Gabapentin

Composition:

capsule contains Gabapentin 100,300,400 mg

Chemistry:

Gabapentin is described as 1-(aminomethyl) cyclohexaneacetic acid . C9H17NO2

Category:

Anticonvulsant, Antineuralgic(USP DI 2007)

Mechanism of action:

The mechanism of action is unknown . Gabapentin does not interact with GABA receptors, is not metabolized to GABA agonist or to GABA, and does not inhibit GABA uptake or degradation . In rats, gabapentin interacts with a novel binding site on cortical neurons that may be associated with the L-system amino acid transporter of brain cell membranes . Analgesic action – The mechanism of action is unknown. Gabapentin prevents pain – related behavior in response to a normally innocuous stimulus (allodynia) and exaggerated response to painful stimuli (hyperalgesia) in animal models. In models of neuropathic pain in rats or mice, gabapentin prevents pain-related responses. Pain-related responses after peripheral inflammation were also decreased by gabapentin . Immediate pain-related behaviors were not altered by gabapentin . (USP DI 2007)

Pharmacokinetics :

Absorption : Rapid (unaffected by food) Distribution : 50-60 L Protein binding : Very low(<3%) Biotransformation : Gabapentin is not metabolized

Half-Life :

Normal renal function : 5 to 7 hours In hemodialysis : 132 hours (on days when patients did not receive dialysis) and 3.8 hours (during dialysis) Time to peak concentration : 2-4 hours

Elimination :

Renal – Entire absorbed dose, as unchanged drug. Gabapentin clearance is directly proportional to creatinine clearance. Higher oral clearance values were observed in children < 5 years of age when normalized per body weight. In infants <1 year of age. Clearance was highly variable . In dialysis- Gabapentin can be removed from plasma by hemodialysis . (USP DI 2007)

Indications :

Accepted Epilepsy (treatment adjunct) – Gabapentin is indicated as an adjunct to other anticonvulsant medications (in the treatment of partial seizures with or without secondary generalization in adults and adolescents) with epilepsy . Gabapentin is also indicated as adjunctive therapy for the treatment of partial seizures in pediatric patients 3 years of age and older with epilepsy . Postherpetic Neuralgia – Gabapentin is indicated for the management of postherpetic neuralgia in adults . [Pain , peripheral neuropathic , diabetic (treatment)] – Gabapentin is indicated for the treatment of diabetic peripheral neuropathic pain .(USP DI 2007)

Contraindications :

Gabapentin is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients . (PDR 2008)

Warning :

Neuropsychiatric adverse Events- Pediatric patients 3-12 years of age : Gabapentin use in pediatric patients with epilepsy 3-12 years of age is associated with the occurrence of central nervous system related adverse events . The most significant of these can be classified into the following categories : 1) Emotional lability 2) Hostility 3) Thought disorder 4) Hyperkinesia Among the gabapentin – treated patients , most of the events were mild to moderate in intensity . Withdrawal precipitated seizure, status epilepticus : Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency .

Tumorigenic potential :

In standard preclinical invivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats . Sudden and unexplained death in patients with epilepsy sudden death could represent seizure- related deaths in which the seizure was not observed, e.g.at night .(PDR 2008)

Precautions :

Patients should be instructed to take gabapentin only as prescribed . Patients should be advised that gabapentin may cause dizziness, somnolence and other symptoms and signs of CNS depression . Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on gabapentin to gauge whether or not it affects their mental and/or motor performance adversely . Patients who require concomitant treatment with morphine may experience increases in gabapentin concenteration . Patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately .(PDR 2008)

Missed dose :

Taking as soon as possible, if less than 2 hours until next dose, taking missed dose immediately and taking next dose 1 to 2 hours later then resuming regular dosing schedule, not doubling doses . (USP DI 2007)

Pregnancy:

FDA Pregnancy Category C : Gabapentin should be used be during pregnancy only if the benefit justifies the potential risk to the fetus. (USP DI 2007)

Breast – feeding :

Gabapentin is distributed into human breast milk following oral administration . A nursed infant could be exposed to a maximum dose of approximately 1 milligram per kilogram per day . Gabapentin should be used in women who are nursing only if the benefits clearly outweight the risks .(USP DI 2007)

Geriatrics :

Plasma clearance of gabapentin is reduced in the elderly , probably due to age-related renal function decline . Dosage reduction based on creatinine clearance is recommended . Further dosage adjustments should be based on clinical response .(USP DI 2007)

 

Phenytoin, carbamazepine ,valproic acid, phenobarbital, naproxen , hydrocodone, morphine, cimetidine, oral contraceptive, antacid, probenecid.(PDR 2008)

Adverse reactions :

Antiepileptic drugs should not be abruptly discontinued because of the possibility of increasing seizure frequency . Sudden and unexplained death occurred in 8 patients among a cohort of 2203 patients treated , which could represent seizure-related deaths. Note : Adverse effects from gabapentin therapy are generally mild to moderate in severity , and tend to diminish with continued use . Those indicating need for medical attention: Incidence more frequent Ataxia (Clumsiness or unsteadiness) – may be dose – related ; nystagmos. In pediatric patients 3 to 12 years of age Neuropsychiatric problems , including emotional lability (anxiely ; behavior problems ; crying ; false sense of well-being ; mental depression ; reacting too quickly , too emotionally , or overreacting , rapidly changing moods ) ; hostility (aggressive behavior ; suspiciousness or distrust) ; hyperkinesia (hyperactivity or increase in body movements : restlessness) ; and thought disorders (con-centration problems and change in school performance). Incidence less frequent. Amnesia (loss of memory) ; depression , irritability , or other mood or changes ; fracture .

Those indicating need for medical attention only if they continue or are bothersome :

Incidence more frequent Abnormal thinking (confusion ; delusions; dementia) ; asthenia (lack or loss of strength) ; fever ; infection (fever or chills ; cough or hoarseness; lower back or side pain ; painful or difficult urination); myalgia (muscle ache or pain); peripheral edema (swelling of hands, feet , or lower legs); somnolence (drowsiness) – may be dose-related: tremor (trembling or shaking) ; viral infection (chills ; cough or hoarseness; fever ; cold or flu-like symptoms) ; vision abnormalities, including blurred vision and diplopia (double vision) . Incidence less frequent or rare Abdominal pain ; abnormal gait (change in walking and balance; clumsiness , or unsteadiness) ; abrasion (pain , redness , rash , swelling , or bleeding where the skin is rubbed off) ; amblyopia (blurred viosion ; change in vision ; impaired vision) ; appetite increased or decreased ; back pain ; bronchitis (cough producing mucus ; difficulty breathing ; shortness of breath ; tightness in chest ; wheezing) ; conjunctivitis (redness , pain , swelling of eye , eyelid , or inner lining of eyelid ; burning , dry or itching eyes ; discharge ; excessive tearing) ; cough ; dental abdry of itching eyes ; discharge ; excessive tearing 0 ; cough ; dental abnormalities ; dryness of mouth or throat ; dysarthria (slurred speech) ; flatulence (bloated full feeling ; excess air or gas in storn ; of rcts , including constipation , diarrhea , dyspepsia , (indigestion) ; nausea , and vomiting ; headache ; hypesthesia ( increase sensitivity to pain , increased sensitivity to touch ; tingling in the hands and feet) ; hyperglycemia (abdominal pain ; blurred vision ; dry mouth ; fatigue ; flushed , dryskin ; fruit-like breath odor ; increased hunger ; increased thirst ; increased urination ; nausea ; sweating ; troubled breathing ; unexplained weight loss ; vomiting ); hypotension (low blood pressure) ; incoordination ; impotence (decrease in sexual desire or ability ) ; injury , accidental ; insomnia ( trouble in sleeping ) ; nervousness ; otitis media (earache ; redness or swelling in ear) ; pharyngitis (body aches or pain ; congestion ; cough ; dryness or soreness of throat ; fever ; hoarseness ; runny nose ; tender ; swollen glands in neck ; trouble in swallowing ; voice changes) ; pruritus ( itching skin) ; respiratory infection (cough ; fever ; sneezing ; sore throat ) ; thinitis (runny nose ) ; skin rash ; tinnitus (noise in ears ) ; trouble in thinking ; twitching ; vasodilatation ( feeling of warmth or heat ; flushing or redness of skin , especially on face and neck ; headache ; feeling faint , dizzy, or lighheadedness ; sweating ) ; weight gain . (USP DI 2007)

Overdose :

Clinical effects of overdose : Diarrhea ; diplopia ; dysarthria ; lethargy ; somnolence . Treatment of overdose: Note : There is no specific antidote for gabapentin overdose. Specific treatment – Hemodialysis ( may be indicated by clinical state or in patients with significant renal impairment ). Supportive care- Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consullation . (USP DI 2007)

Administration and dosage :

Usual adult and adolescent dose : -Anticonvulsant : Oral, initially 300 mg three times a day . The dosage may be gradually increased based on clinical response . Dosages of 900 to 1800 mg per day are effective for most patients .However, dosages as high as 2400 to 3600 mg/day have been well tolerated . Note : Dosage may be increased more slowly to avoid CNS adverse effects . When taking gabapentin three times a day , the maximum time between doses should not exceed twelve hours . For patients with renal function impairment : See Usual geriatric dose . Postherpetic neuralgia: Usual adult dose : Oral , initial single dose of 300 milligram on day 1 : 600 milligrams per day (divided, two times a day) on day 2 ; 900 milligrams per day (divided , three times a day ) on day 3 . Dose may be titrated up to a maximum daily dose of 1800 milligrams (divided, three times a day) . additional benefits were not demonstrated at doses greater than 1800 milligrams per day . Note : For patients with renal function impairment: See Usual geriatric dose. - Diabetic peripheral neuropathic pain: Usual adult dose : Oral, initially 900 mg/day titrated to maximum of 3600 mg/ day . Note : Adults with renal function impairment ma require a reduction in dose as follows - Creatinine clearance (CrCl) > 60: Up to 1800 mg a day . - CrCl = 30 – 60 ml per minute : 300 mg two times a day . - CrCl = 15 – 30 ml per minute : 300 mg per day . - CrCl < 15 ml per minute : 300 mg every other day .

Usual adult and adolescent prescribing limits :

3600 mg/day -Usual pediatric dose : -Anticonvulsant : Children 3 to 12 years : The starting dose should rang from 10 to 15 mg/kg per day, divided into three doses . The effective dose should be reached by upward titration over a period of approximately 3 days. Ages 5 years and older : The effective dose is 25 to 35 mg / kg per day given in divided doses . Ages 3 years and 4 years : The effective dose is 40 mg/kg per day given in divided doses .

Usual pediatric prescribing limit:

Dosage of up to 50 mg/kg per day have been well tolerate in long term clinical studies .

Usual geriatric dose:

Oral, initial dosage recommendations, based on creatinine clearance . Dosage adjustment may be made based on clinical response . The Dosage can be 300 mg one every other day to 3600 mg/day in renal impairment (USP DI 2007)

Packaging and storage :

Store below 30°c , in a well-closed container .

Refrences :

1- USP DI 2007
2- PDR 2008
3- Electronic Martindale 35