitantly may experience increases in Normatol concentrations. The dose of Normatol or opioids should be reduced appropriately.
Respiratory depression
Normatol has been associated with severe respiratory depression. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants and the elderly might be at higher risk of experiencing this severe adverse reaction. Dose adjustments might be necessary in these patients.
Elderly (over 65 years of age)
No systematic studies in patients 65 years or older have been conducted with Normatol. In one double blind study in patients with neuropathic pain, somnolence, peripheral oedema and asthenia occurred in a somewhat higher percentage in patients aged 65 years or above, than in younger patients. Apart from these findings, clinical investigations in this age group do not indicate an adverse event profile different from that observed in younger patients.
Paediatric population
The effects of long-term (greater than 36 weeks) Normatol therapy on learning, intelligence, and development in children and adolescents have not been adequately studied. The benefits of prolonged therapy must therefore be weighed against the potential risks of such therapy.
Abuse and dependence
Cases of abuse and dependence have been reported in the post-marketing database. Carefully evaluate patients for a history of drug abuse and observe them for possible signs of Normatol abuse, e.g. drug-seeking behaviour, dose escalation, development of tolerance.
Laboratory tests
False positive readings may be obtained in the semi-quantitative determination of total urine protein by dipstick tests. It is therefore recommended to verify such a positive dipstick test result by methods based on a different analytical principle such as the Biuret method, turbidimetric or dye-binding methods, or to use these alternative methods from the beginning.
Normatol hard capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Gabapentin may have minor or moderate influence on the ability to drive and use machines. Gabapentin acts on the central nervous system and may cause drowsiness, dizziness or other related symptoms. Even, if they were only of mild or moderate degree, these undesirable effects could be potentially dangerous in patients driving or operating machinery. This is especially true at the beginning of the treatment and after increase in dose.
Normatol may have minor or moderate influence on the ability to drive and use machines. Normatol acts on the central nervous system and may cause drowsiness, dizziness or other related symptoms. Even, if they were only of mild or moderate degree, these undesirable effects could be potentially dangerous in patients driving or operating machinery. This is especially true at the beginning of the treatment and after increase in dose.
The adverse reactions observed during clinical studies conducted in epilepsy (adjunctive and monotherapy) and neuropathic pain have been provided in a single list below by class and frequency: very common (> 1/10); common (> 1/100 to< 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000). Where an adverse reaction was seen at different frequencies in clinical studies, it was assigned to the highest frequency reported.
Additional reactions reported from post-marketing experience are included as frequency Not known (cannot be estimated from the available data) in italics in the list below.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| System organ class | Adverse drug reactions |
| Infections and infestations | |
| Very Common | viral infection |
| Common | pneumonia, respiratory infection, urinary tract infection, infection, otitis media |
| Blood and the lymphatic system disorders | |
| Common | leucopenia |
| Not known | Thrombocytopenia |
| Immune system disorders | |
| Uncommon | allergic reactions (e.g. urticaria) |
| Not known | hypersensitivity syndrome (a systemic reaction with a variable presentation that can include fever, rash, hepatitis, lymphadenopathy, eosinophilia, and sometimes other signs and symptoms), anaphylaxis
|
| Metabolism and nutrition disorders | |
| Common | anorexia, increased appetite |
| Uncommon | hyperglycaemia (most often observed in patients with diabetes) |
| Rare | hypoglycaemia (most often observed in patients with diabetes) |
| Not known | hyponatraemia |
| Psychiatric disorders | |
| Common | hostility, confusion and emotional lability, depression, anxiety, nervousness, thinking abnormal |
| Uncommon | agitation |
| Not known | hallucinations |
| Nervous system disorders | |
| Very Common | somnolence, dizziness, ataxia |
| Common | convulsions, hyperkinesias, dysarthria, amnesia, tremor, insomnia, headache, sensations such as paresthesia, hypaesthesia, coordination abnormal, nystagmus, increased, decreased, or absent reflexes |
| Uncommon | hypokinesia, mental impairment |
| Rare | loss of consciousness |
| Not known | other movement disorders (e.g. choreoathetosis, dyskinesia, dystonia) |
| Eye disorders | |
| Common | visual disturbances such as amblyopia, diplopia |
| Ear and labyrinth disorders | |
| Common | vertigo |
| Not known | tinnitus |
| Cardiac disorders | |
| Uncommon | palpitations |
| Vascular disorders | |
| Common | hypertension, vasodilatation |
| Respiratory, thoracic and mediastinal disorders | |
| Common | dyspnoea, bronchitis, pharyngitis, cough, rhinitis |
| Rare | respiratory depression |
| Gastrointestinal disorders | |
| Common | vomiting, nausea, dental abnormalities, gingivitis, diarrhoea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence |
| Not known | pancreatitis |
| Hepatobiliary disorders | |
| Not known | hepatitis, jaundice |
| Skin and subcutaneous tissue disorders | |
| Common | facial oedema, purpura most often described as bruises resulting from physical trauma, rash, pruritus, acne |
| Not known | Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia, drug rash with eosinophilia and systemic symptoms |
| Musculoskeletal and connective tissue disorders | |
| Common | arthralgia, myalgia, back pain, twitching |
| Not known | rhabdomyolysis, myoclonus |
| Renal and urinary disorder | |
| Not known | acute renal failure, incontinence |
| Reproductive system and breast disorders | |
| Common | impotence |
| Not known | breast hypertrophy, gynaecomastia, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia) |
| General disorders and administration site conditions | |
| Very Common | fatigue, fever |
| Common | peripheral oedema, abnormal gait, asthenia, pain, malaise, flu syndrome |
| Uncommon | generalized oedema |
| Not known | withdrawal reactions (mostly anxiety, insomnia, nausea, pains, sweating), chest pain. Sudden unexplained deaths have been reported where a causal relationship to treatment with gabapentin has not been established. |
| Investigations | |
| Common | WBC (white blood cell count) decreased, weight gain |
| Uncommon | elevated liver function tests SGOT (AST), SGPT (ALT) and bilirubin |
| Not known | blood creatine phosphokinase increased |
| Injury, poisoning and procedural complications | |
| Common | accidental injury, fracture, abrasion |
| Uncommon | fall |
Under treatment with gabapentin cases of acute pancreatitis were reported. Causality with gabapentin is unclear.
In patients on haemodialysis due to end-stage renal failure, myopathy with elevated creatine kinase levels has been reported.
Respiratory tract infections, otitis media, convulsions and bronchitis were reported only in clinical studies in children. Additionally, in clinical studies in children, aggressive behaviour and hyperkinesias were reported commonly.
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 adverse reactions observed during clinical studies conducted in epilepsy (adjunctive and monotherapy) and neuropathic pain have been provided in a single list below by class and frequency: (very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to ≤ 1/100); rare (> 1/10,000 to ≤ 1/1,000); very rare (< 1/10,000).
Where an adverse reaction was seen at different frequencies in clinical studies it was assigned to the highest frequency reported.
Additional reactions reported from post-marketing experience are included as frequency Not known (cannot be estimated from the available data) in italics in the list below.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| System organ class | Adverse drug reactions |
| Infections and infestations | |
| Very common | viral infection |
| Common | pneumonia, respiratory infection, urinary tract infection, infection, otitis media |
| Blood and the lymphatic system disorders | |
| Common | leucopenia |
| Not known | thrombocytopenia |
| Immune system disorders | |
| Uncommon | allergic reactions (e.g. urticaria) |
| Not known | hypersensitivity syndrome (a systemic reaction with a variable presentation that can include fever, rash, hepatitis lymphadenopathy, eosinophilia and sometimes other signs and symptoms), anaphylaxis. |
| Metabolism and nutrition disorders | |
| Common | anorexia, increased appetite |
| Uncommon | hyperglycaemia (most often observed in patients with diabetes) |
| Rare | hypoglycaemia (most often observed in patients with diabetes) |
| Not known | hyponatraemia |
| Psychiatric disorders | |
| Common | hostility, confusion and emotional lability, depression, anxiety, nervousness, thinking abnormal |
| Uncommon | agitation |
| Not known | hallucinations |
| Nervous system disorders | |
| Very common | somnolence, dizziness, ataxia |
| Common | convulsions, hyperkinesias, dysarthria, amnesia, tremor, insomnia, headache, sensations such as paresthesia, hypaesthesia, coordination abnormal, nystagmus, increased, decreased, or absent reflexes |
| Uncommon | hypokinesia, mental impairment |
| Rare | loss of consciousness |
| Not known | other movement disorders (e.g. choreoathetosis, dyskinesia, dystonia) |
| Eye disorders | |
| Common | visual disturbances such as amblyopia, diplopia |
| Ear and labyrinth disorders | |
| Common | vertigo |
| Not known | tinnitus |
| Cardiac disorders | |
| Uncommon | palpitations |
| Vascular disorders | |
| Common | hypertension, vasodilatation |
| Respiratory, thoracic and mediastinal disorders | |
| Common | dyspnoea, bronchitis, pharyngitis, cough, rhinitis |
| Rare | respiratory depression |
| Gastrointestinal disorders | |
| Common | vomiting, nausea, dental abnormalities, gingivitis, diarrhoea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence |
| Not known | pancreatitis |
| Hepatobiliary disorders | |
| Not known | hepatitis, jaundice |
| Skin and subcutaneous tissue disorders | |
| Common | facial oedema, purpura most often described as bruises resulting from physical trauma, rash, pruritus, acne |
| Not known | Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia, drug rash with eosinophilia and systemic symptoms |
| Musculoskeletal and connective tissue disorders | |
| Common | arthralgia, myalgia, back pain, twitching |
| Not known | rhabdomyolysis, myoclonus |
| Renal and urinary disorders | |
| Not known | acute renal failure, incontinence |
| Reproductive system and breast disorders | |
| Common | impotence |
| Not known | breast hypertrophy, gynaecomastia, sexual dysfunction (including changes in libido, ejaculation disorders and anorgasmia) |
| General disorders and administration site conditions | |
| Very common | fatigue, fever |
| Common | peripheral oedema, abnormal gait, asthenia, pain, malaise, flu syndrome |
| Uncommon | generalised oedema |
| Not known | withdrawal reactions (mostly anxiety, insomnia, nausea, pains, sweating), chest pain. Sudden unexplained deaths have been reported where a causal relationship to treatment with Normatol has not been established. |
| Investigations | |
| Common | WBC (white blood cell count) decreased, weight gain |
| Uncommon | elevated liver function tests SGOT (AST), SGPT (ALT) and bilirubin |
| Not known | blood creatine phosphokinase increased |
| Injury, poisoning and procedural complications | |
| Common | accidental injury, fracture, abrasion |
| Uncommon | fall |
Under treatment with Normatol cases of acute pancreatitis were reported. Causality with Normatol is unclear.
In patients on haemodialysis due to end-stage renal failure, myopathy with elevated creatine kinase levels has been reported.
Respiratory tract infections, otitis media, convulsions and bronchitis were reported only in clinical studies in children. Additionally, in clinical studies in children, aggressive behaviour and hyperkinesias were reported commonly.
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.
Acute, life-threatening toxicity has not been observed with gabapentin overdoses of up to 49 g. Symptoms of the overdoses included dizziness, double vision, slurred speech, drowsiness, loss of consciousness, lethargy and mild diarrhoea. All patients recovered fully with supportive care. Reduced absorption of gabapentin at higher doses may limit drug absorption at the time of overdosing and, hence, minimize toxicity from overdoses.
Overdoses of gabapentin, particularly in combination with other CNS depressant medications, may result in coma.
Although gabapentin can be removed by haemodialysis, based on prior experience it is usually not required. However, in patients with severe renal impairment, haemodialysis may be indicated.
An oral lethal dose of gabapentin was not identified in mice and rats given doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, laboured breathing, ptosis, hypoactivity, or excitation.
Acute, life-threatening toxicity has not been observed with Normatol overdoses of up to 49 g. Symptoms of the overdoses included dizziness, double vision, slurred speech, drowsiness, loss of consciousness, lethargy and mild diarrhoea. All patients recovered fully with supportive care. Reduced absorption of Normatol at higher doses may limit drug absorption at the time of overdosing and, hence, minimize toxicity from overdoses.
Overdoses of Normatol, particularly in combination with other CNS depressant medication, may result in coma.
Although Normatol can be removed by haemodialysis, based on prior experience it is usually not required. However, in patients with severe renal impairment, haemodialysis may be indicated.
An oral lethal dose of Normatol was not identified in mice and rats given doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, laboured breathing, ptosis, hypoactivity, or excitation.
Pharmacotherapeutic groups: Other antiepileptics ATC code: N03AX12
Mechanism of action
Gabapentin readily enters the brain and prevents seizures in a number of animal models of epilepsy. Gabapentin does not possess affinity for either GABAA or GABAB receptor nor does it alter the metabolism of GABA. It does not bind to other neurotransmitter receptors of the brain and does not interact with sodium channels. Gabapentin binds with high affinity to the α2δ (alpha-2-delta) subunit of voltage-gated calcium channels and it is proposed that binding to the α2δ subunit may be involved in gabapentin's anti-seizure effects in animals. Broad panel screening does not suggest any other drug targets other than α2δ.
Evidence from several pre-clinical models inform that the pharmacological activity of gabapentin may be mediated via binding to α2δ through a reduction in release of excitatory neurotransmitters in regions of the central nervous system. Such activity may underlie gabapentin's anti-seizure activity. The relevance of these actions of gabapentin to the anticonvulsant effects in humans remains to be established.
Gabapentin also displays efficacy in several pre-clinical animal pain models. Specific binding of gabapentin to the α2δ subunit is proposed to result in several different actions that may be responsible for analgesic activity in animal models. The analgesic activities of gabapentin may occur in the spinal cord as well as at higher brain centers through interactions with descending pain inhibitory pathways. The relevance of these pre-clinical properties to clinical action in humans is unknown.
Clinical efficacy and safety
A clinical trial of adjunctive treatment of partial seizures in paediatric subjects ranging in age from 3 to 12 years, showed a numerical but not statistically significant difference in the 50% responder rate in favour of the gabapentin group compared to placebo. Additional post-hoc analyses of the responder rates by age did not reveal a statistically significant effect of age, either as a continuous or dichotomous variable (age groups 3-5 and 6-12 years). The data from this additional post-hoc analysis are summarised in the table below:
| Response (> 50% Improved) by Treatment and Age MITT* Population | |||
| Age Category | Placebo | Gabapentin | P-Value |
| < 6 Years Old | 4/21 (19.0%) | 4/17 (23.5%) | 0.7362 |
| 6 to 12 Years Old | 17/99 (17.2%) | 20/96 (20.8%) | 0.5144 |
*The modified intent to treat population was defined as all patients randomised to study medication who also had evaluable seizure diaries available for 28 days during both the baseline and double-blind phases.
Pharmacotherapeutic groups: Antiepileptics, Other antiepileptics
ATC code: N03AX12
Mechanism of action
Normatol readily enters the brain and prevents seizures in a number of animal models of epilepsy. Normatol does not possess affinity for either GABAA or GABAB receptor nor does it alter the metabolism of GABA. It does not bind to other neurotransmitter receptors of the brain and does not interact with sodium channels. Normatol binds with high affinity to the α2δ (alpha-2-delta) subunit of voltage-gated calcium channels and it is proposed that binding to the α2δ subunit may be involved in Normatol's anti-seizure effects in animals. Broad panel screening does not suggest any other drug target other than α2δ.
Evidence from several pre-clinical models inform that the pharmacological activity of Normatol may be mediated via binding to α2δ through a reduction in release of excitatory neurotransmitters in regions of the central nervous system. Such activity may underlie Normatol's anti-seizure activity. The relevance of these actions of Normatol to the anticonvulsant effects in humans remains to be established.
Normatol also displays efficacy in several pre-clinical animal pain models. Specific binding of Normatol to the α2δ subunit is proposed to result in several different actions that may be responsible for analgesic activity in animal models. The analgesic activities of Normatol may occur in the spinal cord as well as at higher brain centers through interactions with descending pain inhibitory pathways. The relevance of these pre-clinical properties to clinical action in humans is unknown.
Clinical efficacy and safety
A clinical trial of adjunctive treatment of partial seizures in paediatric subjects, ranging in age from 3 to 12 years, showed a numerical but not statistically significant difference in the 50% responder rate in favour of the Normatol group compared to placebo. Additional post-hoc analyses of the responder rates by age did not reveal a statistically significant effect of age, either as a continuous or dichotomous variable (age groups 3-5 and 6-12 years).
The data from this additional post-hoc analysis are summarised in the table below:
| Response (> 50% Improved) by Treatment and Age MITT* Population | |||
| Age Category | Placebo | Normatol | P-Value |
| < 6 Years Old | 4/21 (19.0%) | 4/17 (23.5%) | 0.7362 |
| 6 to 12 Years Old | 17/99 (17.2%) | 20/96 (20.8%) | 0.5144 |
*The modified intent to treat population was defined as all patients randomised to study medication who also had evaluable seizure diaries available for 28 days during both the baseline and double-blind phases.
Absorption
Following oral administration, peak plasma gabapentin concentrations are observed within 2 to 3 hours. Gabapentin bioavailability (fraction of dose absorbed) tends to decrease with increasing dose. Absolute bioavailability of a 300 mg capsule is approximately 60%. Food, including a high-fat diet, has no clinically significant effect on gabapentin pharmacokinetics.
Gabapentin pharmacokinetics are not affected by repeated administration. Although plasma gabapentin concentrations were generally between 2 μg/mL and 20 μg/mL in clinical studies, such concentrations were not predictive of safety or efficacy. Pharmacokinetic parameters are given in Table 3.
| Table 3 | ||||||
| SUMMARY OF GABAPENTIN MEAN (%CV) STEADY-STATE PHARMACOKINETIC PARAMETERS FOLLOWING EVERY EIGHT HOURS ADMINISTRATION | ||||||
| Pharmacokinetic parameter | 300 mg (N=7) | 400 mg (N=14) | 800 mg (N=14) | |||
| Mean | %CV | Mean | %CV | Mean | %CV | |
| Cmax (μg/mL) | 4.02 | (24) | 5.74 | (38) | 8.71 | (29) |
| tmax (hr) | 2.7 | (18) | 2.1 | (54) | 1.6 | (76) |
| T1/2 (hr) | 5.2 | (12) | 10.8 | (89) | 10.6 | (41) |
| AUC (0-8) μg-hr/mL) | 24.8 | (24) | 34.5 | (34) | 51.4 | (27) |
| Ae% (%) | NA | NA | 47.2 | (25) | 34.4 | (37) |
| Cmax = Maximum steady state plasma concentration tmax = Time for Cmax T1/2 = Elimination half-life AUC(0-8) = Steady state area under plasma concentration-time curve from time 0 to 8 hours postdose Ae% = Percent of dose excreted unchanged into the urine from time 0 to 8 hours postdose NA = Not available | ||||||
Distribution
Gabapentin is not bound to plasma proteins and has a volume of distribution equal to 57.7 litres. In patients with epilepsy, gabapentin concentrations in cerebrospinal fluid (CSF) are approximately 20% of corresponding steady-state trough plasma concentrations. Gabapentin is present in the breast milk of breast-feeding women.
Biotransformation
There is no evidence of gabapentin metabolism in humans. Gabapentin does not induce hepatic mixed function oxidase enzymes responsible for drug metabolism.
Elimination
Gabapentin is eliminated unchanged solely by renal excretion. The elimination half-life of gabapentin is independent of dose and averages 5 to 7 hours.
In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin elimination-rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.
Gabapentin is removed from plasma by haemodialysis. Dosage adjustment in patients with compromised renal function or undergoing haemodialysis is recommended.
Gabapentin pharmacokinetics in children were determined in 50 healthy subjects between the ages of 1 month and 12 years. In general, plasma gabapentin concentrations in children > 5 years of age are similar to those in adults when dosed on a mg/kg basis.
In a pharmacokinetic study in 24 healthy paediatric subjects aged between 1 month and 48 months, an approximately 30% lower exposure (AUC), lower Cmax and higher clearance per body weight have been observed in comparison to available reported data in children older than 5 years.
Linearity/non-linearity
Gabapentin bioavailability (fraction of dose absorbed) decreases with increasing dose which imparts non-linearity to pharmacokinetic parameters which include the bioavailability parameter (F) e.g. Ae%, CL/F, Vd/F. Elimination pharmacokinetics (pharmacokinetic parameters which do not include F such as CLr and T1/2), are best described by linear pharmacokinetics. Steady state plasma gabapentin concentrations are predictable from single-dose data.
Absorption
Following oral administration, peak plasma Normatol concentrations are observed within 2 to 3 hours. Normatol bioavailability (fraction of dose absorbed) tends to decrease with increasing dose. Absolute bioavailability of a 300 mg capsule is approximately 60%. Food, including a high-fat diet, has no clinically significant effect on Normatol pharmacokinetics.
Normatol pharmacokinetics are not affected by repeated administration. Although plasma Normatol concentrations were generally between 2 μg/mL and 20 μg/mL in clinical studies, such concentrations were not predictive of safety or efficacy. Pharmacokinetic parameters are given in Table 3.
| TABLE 3 | ||||||
| Summary of Normatol mean (%cv) steady-state pharmacokinetic parameters following every eight hours administration | ||||||
| Pharmacokinetic parameter | 300 mg (N = 7) | 400 mg (N = 14) | 800 mg (N=14) | |||
|
| Mean | %CV | Mean | %CV | Mean | %CV |
| Cmax μg/mL) | 4.02 | (24) | 5.74 | (38) | 8.71 | (29) |
| tmax (hr) | 2.7 | (18) | 2.1 | (54) | 1.6 | (76) |
| T1/2 (hr) | 5.2 | (12) | 10.8 | (89) | 10.6 | (41) |
| AUC (0-8) μg-hr/mL) | 24.8 | (24) | 34.5 | (34) | 51.4 | (27) |
| Ae% (%) | NA | NA | 47.2 | (25) | 34.4 | (37) |
Cmax = Maximum steady state plasma concentration
tmax = Time for Cmax
T1/2 = Elimination half-life
AUC(0-8) = Steady state area under plasma concentration-time curve from time 0 to 8 hours post-dose
Ae% = Percent of dose excreted unchanged into the urine from time 0 to 8 hours post-dose
NA = Not available
Distribution
Normatol is not bound to plasma proteins and has a volume of distribution equal to 57.7 litres. In patients with epilepsy, Normatol concentrations in cerebrospinal fluid (CSF) are approximately 20% of corresponding steady-state trough plasma concentrations. Normatol is present in the breast milk of breast-feeding women.
Biotransformation
There is no evidence of Normatol metabolism in humans. Normatol does not induce hepatic mixed function oxidase enzymes responsible for drug metabolism.
Elimination
Normatol is eliminated unchanged solely by renal excretion. The elimination half-life of Normatol is independent of dose and averages 5 to 7 hours.
In elderly patients, and in patients with impaired renal function, Normatol plasma clearance is reduced. Normatol elimination-rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance.
Normatol is removed from plasma by haemodialysis. Dosage adjustment in patients with compromised renal function or undergoing haemodialysis is recommended.
Normatol pharmacokinetics in children were determined in 50 healthy subjects between the ages of 1 month and 12 years. In general, plasma Normatol concentrations in children > 5 years of age are similar to those in adults when dosed on a mg/kg basis.
In a pharmacokinetic study in 24 healthy paediatric subjects aged between 1 month and 48 months, an approximately 30% lower exposure (AUC), lower Cmax and higher clearance per body weight have been observed in comparison to available reported data in children older than 5 years.
Linearity/Non-linearity
Normatol bioavailability (fraction of dose absorbed) decreases with increasing dose which imparts non-linearity to pharmacokinetic parameters which include the bioavailability parameter (F) e.g. Ae%, CL/F, Vd/F. Elimination pharmacokinetics (pharmacokinetic parameters which do not include F such as CLr and T1/2), are best described by linear pharmacokinetics. Steady state plasma Normatol concentrations are predictable from single-dose data.
Carcinogenesis
Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for two years. A statistically significant increase in the incidence of pancreatic acinar cell tumors was found only in male rats at the highest dose. Peak plasma drug concentrations in rats at 2000 mg/kg/day are 10 times higher than plasma concentrations in humans given 3600 mg/day. The pancreatic acinar cell tumors in male rats are low-grade malignancies, did not affect survival, did not metastasize or invade surrounding tissue, and were similar to those seen in concurrent controls. The relevance of these pancreatic acinar cell tumors in male rats to carcinogenic risk in humans is unclear.
Mutagenesis
Gabapentin demonstrated no genotoxic potential. It was not mutagenic in vitro in standard assays using bacterial or mammalian cells. Gabapentin did not induce structural chromosome aberrations in mammalian cells in vitro or in vivo, and did not induce micronucleus formation in the bone marrow of hamsters.
Impairment of fertility
No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately five times the maximum daily human dose on a mg/m2 of body surface area basis).
Teratogenesis
Gabapentin did not increase the incidence of malformations, compared to controls, in the offspring of mice, rats, or rabbits at doses up to 50, 30 and 25 times respectively, the daily human dose of 3600 mg, (four, five or eight times, respectively, the human daily dose on a mg/m2 basis).
Gabapentin induced delayed ossification in the skull, vertebrae, forelimbs, and hindlimbs in rodents, indicative of fetal growth retardation. These effects occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during organogenesis and in rats given 2000 mg/kg prior to and during mating and throughout gestation. These doses are approximately 1 to 5 times the human dose of 3600 mg on a mg/m2 basis.
No effects were observed in pregnant mice given 500 mg/kg/day (approximately 1/2 of the daily human dose on a mg/m2 basis).
An increased incidence of hydroureter and/or hydronephrosis was observed in rats given 2000 mg/kg/day in a fertility and general reproduction study, 1500 mg/kg/day in a teratology study, and 500, 1000, and 2000 mg/kg/day in a perinatal and postnatal study. The significance of these findings is unknown, but they have been associated with delayed development. These doses are also approximately 1 to 5 times the human dose of 3600 mg on a mg/m2 basis.
In a teratology study in rabbits, an increased incidence of post-implantation fetal loss, occurred in doses given 60, 300, and 1500 mg/kg/day during organogenesis. These doses are approximately 1/4 to 8 times the daily human dose of 3600 mg on a mg/m2 basis.
Carcinogenesis
Normatol was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for two years. A statistically significant increase in the incidence of pancreatic acinar cell tumours was found only in male rats at the highest dose. Peak plasma drug concentrations in rats at 2000 mg/kg/day are 10 times higher than plasma concentrations in humans given 3600 mg/day. The pancreatic acinar cell tumours in male rats are low-grade malignancies, did not affect survival, did not metastasize or invade surrounding tissue, and were similar to those seen in concurrent controls. The relevance of these pancreatic acinar cell tumours in male rats to carcinogenic risk in humans is unclear.
Mutagenesis
Normatol demonstrated no genotoxic potential. It was not mutagenic in vitro in standard assays using bacterial or mammalian cells. Normatol did not induce structural chromosome aberrations in mammalian cells in vitro or in vivo, and did not induce micronucleus formation in the bone marrow of hamsters.
Impairment of Fertility
No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately five times the maximum daily human dose on a mg/m2 of body surface area basis).
Teratogenesis
Normatol did not increase the incidence of malformations, compared to controls, in the offspring of mice, rats, or rabbits at doses up to 50, 30 and 25 times respectively, the daily human dose of 3600 mg, (four, five or eight times, respectively, the human daily dose on a mg/m2 basis).
Normatol induced delayed ossification in the skull, vertebrae, forelimbs, and hindlimbs in rodents, indicative of foetal growth retardation. These effects occurred when pregnant mice received oral doses of 1000 or 3000 mg/kg/day during organogenesis and in rats given 2000 mg/kg prior to and during mating and throughout gestation. These doses are approximately 1 to 5 times the human dose of 3600 mg on a mg/m2 basis.
No effects were observed in pregnant mice given 500 mg/kg/day (approximately 1/2 of the daily human dose on a mg/m2 basis).
An increased incidence of hydroureter and/or hydronephrosis was observed in rats given 2000 mg/kg/day in a fertility and general reproduction study, 1500 mg/kg/day in a teratology study, and 500, 1000, and 2000 mg/kg/day in a perinatal and postnatal study. The significance of these findings is unknown, but they have been associated with delayed development. These doses are also approximately 1 to 5 times the human dose of 3600 mg on a mg/m2 basis.
In a teratology study in rabbits, an increased incidence of post-implantation foetal loss, occurred in doses given 60, 300, and 1500 mg/kg/day during organogenesis. These doses are approximately 1/4 to 8 times the daily human dose of 3600 mg on a mg/m2 basis.
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