Gabapentin Zentiva 800 Mg Film-Coated Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT
Gabapentin Zentiva 800mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 800 mg gabapentin.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
A white, capsule shaped, film-coated tablet.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Epilepsy
Adults and children over 12 years
Dolevor is an anti-epileptic agent indicated as add-on therapy for partial seizures (with or without secondary generalisation) in patients who have not achieved satisfactory control with, or who exhibit intolerance to, standard anticonvulsants whether used alone or in combination.
Children 6-12 years of age
Dolevor may be used as add-on therapy for partial seizures (with or without secondary generalisation) in children aged between 6-12 years, who have not achieved satisfactory control with, or who exhibit intolerance to, standard anticonvulsants whether used alone or in combination, if the risk-benefit ratio is considered favourable. Treatment should be initiated and supervised by a neurological specialist.
Children under 6 years of age
The use of Dolevor is not recommended in this age group owing to the lack of sufficient supporting data.
Neuropathic Pain
Dolevor is indicated for the treatment of neuropathic pain in adults.
4.2 Posology and method of administration
Note:
Gabapentin capsules, of strengths 100mg, 300mg and 400mg, and Dolevor 800mg tablets (gabapentin) are also available for construction of an appropriate patient dosage regimen.
Epilepsy
Adults and children (over 12 years)
Dolevor tablets are administered orally, and may be taken with or without food.
The anti-epileptic effect of gabapentin generally occurs at a daily dose of 900 to 1200mg. It is not necessary to monitor gabapentin plasma concentrations to optimise therapy.
An effective dose can be achieved rapidly by titration over a few days, by administering 300mg once a day on the first day, 300mg twice a day on the second day and 300mg three times a day on the third day (refer to Table 1 below).
Table 1: Dosing chart for initial titration
|
Dose |
Day 1 |
Day 2 |
Day 3 |
|
900mg |
300mg |
300mg |
300mg |
|
once a day |
two times a day |
three times a day |
Dosage can be increased subsequently with increments of 300mg per day given in three equally divided doses, to a daily maximum of 3600mg. The maximum time between doses in a three times daily schedule should not be more than 12 hours.
Discontinuation of Dolevor, and/or addition of an alternative anticonvulsant medicinal product to the treatment regimen, should be accomplished gradually over a minimum period of one week.
Elderly
Dosage adjustment may be necessary in elderly patients, due to declining renal function with age (refer to Table 2).
Children 6-12 years of age
The recommended dose of Dolevor is 25mg/kg/day to 35 mg/kg/day, given in divided doses three times a day. An effective dose can be achieved by titration over three days, by administering 10 mg/kg/day on the first day, 20 mg/kg/day on the second day and 25mg/kg/day to 35 mg/kg/day on the third day. A suggested maintenance dosing schedule is given below:
Weight Range (kg) Total mg daily dose
26 - 36 900
37 - 50 1200
Neuropathic Pain
Adults (over 18 years)
Dolevor tablets are administered orally, and may be taken with or without food.
Gabapentin should be titrated to a maximum dose of 3600mg per day. An effective dose can be achieved rapidly by titration over a few days, by administering 300mg once a day on the first day, 300mg twice a day on the second day and 300mg three times a day on the third day (refer to Table 1).
Dosage can be increased subsequently with increments of 300mg per day to a daily maximum of 3600mg, given in three divided doses. There is no need to divide the doses equally when titrating gabapentin, and it is not necessary to monitor gabapentin plasma concentrations to optimise therapy. The maximum time between doses in a three times daily schedule should not be more than 12 hours.
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.
Discontinuation of Dolevor, dosage reduction or substitution with an alternative medicinal product, should be achieved gradually during a minimum period of one week.
Elderly
It may be necessary to adjust the dose in elderly patients, due to declining renal function with age (refer to Table 2).
Patients with impaired renal function or undergoing haemodialysis
It is recommended that a dose adjustment is made for patients with impaired renal function and those undergoing haemodialysis. The dosage recommendations for impaired renal function are summarised in Table 2 overleaf.
For patients undergoing haemodialysis who have not previously been given gabapentin, a loading dose of 300 to 400mg is recommended, with a further 200 to 300mg of gabapentin following each 4 hours of haemodialysis.
Table 2: Maintenance dosage of gabapentin in patients with impaired renal function
|
Renal function (creatinine clearance, ml/min) |
Total daily dose1 mg/day | ||
|
> 80 |
900 |
1200 |
2400 |
|
50-79 |
600 |
600 |
1200 |
|
30-49 |
300 |
300 |
600 |
|
15-29 |
1502 |
300 |
300 |
|
< 153 |
1502 |
1502 |
1502 |
1 Total daily dose should be administered as a three times daily regimen. For patients with normal renal function (creatine clearance >80 ml/min), the daily dose will range from 900 - 2400mg. Dosage reduction is recommended for patients with impaired renal function (creatinine clearance <79 ml/min).
2 To be administered as 300mg on alternate days.
3 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.
4.3 Contraindications
Hypersensitivity to the active substance gabapentin, or to any of the excipients of Dolevor tablets.
4.4 Special warnings and precautions for use
Although there is no evidence of rebound seizures with gabapentin, abrupt withdrawal of anticonvulsant agents in epileptic patients may precipitate status epilepticus. When, in the judgement of the clinician, there is a need for dose reduction, discontinuation or substitution of alternative anticonvulsant medicinal products, this should be effected gradually over a period of at least one week.
Gabapentin is not considered effective against primary generalised 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.
If a patient develops acute pancreatitis under treatment with gabapentin, discontinuation of gabapentin should be considered (see section 4.8).
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.
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.
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.
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 (see section 4.8).
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.
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.
Patients taking gabapentin can be the subject of mood and behavioural disturbances. Such reports have been noted in patients receiving gabapentin, although a causal link has not been established.
Caution is recommended in patients with a history of psychotic illness. On commencing treatment with gabapentin, psychotic episodes have been reported in some patients with, and rarely without, a history of psychotic illness. Most of these events resolved when gabapentin was discontinued, or the dosage reduced.
Suicide/suicidal thoughts:
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agent 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 gabapentin.
Therefore patients 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.
4.5 Interaction with other medicinal products and other forms of interaction
In a study involving healthy volunteers (N=12), when a 60mg controlled-release morphine capsule was administered 2 hours prior to a 600mg gabapentin capsule, mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Therefore, patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately.
The anticonvulsant effect of antiepileptics is antagonised by tricyclic antidepressants, selective-serotonin re-uptake inhibitors (SSRIs) and mefloquine, and may be antagonised by monoamine oxidase inhibitors (MAOIs) and tricyclic-related antidepressants. There is a possibility of increased risk of convulsions when antiepileptics are given with chloroquine and hydroxychloroquine.
Gabapentin may be used in combination with other anti-epileptic medicinal products, without concern for alteration of the plasma concentrations of gabapentin or the serum concentrations of other anti-epileptic active substances.
There are no interactions between gabapentin and phenytoin, valproic acid, carbamazepine or phenobarbitone. Steady-state pharmacokinetics of gabapentin are similar in healthy subjects and in patients with epilepsy receiving anti-epileptic agents.
Co-administration of gabapentin with oral contraceptives including norethisterone and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of either component.
In a clinical study where gabapentin was given at the same time as an aluminium and magnesium containing antacid, the bioavailability of gabapentin was reduced by up to 24%. It is recommended that gabapentin should be taken about two hours following any such antacid administration.
The renal excretion of gabapentin is not altered by probenecid, whereas a slight decrease in renal excretion of gabapentin is observed when coadministered with cimetidine. However, this is not expected to be of clinical importance.
False positive readings have been reported with the Ames N-Multistix SG® dipstick test when gabapentin was added to other anticonvulsant drugs. The more specific sulphosalicylic acid precipitation procedure is recommended to determine urinary protein.
4.6 Pregnancy and lactation
Risk related to epilepsy and antiepileptic medicinal products in general
The risk of birth defects is increased by a factor of 2 - 3 in the offspring of mothers treated with an antiepileptic medicinal product. Most frequently reported are cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic drug therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is important that monotherapy is practised whenever possible. Specialist advice should be given to women who are likely to become pregnant or who are of childbearing potential and the need for antiepileptic treatment should be reviewed when a woman is planning to become pregnant. No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both mother and child. Developmental delay in children of mothers with epilepsy has been observed rarely. It is not possible to differentiate if the developmental delay is caused by genetic, social factors, maternal epilepsy or the antiepileptic therapy.
Risk related to gabapentin
There are no adequate data from the use of gabapentin in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Gabapentin should not be used during pregnancy unless the potential benefit to the mother clearly outweighs the potential risk to the foetus.
No definite conclusion can be made as to whether gabapentin is associated with an increased risk of congenital malformations when taken during pregnancy, because of epilepsy itself and the presence of concomitant antiepileptic medicinal products during each reported pregnancy.
Gabapentin is excreted in human milk. Because the effect on the breast-fed infant is unknown, caution should be exercised when gabapentin is administered to a breast-feeding mother. Gabapentin should be used in breastfeeding mothers only if the benefits clearly outweigh the risks.
4.7 Effects on ability to drive and use machines
Gabapentin acts on the central nervous system and may produce drowsiness, dizziness, or related symptoms. Whilst these adverse events are otherwise mild or moderate, they pose a potential danger for patients who are driving or operating machinery, particularly until such time as the individual patient's experience with gabapentin is characterised. This is especially true at the beginning of the treatment and after increase in dose.
4.8 Undesirable effects
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, <1/10), uncommon (>1/1000, <1/100) and rare (>1/10,000; <1/1,000). Where an adverse
reaction was seen at different frequencies in clinical studies, it was assigned to the highest frequency reported.
Additional reactions reported from the post-marketing experience are included as frequency Not known (cannot be estimated from the available data)
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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
Metabolism and Nutrition Disorders
Common: anorexia, increased appetite
Psychiatric disorders
Common: hostility, confusion and emotional lability, depression,
anxiety, nervousness, thinking abnormal
Not known: hallucinations
Nervous system disorders
Very Common: somnolence, dizziness, ataxia,
Common: convulsions, hyperkinesias, dysarthria, amnesia, tremor,
insomnia, headache, sensations such as paraesthesia, hypaesthesia, coordination abnormal, nystagmus, increased, decreased, or absent reflexes
Uncommon: hypokinesia
|
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 disorder | |
|
Common: |
hypertension, vasodilatation |
Respiratory, thoracic and mediastinal disorders
Common: dyspnoea, bronchitis, pharyngitis, cough, rhinitis
Gastrointestinal disorders
Common: vomiting, nausea, dental abnormalities, gingivitis, diarrhoea,
|
Not known: |
abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence pancreatitis |
Hepatobiliary disorders
Not known: hepatitis, jaundice
Skin and subcutaneous tissue disorders
Common: facial oedema, purpura most often described as bruises
|
Not known: |
resulting from physical trauma, rash, pruritus, acne Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia, drug rash with eosinophilia and systemic symptoms (see section 4.4) |
Musculoskeletal, connective tissue and bone 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
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 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 glucose fluctuations in patients with diabetes, blood creatine phosphokinase increased |
|
Injury and poisoning Common: |
accidental injury, fracture, abrasion |
Under treatment with gabapentin cases of acute pancreatitis were reported. Causality with gabapentin is unclear (see section 4.4).
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
4.9 Overdose
Acute, life-threatening toxicity has not been observed in overdoses with gabapentin of up to 49 grams. Symptoms of overdose included dizziness, double vision, slurred speech, drowsiness, 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 thus minimise 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 not usually 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other antiepileptics, ATC code: N03A X12
The precise mechanism of action of gabapentin is not known.
Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but its mechanism of action is different from that of several other active substances that interact with GABA synapses including valproate, barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA uptake inhibitors, GABA agonists, and GABA prodrugs. In vitro studies with radiolabelled gabapentin have characterised a novel peptide binding site in rat brain tissues including neocortex and hippocampus that may relate to anticonvulsant and analgesic activity of gabapentin and its structural derivatives.
The binding site for gabapentin has been identified as the alpha2-delta subunit of voltage-gated calcium channels.
Gabapentin at relevant clinical concentrations does not bind to other common drug or neurotransmitter receptors of the brain including GABAA, GABAb, benzodiazepine, glutamate, glycine or N-methyl-d-aspartate receptors.
Gabapentin does not interact with sodium channels in vitro and so differs from phenytoin and carbamazepine. Gabapentin partially reduces responses to the glutamate agonist N-methyl-D-aspartate (NMDA) in some test systems in vitro, but only at concentrations greater than 100 pM, which are not achieved in vivo. Gabapentin slightly reduces the release of monoamine neurotransmitters in vitro. Gabapentin administration to rats increases GABA turnover in several brain regions in a manner similar to valproate sodium, although in different regions of brain. The relevance of these various actions of gabapentin to the anticonvulsant effects remains to be established. In animals, gabapentin readily enters the brain and prevents seizures from maximal electroshock, from chemical convulsants including inhibitors of GABA synthesis, and in genetic models of seizures.
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.
5.2 Pharmacokinetic properties
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 pg/ml and 20 pg/ml in clinical studies, such concentrations were not predictive of safety or efficacy. Pharmacokinetic parameters are given in Table 3.
Summary of gabapentin mean (%CV) steady-state pharmacokinetic parameters following every eight hours administration
Table 3
|
Pharmacokinetic parameter |
300 mg (N = 7) |
400 mg (N = 14) |
800 mg (N=14) | |||
|
Mean |
%CV |
Mean |
%CV |
Mean |
%CV | |
|
Cmax (pg/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) pg*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.
Metabolism
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 halflife 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 (see section 4.2).
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.
5.3 Preclinical safety data
Carcinogenicity
Gabapentin was administered in the diet to mice at 200, 600, and 2000mg/kg/day and to rats at 250, 1000, and 2000mg/kg/day for two years. A statistically significant increase in the incidence of pancreatic acinar cell tumours was noted only in male rats at the highest dose. Peak plasma drug concentrations and areas under the concentration time curve in rats at 2000mg/kg are 10 times higher than plasma concentrations in humans receiving 3600mg/day.
The pancreatic acinar cell tumours in male rats were low-grade malignancies, without effect on survival, which did not metastasise or invade surrounding tissue. These tumours were similar to those seen in concurrent controls. The relevance of pancreatic acinar cell tumours in male rats to carcinogenic risk in humans is therefore of uncertain significance.
Mutagenesis
Gabapentin has no genotoxic potential. It was not mutagenic in the Ames bacterial plate incorporation assay, or at the HGPRT locus in mammalian cells in the presence or absence of metabolic activation. 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 500, 1000, or 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablets Core:
Macrogol 4000 Pre-gelatinised starch Colloidal anhydrous silica
Magnesium stearate
Tablet film coating:
Polyvinyl alcohol
Titanium dioxide (E171)
Talc
Lecithin
Xanthan gum
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months.
6.4 Special precautions for storage
Store below 25°C.
6.5 Nature and contents of container
PVC/Aluminium blister pack. Supplied in pack sizes of 50, 90, 100 and 200 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Winthrop Pharmaceuticals UK Limited
One Onslow Street
Guildford
Surrey
GU1 4YS
United Kingdom
Trading as
Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS Or
Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK
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MARKETING AUTHORISATION NUMBER(S)
PL 17780/0422
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14/08/2008
DATE OF REVISION OF THE TEXT
20/03/2014
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