Gabapentin

Registered South African indications:

• Epilepsy

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients 
• Pregnancy
• Breastfeeding
• Children <12 years
• Severe renal impairment (tab) 

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients

South African recommendations

• Renal impairment (cap)
• Mild to moderate renal impairment (tab)
• Hepatic impairment
• Elderly
• Risk of experiencing severe respiratory depression (cap)
  - Compromised respiratory function (cap)
  - Respiratory or neurological disease (cap)
  - Renal impairment (cap)
  - Coadministration with central nervous system depressants (cap)
  - Elderly (cap)
• Abrupt withdrawal
• Absence seizures
• >12 hours between doses
• History of drug abuse  (cap) (See additional prescribing points)
• Galactose intolerance (certain formulations)
• Lapp lactase deficiency (certain formulations)
• Glucose-galactose malabsorption (certain formulations)
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Women of childbearing potential 
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly
• Risk of experiencing severe respiratory depression 
  - Compromised respiratory function 
  - Respiratory or neurological disease 
  - Renal impairment 
  - Coadministration with central nervous system depressants
  - Elderly 
• Abrupt withdrawal (See additional prescribing points) 
• Generalized seizures
  - Mixed seizures including absences
• >12 hours between doses
• Prolonged therapy (greater than 36 weeks in paediatric population)
• History of drug abuse (See additional prescribing points)
• Galactose intolerance (cap)
• Total lactase deficiency (cap, certain formulations)
• Lapp lactase deficiency (cap, certain formulations) 
• Glucose-galactose malabsorption (cap) 
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap, tab

South African registered indications and dosages

Epilepsy (Additional agent(s) may be required)
- Controlling both simple and complex partial seizures with or without secondary generalised tonic-clonic seizures
- As adjunctive therapy in patients who have not achieved adequate seizure control with antiepileptic medicines, when used alone or in combination

• Oral (cap): Initial: 300mg, 3 times a day; Dosage may be gradually increased based on the clinical response; Usual effective dose: 900-1800mg/day, in 3 divided doses with not more than 12hrs between doses; Dosages of up to 3600mg/day, in divided doses 3 times a day for short periods have been well tolerated; See table below for titration to an effective dose

 Titration to an effective dose can progress rapidly, this may be accomplished in as few as 3 days using one of the following approaches:

Target dose	Day 1	Day 2	Day 3 and after
900mg/day	1 x 100mg, three times daily	2 x 100mg, three times daily	1 x 300mg, three times daily
900mg/day	1 x 300mg, once daily	1 x 300mg, twice daily	1 x 300mg, three times daily
1200mg/day	2 x 100mg, three times daily	3 x 100mg, three times daily	1 x 400mg, three times daily
1200mg/day	1 x 400mg, once daily	1 x 400mg, twice daily	1 x 400mg, three times daily

• Oral (tab): Initial: Day 1: 300mg, once daily; Day 2: 300mg, twice daily; Day 3: 300mg, 3 times daily; Usual effective dose: 900-1800mg/day, in 3 divided doses with not more than 12hrs between doses; Max: 1800mg/24hrs

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When in the judgement of the medical practitioner 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. It is unnecessary to monitor gabapentin plasma concentrations to optimise gabapentin therapy

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Gabapentin may be used in combination with phenobarbital, phenytoin, valproic acid and carbamazepine without concern for alteration of the plasma concentrations or serum concentrations of gabapentin or the other anti-epileptic medicines

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Gabapentin may be given orally with or without food

Paed. forms avail. in SA and covered in this monograph: cap, tab

South African registered indications and dosages

Epilepsy (Additional agent(s) may be required)
- Controlling both simple and complex partial seizures with or without secondary generalised tonic-clonic seizures
- As adjunctive therapy in patients who have not achieved adequate seizure control with antiepileptic medicines, when used alone or in combination

Oral (cap, tab)

• Younger than 12 years: Contraindicated
• 12 years and older: See adult dosage

Pregnancy

South African recommendations

• Contraindicated
• Gabapentin should not be used during pregnancy as safety and efficacy has not been established. Animal studies have shown reproductive toxicity. The potential risk in humans is not known (cap)
• 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 3600mg, (four, five or eight times, respectively, the human daily dose of a mg/m² basis). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, gabapentin should not be used during pregnancy (tab)

Recommendations in other jurisdictions

• Caution; not recommended
• Gabapentin crosses the human placenta. There are no or limited amount of data from the use of gabapentin in pregnant women. Studies in animals have shown reproductive toxicity
• 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 causally 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
• Risk related to epilepsy and antiepileptic medicinal agents 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

Breastfeeding

South African recommendations

• Contraindicated 
• Gabapentin is excreted in human milk. The effect on the breastfed infant and on milk production is not known, therefore gabapentin should not be used in breastfeeding mothers

Recommendations in other jurisdictions

• Caution
• Gabapentin is excreted in human milk. Because the effect on the breastfed infant is unknown, caution should be exercised when gabapentin is administered to a breastfeeding mother. Gabapentin should be used in breastfeeding mothers only if the benefits clearly outweigh the risks

Fertility

South African recommendations

• There is no effect on fertility in animal studies (cap)
• No information available (tab)

Recommendations in other jurisdictions

• There is no effect on fertility in animal studies

Renal Impairment

South African recommendations

• Mild to moderate: Caution; dose adjustment recommended 
  The elimination of gabapentin is decreased in patients with impaired renal function. For patients with impaired renal function or those undergoing haemodialysis the following maintenance dosage regimen are recommended

Creatinine clearance (ml/min)	Dose (mg/day)	Dosing regimen (mg)
>60	1200	Oral (cap, tab): 400mg, 3 times daily
>30-60	600	Oral (cap, tab): 300mg, twice daily
15-30	300	Oral (cap, tab): 300mg, once daily
<15	150	Oral (cap, tab): 300mg, once every other day
Haemodialysis	-	Oral (cap, tab): Loading dose: 300-400mg, immediately as a single dose; Maintenance: 200-300mg, following each 4hrs of haemodialysis

• Severe: Caution; dose adjustment recommended (cap)
• Severe: Contraindicated (tab)

Recommendations in other jurisdictions

• Caution; dose adjustment recommended 
  Gabapentin 100mg caps can be used to follow dosing recommendations for patients with renal insufficiency

Creatinine clearance (ml/min)	Total daily dosea (mg/day)
≥80	Oral (cap, fct): 900-3600mg, in 3 divided doses
50-79	Oral (cap, fct): 600-1800mg, in 3 divided doses
30-49	Oral (cap, fct): 300-900mg, in 3 divided doses
15-29	Oral (cap, fct): 150b-600mg
<15c	Oral (cap, fct): 150b-300mg

^a Total daily dose should be administered as three divided doses. Reduced dosages are for patients with renal impairment (creatinine clearance <79ml/min)
^b The 150mg daily dose to be administered as 300mg every other day
Oral (cap, fct): 300mg, every other day
^c For patients with CrCl<15ml/min, the daily dose should be reduced in proportion to creatinine clearance (e.g., patients with a CrCl of 7.5ml/min should receive one-half the daily dose that patients with a CrCl of 15ml/min receive)
For anuric patients undergoing haemodialysis who have never received gabapentin: Oral (cap, tab): Loading dose: 300-400mg, immediately as a single dose; Maintenance: 200-300mg, 4hrly after haemodialysis
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 the table above 
In addition to the maintenance dose, an additional 200-300mg dose following each 4 hour haemodialysis treatment is recommended

Hepatic Impairment

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available 

Elderly

South African recommendations

• Caution; no dose adjustment recommended 
  May require dosage adjustment because of declining renal function with age. Elderly patients should be closely monitored for adverse events (somnolence, peripheral oedema and asthenia may be more frequent) (cap)
  No significant changes in the adverse event profile were found in the elderly (i.e. over 65 years of age), an increased incidence of certain adverse events cannot be excluded. However, only small numbers of patients have been studied. Elderly patients should be carefully monitored for adverse events. Elderly patients may require dosage adjustment because of declining renal function with age. Adjust according to creatinine clearance (tab)

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended 
  Elderly patients may require dosage adjustment because of declining renal function with age. Somnolence, peripheral oedema and asthenia may be more frequent in elderly patients

Porphyria Information

• Probably not porphyrinogenic (PNP) 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Hostility
• Confusion
• Emotional lability
• Depression
• Anxiety
• Nervousness
• Abnormal thinking
• Suicidal ideation
• Agitation 
• Hallucinations 
• Somnolence
• Dizziness
• Ataxia
• Seizures
• Hyperkinesias
• Dysarthria
• Amnesia
• Tremor 
• Insomnia
• Headache
• Paresthesia
• Hypaesthesia 
• Abnormal coordination
• Increased, decreased, or absent reflexes
• Hypokinesia
• Mental impairment
• Loss of consciousness
• Other movement disorders
  - Choreoathetosis
  - Dyskinesia
  - Dystonia
  - Hyperkinesias
• Fatigue

Cardiovascular Disorders

• Palpitations
• Hypertension
• Vasodilatation

Respiratory Disorders

• Respiratory infection
• Dyspnoea
• Bronchitis
• Pharyngitis
• Cough
• Rhinitis
• Respiratory depression
• Pneumonia
• Chest pain
• Respiratory tract infections
• Bronchitis

Gastrointestinal Disorders

• Nausea and vomiting
• Dental abnormalities
• Gingivitis 
• Diarrhoea
• Abdominal pain
• Dyspepsia
• Constipation 
• Dry mouth or throat
• Flatulence
• Dysphagia
• Pancreatitis
  - Acute pancreatitis

Hepatobiliary Disorders

• Hepatitis
• Jaundice
• Increased liver function tests
  - Aspartate aminotransferase
  - Alanine aminotransferase
  - Bilirubin

Genitourinary Disorders

• Urinary tract infection
• Acute renal failure
• Impotence
• Incontinence
• Sexual dysfunction 
  - Changes in libido 
  - Ejaculation disorders
  - Anorgasmia 
• Gynaecomastia
• Breast hypertrophy

Endocrine and Metabolic Disorders

• Anorexia
• Increased appetite
• Hyperglycemia (most often observed in patients with diabetes)
• Hypoglycaemia (most often observed in patients with diabetes)
• Hyponatraemia
• Increased weight

Musculoskeletal Disorders

• Arthralgia
• Myalgia
• Back pain
• Twitching
• Myoclonus
• Rhabdomyolysis
• Fracture
• Myopathy
• Increased blood creatine phosphokinase

Skin and Subcutaneous Tissue Disorders

• Facial oedema
• Purpura, bruises resulting from
  - Physical trauma
  - Rash
  - Pruritus
  - Acne
• Stevens-Johnson syndrome 
• Angioedema 
• Erythema multiforme 
• Alopecia 
• Drug rash with eosinophilia and systemic symptoms (DRESS)
• Abrasion

Immune, Blood and Lymphatic System Disorders

• Infection
  - Viral infection
• Allergic reactions
  - Urticaria
• Hypersensitivity syndrome
  - Fever
  - Rash
  - Hepatitis
  - Lymphadenopathy
  - Eosinophilia
• Anaphylaxis
• Leucopenia 
• Thrombocytopenia
• Fever
• Peripheral oedema
• Generalized oedema
• Flu syndrome
• Decreased white blood cell count

Sensory Disorders

• Otitis media
• Visual disturbances
  - Amblyopia
  - Diplopia
• Vertigo
• Tinnitus
• Nystagmus

Other

• Abnormal gait
• Pain
• Withdrawal reactions 
  - Anxiety
  - Insomnia 
  - Nausea 
  - Pains 
  - Sweating 
• Accidental injury
• Sudden unexplained deaths
• Fall
• Aggressive behaviour

• Central nervous system depressants
• Opioids
• Morphine
• Antacids containing aluminium and magnesium (See additional prescribing points)

Other interactions

• Dipstick test (See additional prescribing points)

• Renal function (periodically)

Additional observations

• Suicidality
  - Suicidal thoughts
  - Depression
  - Behavioural changes
• Mental alertness
• Symptoms of respiratory depression and sedation in patients with underlying respiratory disease
• Signs and symptoms of hypersensitivity 
  - Anaphylaxis/angioedema
  - Possible disparate manifestations associated with lymphatic, hepatic, renal, cardiac, and/or hematologic systems 
• Fever
• Rash
• Eosinophilia

Antacids

• Antacids containing magnesium and aluminium hydroxides reduced the mean bioavailability of gabapentin. It is recommended that gabapentin be taken about two hours before or after antacid administration

Somnolence/sedation and dizziness

• Gabapentin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall). Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication (cap, fct)

History of drug abuse

• Cases of abuse and dependence have been reported. Careful evaluation of patients with a history of drug abuse should be observed for possible signs of gabapentin abuse e.g. drug-seeking behaviour, dose-escalation, development of tolerance (cap, fct)

Laboratory tests

South African recommendations

Because false-positive readings were reported with the Ames N-Multistix SG® dipstick test for urinary protein when gabapentin was added to other antiepileptic medicines, the more specific sulfosalicylic acid precipitation procedure is recommended to determine the presence of urine protein 

Recommendations in other jurisdictions

• 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

Mixed seizures including absences (Recommendations in other jurisdictions)

• Gabapentin is not considered effective against primary generalized seizures such as absences and may aggravate these seizures in some patients. Therefore, gabapentin should be used with caution in patients with mixed seizures including absences

Gabapentin readily enters the brain and prevents seizures in a number of animal models of epilepsy. Gabapentin does not possess affinity for either gamma-aminobutyric acid receptor A or B (GABAA or GABAB) nor does it alter the metabolism of GABA. It does not bind to other neurotransmitter receptors of the brain and does not interact with sodium channels. Gabapentin binds with high affinity to the α2δ (alpha-2-delta) subunit of voltage-gated calcium channels and it is proposed that binding to the α2δ subunit may be involved in gabapentin's anti-seizure effects in animals. Broad panel screening does not suggest any other drug targets other than α2δ. Evidence from several pre-clinical models inform that the pharmacological activity of gabapentin may be mediated via binding to α2δ through a reduction in release of excitatory neurotransmitters in regions of the central nervous system. Such activity may underlie gabapentin's anti-seizure activity. The relevance of these actions of gabapentin to the anticonvulsant effects in humans remains to be established. Gabapentin also displays efficacy in several pre-clinical animal pain models. Specific binding of gabapentin to the α2δ subunit is proposed to result in several different actions that may be responsible for analgesic activity in animal models. The analgesic activities of gabapentin may occur in the spinal cord as well as at higher brain centers through interactions with descending pain inhibitory pathways. The relevance of these pre-clinical properties to clinical action in humans is unknown.

Capsule 100mg

• Biotech Gabapentin 100mg (Biotech Laboratories) 
• Epigab 100 (Teva Pharmaceuticals)
• Epleptin 100mg (Ranbaxy)
• Gabapentin 100 Oethmaan (Oethmaan Biosims) 
• Neurontin 100 (Pfizer Laboratories) originator
• Ran-Gabapentin 100 (Ranbaxy)

Capsule 300mg

• Biotech Gabapentin 300mg (Biotech Laboratories) 
• Epigab 300 (Teva)
• Epleptin 300mg (Ranbaxy)
• Gabapentin 300 Oethmaan (Oethmaan Biosims)
• Neurexal 300 (Sandoz SA) (Discontinued:  01/04/2018)
• Neurontin 300 (UpJohn) originator
• Ran-Gabapentin 300 (Ranbaxy)

Capsule 400mg

• Biotech Gabapentin 400mg (Biotech Laboratories)
• Epigab 400 (Teva Pharmaceuticals)
• Epleptin 400mg (Ranbaxy)
• Gabapentin 400 Oethmaan (Oethmaan Biosims)
• Neurontin 400 (UpJohn) originator
• Ran-Gabapentin 400 (Ranbaxy)

Tablet 600mg

• Neurontin 600 (Pfizer Laboratories) originator

Tablet 800mg

Neurontin 800 (Pfizer Laboratories) originator (Discontinued:  01/04/2018)