[UPDATE 05/05/2009] FDA notified healthcare professionals that it approved updated labeling for antiepileptic drugs used to treat epilepsy, psychiatric disorders, and other conditions (e.g., migraine and neuropathic pain syndromes). FDA also required development of a medication guide, to be issued to patients each time the product is dispensed. Since issuing safety alerts on December 16, 2008 and January 31, 2008, FDA has been working with the manufacturers of drugs in this class to better understand the suicidality risk. Eleven antiepileptic drugs were included in a pooled analysis of placebo-controlled clinical studies in which these drugs were used to treat epilepsy as well as psychiatric disorders and other conditions. The increased risk of suicidal thoughts or behavior was generally consistent among the eleven drugs, with varying mechanisms of action and across a range of indications. This observation suggests that the risk applies to all antiepileptic drugs used for any indication.
The drugs included in the analyses include (some of these drugs are also available in generic form):
Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
Felbamate (marketed as Felbatol)
Gabapentin (marketed as Neurontin)
Lamotrigine (marketed as Lamictal)
Levetiracetam (marketed as Keppra)
Oxcarbazepine (marketed as Trileptal)
Pregabalin (marketed as Lyrica)
Tiagabine (marketed as Gabitril)
Topiramate (marketed as Topamax)
Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
Zonisamide (marketed as Zonegran)
For more information visit the FDA website at: [Web] and [Web].
[UPDATE 12/16/2008] The FDA has completed its analysis of reports of suicidality (suicidal behavior or ideation [thoughts]) from placebo-controlled clinical trials of drugs used to treat epilepsy, psychiatric disorders, and other conditions. Based on the outcome of this review, FDA is requiring that all manufacturers of drugs in this class include a Warning in their labeling and develop a Medication Guide to be provided to patients prescribed these drugs to inform them of the risks of suicidal thoughts or actions.
For more information visit the FDA website at: [Web] and [Web].
[Posted 01/31/2008] FDA informed healthcare professionals that the Agency has analyzed reports of suicidality (suicidal behavior or ideation) from placebo-controlled clinical studies of eleven drugs used to treat epilepsy as well as psychiatric disorders, and other conditions. In the FDA’s analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions.
Healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.
The drugs included in the analyses include (some of these drugs are also available in generic form):
Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR)
Felbamate (marketed as Felbatol)
Gabapentin (marketed as Neurontin)
Lamotrigine (marketed as Lamictal)
Levetiracetam (marketed as Keppra)
Oxcarbazepine (marketed as Trileptal)
Pregabalin (marketed as Lyrica)
Tiagabine (marketed as Gabitril)
Topiramate (marketed as Topamax)
Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon)
Zonisamide (marketed as Zonegran)
Although the 11 drugs listed above were the ones included in the analysis, FDA expects that the increased risk of suicidality is shared by all antiepileptic drugs and anticipates that the class labeling changes will be applied broadly. For more information visit the FDA website at: [Web] and [Web].
REMS:
FDA approved a REMS for gabapentin to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page ([Web]) or the ASHP REMS Resource Center ([Web]).
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Seizure Disorders
Management (in combination with other anticonvulsants) of partial seizures with or without secondary generalization in adults and children >12 years of age.
Management (in combination with other anticonvulsants) of partial seizures in children 3–12 years of age.
Neuropathic Pain
Management of postherpetic neuralgia in adults.
Treatment of pain associated with diabetic neuropathy†. 40% of patients who receive gabapentin for pain associated with diabetic neuropathy obtain good pain relief.
Some evidence of benefit for the relief of chronic neurogenic pain† in a variety of conditions including trigeminal neuralgia†, pain and control of paroxysmal symptoms of multiple sclerosis†, complex regional pain syndromes†, HIV-related peripheral neuropathy†, and neuropathic pain associated with cancer†. Also has been used in the treatment of restless legs syndrome†. Additional study needed to further elucidate precise role in the management of these conditions.
Vasomotor Symptoms
Has been used for the management of vasomotor symptoms (e.g., hot flashes) in women with breast cancer†.
Has been used for the management of vasomotor symptoms (e.g., hot flashes) associated with menopause†.
Dosage and Administration
General
Seizure Disorders
Monitoring of plasma gabapentin concentrations is not necessary to optimize therapy. Because addition of gabapentin to existing anticonvulsant therapy does not appreciably alter steady-state plasma concentrations of concomitantly administered anticonvulsants, additional monitoring of plasma concentrations of anticonvulsants generally is not necessary. (See Specific Drugs under Interactions.)
Discontinuance of gabapentin and/or addition of an alternative anticonvulsant drug to therapy should be done gradually over ≥1 week.
Administration
Oral Administration
Administer orally without regard to meals.
If Neurontin® film-coated scored tablets containing 600 or 800 mg of gabapentin are to be used in patients requiring a 300- or 400-mg dose, divide the tablet in half to allow administration of the appropriate dose. Instruct patients to take one-half tablet and to use the remaining half-tablet for the next dose. Half-tablets that are not used within several days should be discarded.
Seizure Disorders
Administer orally 3 times daily. The interval between doses in this schedule should not exceed 12 hours.
Dosage
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Pediatric Patients
Seizure Disorders
Partial Seizures
Oral
Children 3–12 years of age: Initially, 10–15 mg/kg daily in 3 divided doses. Maintenance dosage of 40 mg/kg daily in 3 divided doses for children 3 or 4 years of age and 25–35 mg/kg daily in 3 divided doses for children 5–12 years of age.
Children >12 years of age: Initially, 300 mg 3 times daily. Maintenance dosage of 900 mg to 1.8 g daily in 3 divided doses.
Adults
Seizure Disorders
Partial Seizures
Oral
Initially, 300 mg 3 times daily. Maintenance dosage of 900 mg to 1.8 g daily in 3 divided doses.
Neuropathic Pain
Postherpetic Neuralgia
Oral
300 mg on the first day, 300 mg twice daily on the second day, and 300 mg 3 times daily on the third day. Increase dosage as needed for relief of pain up to a total daily dosage of 1.8 g in 3 divided doses. No evidence of additional benefit with dosages >1.8 g daily.
Diabetic Neuropathy
Oral
Dosages of 900 mg to 3.6 g daily have been used; however, pain relief generally observed in patients receiving dosages >1.8 g daily.
Vasomotor Symptoms
Oral
300 mg 3 times daily has been effective; higher dosages may provide additional benefit.†
Prescribing Limits
Pediatric Patients
Children 3–12 years of age: Dosages up to 50 mg/kg daily in divided doses have been tolerated as adjunctive therapy in the management of partial seizures.
Children >12 years of age: Dosage of 3.6 g daily has been tolerated as adjunctive therapy in the management of partial seizures.
Adults
Dosage of 3.6 g daily has been tolerated as adjunctive therapy in the management of partial seizures.
Special Populations
Renal Impairment
Not studied in children <12 years of age with renal impairment.
In adults and children ≥12 years of age, base dosage on measured or estimated Clcr:
Dosage for Adults and Children ≤12 Years of Age with Renal Impairment
aIn patients with Clcr <15 mL/min, reduce dosage proportionally (e.g., a patient with a Clcr of 7.5 mL/min should receive one-half the dosage that a patient with a Clcr of 15 mL/min should receive).
bGive maintenance doses based on Clcr, with supplemental doses (125–350 mg) given after each 4-hour hemodialysis session.
Geriatric Patients
Select dosage carefully, usually initiating therapy at the low end of the dosage range. Adjust dosage based on Clcr.
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Cognitive/Neuropsychiatric Effects
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Emotional lability (primarily behavioral problems), hostility (including aggressive behaviors), thought disorders (including concentration and school performance changes), and hyperkinesia (primarily restlessness and hyperactivity) associated with use in children 3–12 years of age with epilepsy.
Withdrawal Seizures
Abrupt withdrawal may result in increased seizure frequency; withdraw gabapentin gradually and reduce dosage slowly over ≥1 week.
Status Epilepticus
Not established whether incidence of status epilepticus (1.5% in controlled and uncontrolled trials of gabapentin) is higher or lower than would be expected in patients with epilepsy not treated with the drug.
Tumorigenic Potential
Unexpectedly high incidence of pancreatic acinar adenocarcinomas in male but not female rats. Clinical relevance unknown.
Sudden, Unexplained Deaths in Epilepsy
Higher incidence of sudden and unexplained deaths than would be expected in a healthy (nonepileptic) population; however, incidence is within range of estimates for patients with epilepsy or refractory epilepsy.
Specific Populations
Pregnancy
Category C.
Lactation
Distributed into milk; use only if potential benefits outweigh the risks.
Pediatric Use
Safety and efficacy as adjunctive therapy in the management of partial seizures not established in children <3 years of age.
Safety and efficacy for the management of postherpetic neuralgia not established in children.
Geriatric Use
Insufficient experience with gabapentin for the management of partial seizures in patients ≥65 years of age to determine whether they respond differently than younger adults. Select dosage carefully. (See Geriatric Patients under Dosage and Administration.)
Appeared to be more effective for the management of postherpetic neuralgia in patients >75 years of age than in younger patients; apparent difference in efficacy may be related to decreased renal function in older patients.
Adverse effects in older patients with postherpetic neuralgia generally similar to those in younger adults; however, the incidence of peripheral edema and ataxia appears to increase with age.
Geriatric patients may have decreased hepatic, renal, or cardiac function, with increased risk of adverse effects. Use with caution; renal function monitoring may be useful.
Renal Impairment
Clearance decreased; adjust dosage in adults and children ≥12 years of age with renal impairment. (See Renal Impairment under Dosage and Administration.)
Use in children <12 years of age with renal impairment has not been studied.
Common Adverse Effects
Children 3–12 years of age receiving gabapentin as adjunctive therapy for partial seizures: viral infection, fever, nausea and/or vomiting, somnolence, hostility.
Adults and children >12 years of age receiving gabapentin as adjunctive therapy for partial seizures with or without secondary generalization: somnolence, dizziness, ataxia, fatigue, nystagmus.
Adults receiving gabapentin for management of postherpetic neuralgia: dizziness, somnolence, peripheral edema.
Interactions
Not metabolized by CYP isoenzymes. Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro; causes slight inhibition of CYP2A6 at high concentrations.
Bioavailability of 60–27% for doses ranging from 900 mg to 4.8 g daily. Bioavailability is not dose proportional.
Food
Food increases extent of absorption and peak plasma concentration by 14%.
Distribution
Extent
Readily crosses the blood-brain barrier and concentrates in brain tissue. Distributed into breast milk. Not known whether gabapentin crosses the placenta.
Plasma Protein Binding
<3%.
Elimination
Metabolism
Not appreciably metabolized.
Elimination Route
Excreted renally as unchanged drug.
Half-life
5–7 hours.
Special Populations
In children <5 years of age, clearance normalized for weight is higher than in adults and children ≥5 years of age.
In patients with renal impairment, plasma clearance is decreased and half-life is prolonged. In patients with Clcr <30 mL/minute, half-life of 52 hours reported. In anuric patients, half-life reported to be 132 hours on nondialysis days and 3.8 hours during hemodialysis.
Stability
Storage
Oral
Capsules and Tablets
25°C (may be exposed to 15–30°C).
Oral Solution
2–8°C.
Actions
Mechanism of anticonvulsant action is unknown. Does not bind to GABA receptors, affect GABA reuptake or metabolism, or act as a precursor of GABA or other substances active at GABA receptors.
Mechanism of analgesic action is unknown. Prevents allodynia (pain-related behavior in response to normally innocuous stimuli) and hyperalgesia (exaggerated response to painful stimuli) in several animal models of neuropathic pain. Decreases pain-related responses after peripheral inflammation in animals; however, has not altered immediate pain-related behaviors. Clinical relevance of these findings is not known.
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Importance of taking gabapentin exactly as prescribed. Importance of not abruptly discontinuing therapy.
Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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