Neurosantin

Gabapentin.

Each capsule contains: Gabapentin 300 mg.

Pharmacology: Gabapentin is structurally related to the neurotrans­mitter GABA (gamma-aminobutyric acid) but its mech­anism of action is different from that of several other drugs that interact with GABA synapses including valproate, barbiturates, benzodiazepines, GABA trans­aminase inhibitors GABA uptake inhibitors, GABA agonists, and GABA prodrugs. In vitro studies with radio­ labeled Gabapentin have characterized a novel peptide binding site in rat brain tissues including neo­cortex and hippocampus that may relate to anti­ convulsant activity of Gabapentin and its structural derivates.
Gabapentin at relevant clinical concentrations does not bind to other common drug or neurotransmitter receptors of the brain including GABA_A, GABA_B, 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.
Pharmacokinetic: Gabapentin bioavailability is not dose-proportional. That is, as the dose is increased, bioavailability decreases. Following oral administration, peak plasma Gabapentin concentration are observed within 2 to 3 hours. Absolute bioavailability of Gabapentin capsules is approximately 60%. Food, including a high-fat diet, has no effect on Gabapentin pharmacokinetics.
Gabapentin elimination from plasma is best described by linear pharmacokinetics.
The elimination half-life of Gabapen tin is independent of dose and averages 5 to 7 hours.
Gabapentin pharmacokinetics are not effected by repeated administration, and steady state plasma concentrations are predictable from single dose data. Plasma Gabapentin concentrations are dose proportional at doses of 300 or 400 mg given every 8 hours.
Pharmacokinetic parameters are given in Table 1 as follows.


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Gabapentin is not bound to plasma proteins and has a volume of distribution equal to 57.7 liters. In patients with epilepsy, Gabapentin concentrations in Cerebro spinal fluid (CSF) are approximately 20% of corre­sponding steady-state trough plasma concentrations. Gabapentin is eliminated solely by renal excretion. There is no evidence of metabolism in man. Gabapentin does not induce hepatic mixed function oxidase enzymes responsible for drug metabolism.
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 hemodialysis. Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is recommended.
In general, plasma Gabapentin concentrations in children are similar to those in adults.

Epilepsy: Gabapentin is indicated as adjunctive therapy in the treatment of partial seizures with and without se­condary generalization in adults and children age 3 years and above. Safety and effectiveness for adjunctive therapy in pediatric patients below the age of 3 years have not been established.
Neuropathic Pain: Gabapentin is indicated for the treatment of neuropathic pain in adults age 18 years and above.
Safety and effectiveness in patients below the age 18 years have not been established.

Gabapentin is given orally with or without food.
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.
Epilepsy: Adults and pediatric Patients Over 12 Years of Age: The effective dosing range was 900 to 1800 mg/day.
Therapy may be initiated by administering 300 mg (TID) on Day 1, or by titrating the dose as described in Table 2. Thereafter, the dose can be increased in three equally divided doses up to a maximum dose of 2400 mg/day. The maximum time between doses in the three times a day (TID) schedule should not exceed 12 hours to prevent breakthrough convulsions.


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Pediatric patients Age 3-12 Years: The starting dose should range from 10 to 15 mg/kg/day given in equally divided doses (three times a day), and the effective dose reached by upward titration over a period of approximately three days. The effective dose of Gabapentin in pediatric patients age 5 years and older is 25 to 35 mg/kg/day given in equally divided doses (three times a day). The effective dose in pe­diatric patients ages 3 to less than 5 years is 40 mg/kg/day given in equally divided doses (three times a day). Dosages up to 50 mg/kg/day have been well tolerated in a long-term clinical study. 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 drugs without concern for alteration of the plasma concentrations of Gabapentin or serum concentrations of other antiepileptic drugs.
Neuropathic pain in Adults: NEUROSANTIN should be titrated to a maximum dose of 1800 mg per day. Titration to an effective dose can be progress rapidly and can be accomplished over a few days by administering 300 mg once a day on day l. 300 mg twice a day on day 2 and 300 mg three times a day on day 3, as described in Table 3.
Thereafter, the dose can be increased using increments of 300 mg per day given in three divided doses to a maximum of 1800 mg per day.
Dosage Adjustment in Impaired Renal function for Patients with Neuropathic Pain or Epilepsy: Dosage adjustment is recommended in patients with compromised renal function as described in Table 3 and/or those undergoing hemodialysis.


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Dosage Adjustment in Patients Undergoing Hemodia­lysis: For patients undergoing hemodialysis who have never received Gabapentin, a loading dose of 300 to 400 mg is recommended, then 200 to 300 mg of Gabapentin following each 4 hours of hemodialysis. On dialysis-free days there should be no treatment with NEUROSAN­TIN.
If NEUROSANTIN discontinued and/or an alternate anticonvulsant medication is added to the therapy, this should be done gradually over a minimum of 1 week.
Method and duration of administration: NEUROSANTIN capsules should be swallowed whole with sufficient fluid intake. Administration may be made during or between meals. In three-times daily admin­istration, care should be taken that the interval between two single doses does not exceed 12 hours.
Whether a missed dose of NEUROSANTIN (this mean more than 12 hours passed since the last administration) should be made up for by taking an additional dose of NEUROSANTIN later or not is at the physician's dis­cretion.
In concurrent treatment with magnesium or aluminium containing antacids, NEUROSANTIN should be taken at least 2 hours after administration of the antacid. This largely avoids a reduction in Gabapentin bioavai­lability.
The duration of administration depends on the clinical requirements.
In the treatment of epilepsy, usually long-term therapy is required.
If therapy with NEUROSANTIN capsules should be discontinued, the dose reduced, or switched to another drug, this should be done gradually over a minimum of one week, although there is no evidence of a rebound phenomenon (increased occurrence of epileptic sei­zures following abrupt withdrawal of therapy).
In the treatment of neuropathic pain, efficacy and safety has not been examined in clinical studies for treatment periods longer than 5 months.

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 diarrhea. 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, minimize toxicity from overdoses.
Although Gabapentin can be removed by hemodialysis, based on prior experience it is usually not required. How­ever, in patients with severe renal impairment, hemo­dialysis may be indicated.
An oral lethal dose of Gabapentin was not indentified in mice and rats given doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, hypoactivity, or excitation.

Gabapentin is contra-indicated in patients who are hypersensitive to Gabapentin or the product's com­ponents.
NEUROSANTIN is contra-indicated in patients with acute pancreatitis.
NEUROSANTIN is not effective against primarily generalized seizures, such as absences.
No systematic studies in patients 65 years or older have been conducted with NEUROSANTIN. However, clinical investigations in this age group do not indicate an adverse event profile different from that observed in younger patients.
Epilepsy: There is not yet sufficient experience for add-on therapy in children below 3 years of age.

Although there is no evidence of rebound seizures with Gabapentin, abrupt withdrawal of anticonvulsants in epileptic patients may precipitate status epilepticus. (See DOSAGE & ADMINISTRATION).
Gabapentin is not generally considered effective in the treatment of absence seizures.
Patients who require concomitant treatment with mor­phine may experience increases in Gabapentin con­centration. Patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of Gabapentin or morphine should be reduced appropriately. (See INTERACTIONS).
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.
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 sign or symptoms cannot be established.
Effect on Ability to Drive and Use Machines: Patients should be advised not to drive a car or operate potentially dangerous machinery until it is known that this medication does not affect their ability to engage in these activities.

Usage in Pregnancy: There are no adequate and well-controlled studies in pregnant women. This drug should be used during preg­nancy only if the potential benefit to the patient justifies the potential risk to the fetus.
Usage in Nursing Mothers: 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 nursing mother. Gabapentin should be used in nursing mothers only if the benefits clearly outweigh the risks.

Epilepsy: Since Gabapentin was most often administered in combination with other antiepileptic agents. It was not possible to determine which agent(s), if any, was associated with adverse events.
Incidence in Controlled Adjunctive Therapy Clinical Trials: Lists treatment-emergent signs and symptoms that occurred in at least 1% of patients with partial seizure­ participating in placebo-controlled adjunctive therapy studies. In these studies, either gabapentin or placebo was added to the patient's current antiepileptic drug therapy.
Adverse events were usually reported as mild to moderate: Body as a Whole: abdominal pain, back pain, fatigue, fever, headache, viral infection.
Cardiovascular: vasodilation.
Digestive System: constipation, dental abnormalities, diarrhea, increased appetite, mouth or throat dry, nausea and/or vomiting, dyspepsia.
Hematologic and Lymphatic: leucopenia, WBC decreased.
Metabolic and Nutritional: peripheral edema, weight increase.
Musculoskeletal system: fracture, myalgia.
Nervous system: amnesia, ataxia, confusion, coordination abnormal, depression, dizziness, dysarthria, emotional lability, insomnia, nervousness, nystagmus, somnolence, thinking abnormal, tremor, twitching.
Respiratory system: coughing, pharyngitis, rhinitis.
Skin and Appendages: abrasion, acne, pruritus, rash.
Special Senses: amblyopia, diplopia.
Urogenital system: impotence.
Other Adverse Events: Body as A Whole: asthenia, malaise, facial edema.
Cardiovascular System: hypertension.
Digestive System: flatulence, anorexia, gingivitis.
Hemic, Limphatic Systems: purpura most often described as bruises resulting from physical trauma.
Musculoskeletal System: arthralgia.
Nervous System: vertigo, hyperkinesia, increased, decreased or absent reflexes, parasthesia, anxiety, hostility.
Respiratory System: pneumonia.
Urogenital System: urinary tract infection.
Special Senses: abnormal vision most often described as a visual disturbance.
Geriatric Use: Side effects reported among these patients did not differ in kind from those reported in younger individuals. For patients with compromised renal function, the dosage should be adjusted. (See DOSAGE & ADMINISTRATION).
Pediatric Use: The most commonly observed adverse events reported with the use of Gabapentin in combination with other antiepileptic drugs in children 3 to 12 years of age, not seen in equal frequency among placebo-treated patients, were viral infection, fever, nausea and/or vomiting, and somnolence.
Body system/Adverse Event: Body as a Whole: viral infection, fever, weight increase, fatigue.
Digestive system: nausea and/or vomiting.
Nervous system: somnolence, hostility, emotional lability, dizziness, hyperkinesia.
Respiratory system: bronchitis, respiratory infection.
Other Adverse Events: pharyngitis, upper respiratory infection, headache, rhinitis, convulsions, diarrhea, anorexia, coughing, and otitis media.
Withdrawal from Treatment Due to Adverse Events: Adjunctive Therapy: The most frequently occurring events that contributed to discontinuation of Gabapentin included somnolence, ataxia, dizziness, fatigue, nausea and/or vomiting. Almost all participants had multiple complaints, none of which could be characterized as primary.
Pediatric: The adverse event most commonly associated with withdrawal in children were somnolence, hyperkinesia, and hostility.
Neuropathic Pain
Body system/Adverse Event: Body as a whole: abdominal pain, accidental injury, asthenia, back pain, flu syndrome, headache, infec­tion, pain.
Digestive system: constipation, diarrhea, dry mouth, dyspepsia, flatulence, nausea, vomiting.
Metabolic and Nutritional: peripheral edema, weight gain.
Nervous system: abnormal gait, amnesia, ataxia, con­fusion, dizziness, hypesthesia, somnolence, thinking abnormal, tremor, vertigo.
Respiratory system: dyspnea, pharyngitis.
Skin and Appendages: rash.
Special senses: amblyopia.
Post-marketing Experience: Sudden, unexplained deaths have been reported where a causal relationship to treatment with Gabapentin has not been established.
Acute kidney failure, allergic reaction including urticaria, alopecia, angioedema, blood glucose fluctuations in patients with diabetes, breast hypertrophy, chest pain, elevated liver function test (LFTs), erythema multiforme, generalized edema, gynecomastia, hallucinations, he­patitis, jaundice, movement disorders such as choreo­athetosis, dyskinesia, and dystonia, myoclonus, palpi­tation, pancreatitis, Stevens-Johnson syndrome, throm­bocytopenia, tinnitus, and urinary incontinence.
Adverse events following the abrupt discontinuation of Gabapentin have also been reported. The most fre­quently reported events were anxiety, insomnia, nausea, pain, and sweating.

Morphine: When a 60-mg controlled-release morphine capsule was administered 2 hours prior to a 600-mg Gabapentin capsule, mean Gabapentin AUC in­creased compared to Gabapentin administered without morphine. This was associated with an in­creased pain threshold (cold pressor test). The clinical significance of such changes has not been defined. Morphine pharmacokinetic parameter values were not effected by administration of Gabapentin 2 hours after morphine. The observed opioid-mediated side effects associated with morphine plus Gabapentin did not differ significantly from morphine plus placebo. The magnitude of interaction at other doses is not known. (See PRECAUTIONS).
No interaction between Gabapentin and phenobar­bital, phenytoin, valproic acid, or carbamazepine.
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 aluminum and magnesium, reduced Gaba­pentin bioavailability. It is recommended that Gaba­pentin be taken about 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.
Alcohol or centrally acting drugs of abuse may exaggerated some Gabapentin central nervous system side effects (e.g. somnolence and ataxia).
Laboratory test: False positive readings were reported with the Ames N-Multistix SG dipstick test when Gabapentin was added to other anticonvulsant drugs. To determine urinary protein, the more specific sulfosalicylic acid precipitation procedure is recommended.

Store below 25°C and in a dry place.

To assure safe and effective use of Gabapentin, the following information and instructions should be given to patients: Inform your physician about any prescription or non­ prescription medications, alcohol, or drugs you are now taking or plan to take during your treatment with Gabapentin.
You should inform your physician if you are pregnant, or if you are planning to become pregnant, or if you become pregnant while you are taking Gabapentin.
Gabapentin is excreted in human milk, and the effect on the nursing infant is unknown. You should inform your physician if you are breast feeding an infant, (See USE IN PREGNANCY & LACTATION: USAGE IN NURSING MOTHERS.)
Gabapentin may impair your ability to drive a car or operate potentially dangerous machinery. Until it is known that this medication does not affect your ability to engage in these activities, do not drive a car or operate potentially dangerous machinery.
You should not allow more than 12 hours between Gabapentin doses to prevent breakthrough con­vulsions.
Prior to initiation of treatment with gabapentin, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity such as fever or lymphadenopathy may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.

Anticonvulsants

N02BF01 - gabapentin ; Belongs to the class of gabapentinoids. Used to relieve pain and other conditions.

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