Gabapentin 100mg, 300mg & 400mg Capsules

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content:
Lactose anhydrous
Maize starch
Talc
Gelatin
Titanium dioxide (E171)

Capsule Shell:
Gelatin
Titanium dioxide (E171)
Sodium lauryl sulphate
300mg & 400mg only: Iron oxide yellow (E172)
400mg only: Iron oxide red (E172) and iron oxide yellow (E172)

10. DATE OF REVISION OF THE TEXT

JulyOctober 2017

4.4 Special warnings and precautions for use

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.

4.8 Undesirable effects

Respiratory, thoracic and mediastinal disorders
Common: Dyspnoea, bronchitis, pharyngitis, cough, rhinitis
Rare: Respiratory depression

10. DATE OF REVISION OF THE TEXT

January July 2017

4.8 Undesirable effects


Psychiatric disorders

Uncommon: agitation



4.2 Posology and method of administration

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 eElderly 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 rRenal 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.

4.4 Special warnings and precautions for use

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 anti-epileptic 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 aetiology 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 (see section 4. 8).

Dizziness, somnolence, loss of consciousness, confusion and mental impairment
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, confusion and mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.inal product.

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 (see section 4.5).

Use in eElderly patients (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.

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 anti-epileptic 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 aetiology 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.

Lactose
Gabapentin capsules contain 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

There are spontaneous and literature case reports of respiratory depression and/or sedation associated with gabapentin and opioid use. In some of these reports, the authors considered this a particular concern with the combination of gabapentin and opioids, especially in elderly patients.

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 who require concomitant treatment with opioids should be carefully observed for signs of CNS depression, such as somnolence, sedation and respiratory depression and the dose of gabapentin or morphine opioid should be reduced appropriately.

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 (≥ 1/1,000 to < 1/100), rare (≥1/10,000 to < 1/1,000), very rare (<10,000) and not known (cannot be estimated from the available data)). 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.

Infections and infestations
Very cCommon: 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 (see section 4.4)

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
Not known: Hallucinations

Nervous system disorders
Very commonCommon: Somnolence, dizziness, ataxia
Common: Convulsions, hyperkinesias, dysarthria, amnesia, tremor, insomnia, headache, sensations such as paraesthesia, hypoaesthesia, coordination abnormal, nystagmus, increased, decreased, or absent reflexes
Uncommon: Hypokinesia, mental impairment
Rare: Loss of consciousness
Not known: other Mmovement 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, 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 (see section 4.4)

Musculoskeletal and connective tissue disorders
Common: Arthralgia, myalgia, back pain, twitching
Not known: Rhabdomyolysis, myoclonus

Renal and urinary disorders
Not known: Acute renal failure, Iincontinence, acute renal failure

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 commonCommon: Fatigue, fever
Common: Peripheral oedema, abnormal gait, asthenia, pain, malaise, flu syndrome
Uncommon: Generalized 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, 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 (see section 4.4). In patients on haemodialysis due to end-stage renal failure, myopathy with elevated creatine kinase levels has been reported.

5.1  Pharmacodynamic properties

Pharmacotherapeutic groups: Antiepileptics, Other antiepileptics, ATC code: N03AX12

5.3 Preclinical safety data

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 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 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.

 

4.2 Posology and method of administration

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


4.4 Special warnings and precautions for use

Dizziness, somnolence, loss of consciousness, confusion and mental impairment
Gabapentin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population. There have also been post-marketing reports of loss of consciousness, 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 medicinal productmedication.

 

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 (see section 4.5).


4.5 Interaction with other medicinal products and other forms of interaction

There are spontaneous and literature case reports of respiratory depression and/or sedation associated with gabapentin and opioid use. In some of these reports, the authors considered this a particular concern with the combination of gabapentin and opioids, especially in elderly patients.

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 who require concomitant treatment with opioids patients should be carefully observed for signs of CNS depression, such as somnolence, sedation and the dose of gabapentin or morphine should be reduced appropriately.


4.6 Fertility, pregnancy and lactation

Fertility
There is no effect on fertility in animal studies (see section 5.3).


4.8 Undesirable effects

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.

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

Nervous system disorders
Uncommon: Hypokinesia, mental impairment

Hepatobiliary disorders
Rare: Hepatotoxicity
Not known: Hepatitis, jaundice

General disorders and administration site conditions
Common: Peripheral or generalised oedema, abnormal gait, asthenia, pain, malaise, flu syndrome
Uncommon: Generalized oedema

5.1 Pharmacodynamic properties

Mechanism of action
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 radiolabeled 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 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 target 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.

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.

Pharmacodynamic effects
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-Daspartate (NMDA) in some test systems in vitro, but only at concentrations greater than 100μm, which are not achieved in vivo. Gabapentin slightly reduces the release of monoamine neurotransmitters in vitro. Gabapentin administration to rats increases GABA turn over in several brain regions in a manner similar to valproate sodium, although in different regions of the 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.

Clinical efficacy and safety 
Paediatric population
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).

5.3 Preclinical safety data

Peak plasma drug concentrations in rats at 2000 mg/kg/day are 10 times higher than plasma concentrations in humans given the recommended maximum therapeutic dose of 3600 mg/day.

10. DATE OF REVISION OF THE TEXT

January August 2015



(internal reference: PR620474 Safety & BL updates)

 

 

 

 

 

 

 

 

 

Extensive list of changes as per new QRD template and brand leader. please refer to the attached document for all changes.

4.4 Special warnings and precautions for use

Added:

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.

4.8 Undesirable effects

...and frequency (very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1,000, ≤ 1/100), and rare (≥  1/10,000; ≤ 1/1,000) and not known (cannot be estimated from the available data)).

Skin and subcutaneous tissue disorders
Common: Facial oedema, purpura most often described as bruises resulting from physical trauma, rash, pruritus, acne
Rare:  Stevens-Johnson syndrome, angioedema, erythema multiforme, alopecia
Not Known: drug rash with eosinophilia and systemic symptoms (see section 4.4)

10. DATE OF REVISION OF THE TEXT

Changed to January 2013


(Internal ref: VRF 6826 - CMDh updates DRESS)

Shelf-life for blister pack extended from 2 years to 3 years

1. NAME OF THE MEDICINAL PRODUCT
Gabapentin Xmg Hard Capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

100mg:
Each capsule contains 100 mg gabapentin.
Each hard capsule contains 22.5mg lactose anhydrous

300mg:
Each capsule contains 300 mg gabapentin.
Each hard capsule contains 67.5mg lactose anhydrous

400mg:
Each capsule contains 400 mg gabapentin.
Each hard capsule contains 90.0mg lactose anhydrous


4.8 Undesirable effects

Hepatobiliary disorders
Rare:  Hepatitis, jaundice, hepatotoxicity

Reproductive system and breast disorders
Common: Impotence, female anorgasmia

CORRECT TYPOS

Section 4.2
Dosing Chart - Inistial Initial Titration

Section 4.6
...increased risk of congenital malframtion malformation when taken during pregnancy....

Section 4.8
Repiratory Respiratory , thoracic and mediastinal disorders

.... gingivitis, diarrhea diarrhoea, abdominal pain....

Repiratory Respiratory tract infections, otitis media,......

Section 5.1
.....GABA update inhibitors, GABA agnoists agonists, and GABA prodrugs....

In vitro studies with radiolabeled gabanetin gabapentin have characterised a novel peptide binding site in rat brain tissues including neocortex and characterised a novel peptide binding site in rat brain tissues including neocortex and hippocampus that may related relate to anticonvulsant and analgesic activity of gabapentin and its structural derivatives.

Gabapnetin Gabapentin administration to rats increases GABA turn over.....

....from 3 to 12 years, showed a numberical numerical but not statistically....

Section 5.2
Metabolism
Gabpentin Gabapentin does not induce hepatic.....

Linearity/ Non-linearity
....increasing dose which imparts non0linearity non-linearity to pharmacokinetic parameters .....

Section 5.3
Mutagenesis
..... aberrations in mammalian cells in vitro or in vivo, and did not induce ....

Section 4.4. addition of the following wording:

Sucidal 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 considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge

Section 10, Change of Date of Revision of Text to December 2008