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1. Gabapentin Medreich 400mg Capsules
2. Gabapentin Medreich 400mg Capsules

1. NAME OF THE MEDICINAL PRODUCT

Gabapentin Medreich 400mg Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 400mg gabapentin and 67.333 mg of lactose.

‘For a full list of excipients, see section 6.1’.

3. PHARMACEUTICAL FORM

‘Capsule, hard [capsule]’.

Size ‘0’ orange/orange hard gelatin capsule marked ‘MG 400’

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 Neuropathic Pain Adults (over the age of 18)

Gabapentin should be titrated to a maximum dose of 1800 mg per day.

Titration to an effective dose can progress rapidly and can be accomplished over a few days by administering 300mg once a day on day 1, 300mg twice a day on day 2 and 300mg three times a day on day 3, as described in Table 1.

Thereafter, the dose can be increased using increments of 300mg per day given in three divided doses to a maximum of 1800mg per day. It is not necessary to divide the doses equally when titrating Gabapentin.

It is not necessary to monitor Gabapentin plasma concentrations to optimise Gabapentin therapy.

The maximum time between doses in a three times daily schedule should not exceed 12 hours. Gabapentin may be given orally with or without food.

If Gabapentin is discontinued, or the dose reduced or substituted with an alternative medication, this should be done gradually over a minimum of one week.

Elderly

Elderly patients may require dosage adjustment because of declining renal function with age (see Table 2).

Epilepsy

Adults and Children aged over 12

The anti-epileptic effect of Gabapentin generally occurs at 900 to 1200mg/day.

It is not necessary to monitor gabapentin plasma concentrations to optimise gabapentin therapy.

Titration to an effective dose can progress rapidly and can be accomplished over a few days by administering 300mg once a day on day 1, 300mg twice day on day 2 and 300mg three times a day on day 3, as described in Table 1.

Thereafter, the dose can be increased using increments of 300mg per day given in three equally divided doses to a maximum dose of 2400mg per day.

The maximum time between doses in a three times daily schedule should not exceed 12 hours. Gabapentin may be given orally with or without food.

If gabapentin is discontinued and/or an alternate anticonvulsant medication is added to the therapy, this should be done gradually over a minimum of one week.

Elderly

Elderly patients may require dosage adjustment because of declining renal function with age (see table 2).

Children 6-12 years of age

The recommended dose of gabapentin is 25 to 35 mg/kg/day given in divided doses (3 times a day). Titration to an effective dose can take place over 3 days by giving 10 mg/kg/day on Day 1, 20 mg/kg/day on Day 2 and 25 to 35 mg/kg/day on Day 3.

The following maintenance dosing schedule is suggested:

Weight Range kg    Total    mg Dose/Day

26-36    900

37-50    1200

Dosage Adjustment in Patients with Compromised Renal Function or those UndergoingHaemodialysis

Dosage adjustment is recommended in patients with compromised renal function as described in Table 2, or those undergoing haemodialysis.

Patients with Compromised Renal Function:

Table 2: MAINTENANCE DOSAGE OF GABAPENTIN IN ADULTS WITH REDUCED RENAL FUNCTION

Renal function Creatinine Clearance (ml/minute)	Total Daily Dosea mg/day NORMAL DOSAGE
> 80	900	1200	2400
50-79	600	600	1200
30-49	300	300	600
15-29	150b	300	300
<15	150b	150b	150b

^a Total daily dose should be administered as a tid regimen. Doses used to treat patients with normal renal function (creatinine clearance >80 ml/min) range from 900 to 2400 mg/day. Reduced dosages are for patients with renal impairment (creatinine clearance <79 ml/min).

^b To be administered as 300 mg every other day.

Patients Undergoing Haemodialysis:

For patients undergoing haemodialysis who have never received gabapentin, a loading dose of 300 to 400mg is recommended then 200 to 300mg of gabapentin following each 4 hours of haemodialysis.

4.3 Contraindications

Gabapentin is contra-indicated in patients who are hypersensitive to gabapentin or to the product's components.

4.4 Special warnings and precautions for use

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 antiepileptic 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). When, in the judgement of the clinician, there is a need for dose reduction, discontinuation or substitution of alternative anticonvulsant medication, this should be done gradually over a minimum of one week.

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 generally considered effective in the treatment of primary generalized seizures such as absence seizures 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.

Patients taking gabapentin can be the subject of mood and behavioural disturbances. Such reports have been noted in patients on gabapentin although a causal link has not been established.

Caution is recommended in patients with a history of psychotic illness. On commencing gabapentin therapy, 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 was reduced.

This product contains Lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

In a study involving healthy volunteers (N=12), when a 60-mg controlled-release morphine capsule was administered 2 hours prior to a 600-mg 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.

Gabapentin may be used in combination with other anti-epileptic drugs without concern for alteration of the plasma concentrations of gabapentin or serum concentrations of other anti-epileptic drugs.

There is no interaction between gabapentin and phenytoin, valproic acid, carbamazepine or phenobarbitone. Gabapentin steady-state pharmacokinetics are similar for healthy subjects and patients with epilepsy receiving antiepileptic agents.

Co-administration of gabapentin with oral contraceptives including norethisterone (norethindrone) and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of either component.

In a clinical study where gabapentin and an aluminium and magnesium containing antacid when given at the same time, gabapentin's bioavailability was reduced by up to 24%. It is recommended that Gabapentin is taken about two hours following any such antacid administration. The slight decrease in renal excretion of gabapentin observed when co-administered with Cimetidine is not expected to be of clinical importance.

Renal excretion of gabapentin is unaltered by probenecid. Food has no effect on gabapentin pharmacokinetics. Because false positive readings were 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.

Safe use in human pregnancy has not been established. Reproduction studies in mice, rats or rabbits at doses up to 50, 30 and 25 times respectively, the daily human dose of 3600mg revealed no evidence of impaired fertility or harm to the foetus due to gabapentin administration. However, because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.

Gabapentin is excreted in human milk. Because the effect on the nursing infant is unknown, caution should be exercised when gabapentin is administered to a breast-feeding mother. Gabapentin should be used in breast-feeding mothers only if the benefits clearly outweigh the risks. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from gabapentin, caution should be exercised a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother, 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 produce drowsiness, dizziness, or other related symptoms. These otherwise mild or moderate adverse events could be potentially dangerous in patients driving or operating machinery, particularly until such time as the individual patient's experience with the drug is established. 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	psychoses/hallucinations
Nervous system disorders
Very Common	somnolence, dizziness, ataxia
Common	convulsions, hyperkinesias, dysarthria, amnesia, tremor,

Body System	Adverse drug reactions
insomnia, headache, sensations such as paresthesia, hypoesthesia, coordination abnormal, nystagmus, increased, decreased, or absent reflexes
Uncommon	hypokinesia
Not known	other movement disorders such as 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, diarrhoea, abdominal pain, dyspepsia, constipation, dry mouth or throat, flatulence
rare	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

Body System	Adverse drug reactions
Common	arthralgia, myalgia, back pain, twitching
Not known	myoclonus
Renal and urinary disorder
Not known	acute renal failure (acute kidney failure)
rare	urinary incontinence
Reproductive system and breast disorders
Common	male sexual dysfunction (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	Adverse events following the abrupt discontinuation of gabapentin have also been reported. Withdrawal reactions (most frequently reported are 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, weight increase
Uncommon	elevated liver function tests SGOT (AST), SGPT (ALT) and bilirubin
Not known	blood glucose fluctuations in patients with diabetes
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.

Epilepsy (Children)

In children aged 3-12 years in placebo controlled and long term trials, the most common >10%) side-effects were emotional lability, nervousness and thinking abnormally. All reports

Version: 01 Page 11 of these events were rated as mild or moderate and discontinuation or dose reduction were infrequent.

In children aged 3-12 years in controlled add-on trials, side-effects that occurred with an incidence of 2% or greater than placebo were: somnolence, fatigue, weight increase, hostility, emotional lability, dizziness, hyperkinesia, nausea/vomiting, viral infection, fever, bronchitis, respiratory infection. Some of these side-effects could be attributed to common viral childhood illness.

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 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

Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but its mechanism of action is different from that of several drugs that interact with GABA synapses. The identification and function of the gabapentin binding site remains to be elucidated and the relevance of its various actions to the anticonvulsant effect to be established. Analgesic activity has been shown in animal models of inflammatory and neuropathic pain.

One placebo controlled randomised trial was undertaken in 247 children aged 3-12 years with refractory seizures. Participants received 25-35 mg/kg/day or placebo as add-on therapy. Efficacy was not established in children under 6 years of age.

5.2 Pharmacokinetic properties

Mean plasma gabapentin concentrations (Cmax) occurred approximately 3 hours (Tmax) following single oral doses of gabapentin regardless of dose size or formulation. Mean Tmax values following multiple dose administration were approximately 1 hour shorter than the values following single-dose administration.

Mean Cmax and AUC values increased with increasing dose; however, the increase was less than dose proportional. Deviation from linearity was very slight up to 600mg for both parameters and thus should be minimal at doses of 300mg to 400mg three times daily where the anti-epileptic effect generally occurs.

Following repeated gabapentin administration, steady state was achieved within 1 to 2 days after the start of the multiple dosing and was maintained throughout the dosing regime.

Plasma gabapentin concentration-time profiles were similar between gabapentin solution and capsule formulations following single doses of 300 and 400mg. Absolute bioavailability of a 300mg oral dose of gabapentin was approximately 60%. At doses of 300mg and 400mg, gabapentin bioavailability was unchanged following multiple-dose administration.

The presence of food did not influence the bioavailability of gabapentin.

Gabapentin is not metabolised in humans and does not induce hepatic mixed function oxidase enzymes.

Gabapentin elimination from plasma following IV administration was best described by linear pharmacokinetics. Elimination half-life (T/) of gabapentin ranged from 5 to 7 hours. Gabapentin elimination parameters, apparent plasma T/ and renal clearance (CL_R) were independent of dose and remained unchanged following repeated administration. Renal clearance was the sole elimination pathway for gabapentin. Since gabapentin is not metabolised in humans, the amount of drug recovered in urine is indicative of gabapentin bioavailability. Following a single 200mg oral dose of [C₁₄] gabapentin recovery of radioactivity was essentially complete with approximately 80% and 20% of the dose recovered in urine and faeces, respectively.

As renal function (as determined by creatinine clearance) decreases with increasing age, gabapentin oral clearance, renal clearance and elimination-rate constant decrease proportionally.

Gabapentin pharmacokinetics were determined in a single dose study and a population study in paediatric subjects aged between 1 month and 13 years.

Clearance of gabapentin based on body weight in children above 4 years of age is similar to that in adults. Children between 2-4 years appear to have higher clearances per body weight. Below 2 years the clearance of gabapentin is highly variable.

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 and areas under the concentration time curve in rats at 2000 mg/kg is 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 metastasise 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 therefore of uncertain significance (unclear).

Mutagenesis

Gabapentin has no genotoxic potential. It was not mutagenic in the Ames bacterial plate incorporation assay (standard 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 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

Each capsule contains the following excipients:

Capsules Fill:

Lactose monohydrate Maize starch Talc

Capsule shell:

Titanium dioxide (E171) Gelatin

Printing ink:

Shellac

Titanium dioxide

FD&C Blue 1/Brilliant Blue FCF lake

6.2 Incompatibilities Not applicable

6.3 Shelf life 24 months

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

The capsules are packed in blisters constituted from a clear, colourless PVC and aluminium foil. Each blister has 10 capsules and 10 such blisters are packed in a monocarton.

6.6 Special precautions for disposal No special requirements

7.    Marketing Authorisation Holder

Medreich Plc Warwick House Plane Tree Crescent Feltham TW13 7HF

8    MARKETING AUTHORISATION NUMBER(S)

PL 21880/0077

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

26/11/2012

10 DATE OF REVISION OF THE TEXT

13/02/2014

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