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GABAPENTIN MILPHARM 600 MG FILM-COATED TABLETS

Active substance(s): GABAPENTIN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Gabapentin Milpharm 600 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 600 mg gabapentin.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
600 mg:
White, biconvex, elliptical, film-coated tablets, with deep break line on both sides and
debossed with ‘D’ and ‘24’ on either side of the break line on one side and plain on
other side. The size is 17.3 mm X 9.0 mm

The tablet can be divided into equal doses.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Epilepsy
Gabapentin 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 (see section 5.1).
Gabapentin 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
Gabapentin is indicated for the treatment of peripheral neuropathic pain such
as painful diabetic neuropathy and post-herpetic neuralgia in adults.

4.2

Posology and method of administration
For oral use.
Gabapentin can be given with or without food and should be swallowed with
sufficient fluid-intake (e.g. a glass of water).
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
300 mg once a day
300 mg two times a day

Day 3
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 longterm 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.
Use in elderly patients (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.
Use in patients with renal impairment
Dosage adjustment is recommended in patients with compromised renal
function as described in Table 2 and/or those undergoing haemodialysis.
Gabapentin 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
Total Daily Dosea (mg/day)
(ml/min)
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.

4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section
6.1.

4.4

Special warnings and precautions for use
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic 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.
If a patient develops acute pancreatitis under treatment with gabapentin,
discontinuation of gabapentin should be considered (see section 4.8).
Although there is no evidence of rebound seizures with gabapentin, abrupt
withdrawal of anticonvulsant agents in epileptic patients may precipitate status
epilepticus (see section 4.2).
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.
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.

4.5

Interaction with other medicinal products and other forms of interaction
In a study involving healthy volunteers (N=12), when a 60 mg controlledrelease morphine capsule was administered 2 hours prior to a 600 mg
gabapentin, 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.
No interaction between gabapentin and phenobarbital, phenytoin, valproic
acid, or carbamazepine has been observed.
Gabapentin steady-state pharmacokinetics are similar for healthy subjects and
patients with epilepsy receiving these anti-epileptic agents.
Coadministration of gabapentin with oral contraceptives containing
norethindrone and/or ethinyl estradiol, does not influence the steady-state
pharmacokinetics of either component.
Coadministration of gabapentin with antacids containing aluminium and
magnesium, reduces gabapentin bioavailability up to 24%.. It is recommended
that gabapentin be taken at the earliest two hours following antacid
administration.
Renal excretion of gabapentin is unaltered by probenecid.
A slight decrease in renal excretion of gabapentin that is observed when it is
coadministered with cimetidine is not expected to be of clinical importance.

4.6

Fertility, 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 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.

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 to<
1/10); uncommon ( 1/1000 to < 1/100); rare ( 1/10000 to < 1/1000); very rare (<
1/10000).. 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.

Body System

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

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 paresthesia,
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 disorders
Common

hypertension, vasodilatation

Respiratory, thoracic and mediastinal disorders
Common

dyspnoea, bronchitis, pharyngitis, cough, rhinitis

Gastrointestinal disorders
Common

vomiting, nausea, dental abnormalities, gingivitis, diarrhea,
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
(see section 4.4)

Musculoskeletal, connective tissue and bone 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

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 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

4.9

Overdose
Acute, life-threatening toxicity has not been observed with gabapentin
overdoses of up to 49 grams. Symptoms of the overdoses 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, hence, 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 groups: Other antiepileptics ATC code: N03AX12
The precise mechanism of action of gabapentin is not known.
Gabapentin is structurally related to the neurotransmitter GABA (gammaaminobutyric 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

radiolabeled gabapentin have characterized 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 µM, 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
17/99 (17.2%)
20/96 (20.8%)
0.5144
Old
*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 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 300 mg
400 mg
800 mg
parameter
(N = 7)
(N = 14)
(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)
24.8
(24)
34.5
(34)
51.4
(27)
µg•hr/ml)
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 steadystate 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
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 (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.
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
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 tumours was
found only in male rats at the highest dose. Peak plasma drug concentrations
in rats at 2000 mg/kg 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
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 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
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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Maize Starch
Crospovidone (Type A)
Copovidone (VA 64)
Microcrystalline Cellulose (KG-1000)
Microcrystalline Cellulose (PH-102)
Magnesium Stearate
Coating material:
Hydroxypropyl cellulose
Talc

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years

6.4

Special precautions for storage
Store below 25°C.

6.5

Nature and contents of container
Gabapentin film-coated tablets are packed in
Polyamide/Aluminium/PVC – Aluminium foil blister pack: 10, 20, 30, 50, 60,
90, 100, 200 and 500 tablets
HDPE container: 20 and 500 tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Milpharm Limited
Ares, Odyssey Business Park
West End Road, South Ruislip HA4 6QD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL: 16363/0269

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
31/10/2013

10

DATE OF REVISION OF THE TEXT
31/10/2013

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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