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Special Alerts

Antiepileptics: Increased Risk of Suicidal Behavior or Ideation - February, 2008

The U.S. Food and Drug Administration (FDA) is informing healthcare professionals of an increased risk of suicidality (suicidal behavior or ideation) observed from analysis of clinical studies using various antiepileptic medications compared to placebo. The analysis was performed on 199 placebo-controlled studies involving 43,892 patients (27,863 treated patients versus 16,029 placebo patients) aged ?5 years receiving one of the following 11 drugs: carbamazepine (Carbatrol®, Equetro™, Tegretol®, Tegretol® XR), felbamate (Felbatol®), gabapentin (Neurontin®), lamotrigine (Lamictal®), levetiracetam (Keppra®), oxcarbazepine (Trileptal®), pregabalin (Lyrica®), tiagabine (Gabitril®), topiramate (Topamax®), valproate (Depakote®, Depakote® ER, Depakene®, Depacon®), and zonisamide (Zonegran®). Studies examined medication efficacy in a variety of disorders, including epilepsy, psychiatric disorders (eg, depression, bipolar disorder), and other conditions (eg, migraine, neuropathic pain). According to the FDA, the results revealed a statistically significant increased risk of suicidality in 0.43% treated patients compared to 0.22% placebo patients, or an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the treated groups relative to placebo. This increased risk was reported anywhere from 1 week of therapy through 24 weeks. However, most trials were ?24 weeks duration and the risk of suicide extending beyond 24 weeks is currently unknown. The relative risk of suicidal behavior or ideation in the treated patients was higher for patients with epilepsy (RR=3.6) compared to patients treated for psychiatric (RR=1.6) or other conditions (RR=2.3). Overall, the incidence of suicidal behavior or ideation occurred consistently across all demographic subgroups and with each of the drugs studied. Of note, four patients receiving an antiepileptic committed suicide relative to none in the placebo groups.

Forthcoming product labeling changes are likely to extend to all antiepileptic drugs and not limited to the drugs used in the studies, pending discussions scheduled for the upcoming advisory committee meeting. Healthcare professionals and family members/caregivers are encouraged to monitor patients receiving any antiepileptic medication for signs/symptoms of suicidality (eg, anxiety, depression, behavior changes). Patients should not stop taking their antiepileptic therapy unless advised by a healthcare professional.

Additional information can be found at http://www.fda.gov/medwatch/safety/2008/safety08.htm#Antiepileptic

Medication Safety Issues

Sound-alike/look-alike issues:

Neurontin® may be confused with Neoral®, Noroxin®

Pronunciation

(GA ba pen tin)

U.S. Brand Names

• Neurontin®

Generic Available

Yes: Capsule, tablet

Canadian Brand Names

• Apo-Gabapentin®
• BCI-Gabapentin
• Gen-Gabapentin
• Neurontin®
• Novo-Gabapentin
• Nu-Gabapentin
• PMS-Gabapentin

Pharmacologic Category

• Anticonvulsant, Miscellaneous

Pharmacologic Category Synonyms

• AED, Miscellaneous
• Anti-epileptic Drug, Miscellaneous
• Miscellaneous Anticonvulsant

Use: Labeled Indications

Adjunct for treatment of partial seizures with and without secondary generalized seizures in patients >12 years of age with epilepsy; adjunct for treatment of partial seizures in pediatric patients 3-12 years of age; management of postherpetic neuralgia (PHN) in adults

Use: Dental

Neuropathic pain (consult with physician)

Use: Unlabeled/Investigational

Social phobia; chronic pain

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal studies have documented teratogenic effects. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

Lactation

Enters breast milk/use caution

Breast-Feeding Considerations

Gabapentin is excreted in human breast milk. A nursed infant could be exposed to ~1 mg/kg/day of gabapentin; the effect on the child is not known. Use in breast-feeding women only if the benefits to the mother outweigh the potential risk to the infant.

Contraindications

Hypersensitivity to gabapentin or any component of the formulation

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Disease-related concerns:

• Renal impairment: Use with caution in patients with severe renal impairment; dose adjustment required.

Concurrent drug therapy issues:

• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.

Special populations:

• Pediatrics: Safety and efficacy have not been established in children <3 years of age. Children 3-12 years of age have shown increased incidence of CNS-related adverse effects, including emotional lability, hostility, thought disorder, and hyperkinesia.

Other warnings/precautions:

• Tumorigenic potential: Male rat studies demonstrated an association with pancreatic adenocarcinoma (clinical implication unknown).

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.

Adverse Reactions

As reported in patients >12 years of age, unless otherwise noted in children (3-12 years)

>10%:

Central nervous system: Somnolence (20%; children 8%), dizziness (17% to 28%; children 3%), ataxia (13%), fatigue (11%)

Miscellaneous: Viral infection (children 11%)

1% to 10%:

Cardiovascular: Peripheral edema (2% to 8%), vasodilatation (1%)

Central nervous system: Fever (children 10%), hostility (children 8%), emotional lability (children 4%), fatigue (children 3%), headache (3%), ataxia (3%), abnormal thinking (2% to 3%; children 2%), amnesia (2%), depression (2%), dysarthria (2%), nervousness (2%), abnormal coordination (1% to 2%), twitching (1%), hyperesthesia (1%)

Dermatologic: Pruritus (1%), rash (1%)

Endocrine & metabolic: Hyperglycemia (1%)

Gastrointestinal: Diarrhea (6%), nausea/vomiting (3% to 4%; children 8%), abdominal pain (3%), weight gain (adults and children 2% to 3%), dyspepsia (2%), flatulence (2%), dry throat (2%), xerostomia (2% to 5%), constipation (2% to 4%), dental abnormalities (2%), appetite stimulation (1%)

Genitourinary: Impotence (2%)

Hematologic: Leukopenia (1%), decreased WBC (1%)

Neuromuscular & skeletal: Tremor (7%), weakness (6%), hyperkinesia (children 3%), abnormal gait (2%), back pain (2%), myalgia (2%), fracture (1%)

Ocular: Nystagmus (8%), diplopia (1% to 6%), blurred vision (3% to 4%), conjunctivitis (1%)

Otic: Otitis media (1%)

Respiratory: Rhinitis (4%), bronchitis (children 3%), respiratory infection (children 3%), pharyngitis (1% to 3%), cough (2%)

Miscellaneous: Infection (5%)

Postmarketing and additional clinical reports (limited to important or life-threatening): Acute renal failure, anemia, angina, angioedema, aphasia, arrhythmias (various), aspiration pneumonia, blindness, bradycardia, bronchospasm, cerebrovascular accident, CNS tumors, coagulation defect, colitis, Cushingoid appearance, dyspnea, encephalopathy, facial paralysis, fecal incontinence, glaucoma, glycosuria, heart block, hearing loss, hematemesis, hematuria, hemiplegia, hemorrhage, hepatitis, hepatomegaly, hyper-/hypotension, hyperlipidemia, hyper-/hypothyroidism, hyper-/hypoventilation, gastroenteritis, heart failure, leukocytosis, liver function tests increased, local myoclonus, lymphadenopathy, lymphocytosis, meningismus, MI, migraine, nephrosis, nerve palsy, non-Hodgkin's lymphoma, ovarian failure, pulmonary thrombosis, pericardial rub, pulmonary embolus, pericardial effusion, pericarditis, pancreatitis, peptic ulcer, purpura, paresthesia, palpitation, peripheral vascular disorder, pneumonia, psychosis, renal stone, retinopathy, skin necrosis, status epilepticus, subdural hematoma, suicidal behavior/ideation, syncope, tachycardia, thrombocytopenia, thrombophlebitis

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated in persons with a history of convulsions. If anticonvulsant is being used for another indication monitor response to treatment closely, as concurrent mefloquine may decrease response to treatment. Risk D: Consider therapy modification

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Does not change rate or extent of absorption.

Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased). Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Mechanism of Action

Gabapentin is structurally related to GABA. However, it does not bind to GABA_A or GABA_B receptors, and it does not appear to influence synthesis or uptake of GABA. High affinity gabapentin binding sites have been located throughout the brain; these sites correspond to the presence of voltage-gated calcium channels specifically possessing the alpha-2-delta-1 subunit. This channel appears to be located presynaptically, and may modulate the release of excitatory neurotransmitters which participate in epileptogenesis and nociception.

Pharmacodynamics/Kinetics

Absorption: 50% to 60% from proximal small bowel by L-amino transport system

Distribution: V_d: 0.6-0.8 L/kg

Protein binding: <3%

Bioavailability: Inversely proportional to dose due to saturable absorption:

900 mg/day: 60%

1200 mg/day: 47%

2400 mg/day: 34%

3600 mg/day: 33%

4800 mg/day: 27%

Half-life elimination: 5-7 hours; anuria 132 hours; during dialysis 3.8 hours

Excretion: Proportional to renal function; urine (as unchanged drug)

Dosage

Oral:

Children: Anticonvulsant:

3-12 years: Initial: 10-15 mg/kg/day in 3 divided doses; titrate to effective dose over ~3 days; dosages of up to 50 mg/kg/day have been tolerated in clinical studies

3-4 years: Effective dose: 40 mg/kg/day in 3 divided doses

?5-12 years: Effective dose: 25-35 mg/kg/day in 3 divided doses

See “Note” in adult dosing.

Children >12 years and Adults:

Anticonvulsant: Initial: 300 mg 3 times/day; if necessary the dose may be increased up to 1800 mg/day. Doses of up to 2400 mg/day have been tolerated in long-term clinical studies; up to 3600 mg/day has been tolerated in short-term studies.

Note: If gabapentin is discontinued or if another anticonvulsant is added to therapy, it should be done slowly over a minimum of 1 week

Pain (unlabeled use): 300-1800 mg/day given in 3 divided doses has been the most common dosage range

Adults: Postherpetic neuralgia or neuropathic pain: Day 1: 300 mg, Day 2: 300 mg twice daily, Day 3: 300 mg 3 times/day; dose may be titrated as needed for pain relief (range: 1800-3600 mg/day, daily doses >1800 mg do not generally show greater benefit)

Elderly: Studies in elderly patients have shown a decrease in clearance as age increases. This is most likely due to age-related decreases in renal function; dose reductions may be needed.

Dosing adjustment in renal impairment: Children ?12 years and Adults: See table.

Hemodialysis: Dialyzable

Dental Usual Dosing

Pain (unlabeled use): Children >12 years and Adults: Oral: 300-1800 mg/day given in 3 divided doses has been the most common dosage range

Postherpetic neuralgia or neuropathic pain: Adults: Oral: Day 1: 300 mg, Day 2: 300 mg twice daily, Day 3: 300 mg 3 times/day; dose may be titrated as needed for pain relief (range: 1800-3600 mg/day, daily doses >1800 mg do not generally show greater benefit)

Administration: Oral

Administer first dose on first day at bedtime to avoid somnolence and dizziness. Dosage must be adjusted for renal function; when given 3 times daily, the maximum time between doses should not exceed 12 hours.

Monitoring Parameters

Monitor serum levels of concomitant anticonvulsant therapy

Test Interactions

False positives have been reported with the Ames N-Multistix SG® dipstick test for urine protein

Dietary Considerations

May be taken without regard to meals.

Patient Education

Take exactly as directed; do not increase dose or frequency. It may take 2-3 weeks to achieve desired results; may cause physical and/or psychological dependence. If prescribed once-a-day, take dose at bedtime. If taking antacids, take at least 2 hours after antacids. Do not stop medication abruptly, may lead to increased seizure activity. Avoid alcohol, caffeine, and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or anorexia (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); diarrhea (buttermilk, yogurt, or boiled milk may help); postural hypotension (use caution when climbing stairs or changing position from lying or sitting to standing); or decreased sexual function or libido (reversible). Report persistent CNS effects (nervousness, restlessness, insomnia, anxiety, excitation, headache, sedation, seizures, mania, abnormal thinking); suicidal ideation or depression; rash or skin irritation; muscle cramping, tremors, or change in gait; chest pain or palpitations; change in urinary pattern; or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Geriatric Considerations

Studies in the elderly have shown a decrease in clearance as age increases. This is most likely due to age-related decreases in renal function; calculations of Cl_cr recommended since dose reductions may be needed.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation), dry throat, and dental abnormalities.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Comment

Large double-blind studies have failed to differentiate this drug from placebo when used as an adjunctive treatment for bipolar disorder. Gabapentin may be useful for some of the anxiety disorders.

Nursing: Physical Assessment/Monitoring

Assess effectiveness and interactions of other medications patient may be taking. Monitor therapeutic effectiveness, laboratory values, and adverse reactions at beginning of therapy and periodically with long-term use. Assess for CNS depression. Taper dosage slowly when discontinuing. Assess knowledge/teach patient safety and seizure precautions, appropriate use, interventions to reduce side effects, and adverse symptoms to report.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule: 100 mg, 300 mg, 400 mg

Neurontin®: 100 mg, 300 mg, 400 mg

Solution, oral:

Neurontin®: 250 mg/5 mL (480 mL) [cool strawberry anise flavor]

Tablet: 100 mg, 300 mg, 400 mg, 600 mg, 800 mg

Neurontin®: 600 mg, 800 mg

Pricing: U.S. (www.drugstore.com)

Capsules (Gabapentin)

100 mg (90): $25.99

300 mg (90): $59.99

400 mg (90): $74.99

Capsules (Neurontin)

100 mg (100): $74.99

300 mg (30): $55.64

400 mg (30): $66.14

Solution (Neurontin)

250 mg/5 mL (470): $136.58

Tablets (Gabapentin)

600 mg (90): $92.99

800 mg (90): $72.99

Tablets (Neurontin)

600 mg (90): $299.23

800 mg (90): $363.26

Extemporaneously Prepared

A 100 mg/mL suspension was stable for 91 days when refrigerated or 56 days when kept at room temperature when compounded as follows:

Triturate sixty-seven 300 mg tablets in a mortar, reduce to a fine powder, then add a small amount of one of the following vehicles to make a paste; then add the remaining vehicle in small quantities while mixing:

Vehicle 1. Methylcellulose 1% (100 mL) and Simple Syrup N.F. (100 mL) mixed together in a graduate, or

Vehicle 2. Ora-Sweet® (100 mL) and Ora-Plus® (100 mL) mixed together in a graduate

Shake well before using and keep in refrigerator

Nahata MC, Morosco RS, and Hipple TF, Stability of Gabapentin in Extemporaneously Prepared Suspensions at Two Temperatures, American Society of Health System Pharmacists Midyear Meeting, December 7-11, 1997.

References

Adler CH, “Treatment of Restless Legs Syndrome With Gabapentin,” Clin Neuropharmacol, 1997, 20(2):148-51.

Andrews CO and Fischer JH, “Gabapentin: A New Agent for the Management of Epilepsy,” Ann Pharmacother, 1994, 28(10):1188-96.

Bourgeois BF, “Antiepileptic Drugs in Pediatric Practice,” Epilepsia, 1995, 36(Suppl 2):34-45.

Brown JT and Randall A, “Gabapentin Fails to Alter P/Q-Type Ca2+ Channel-Mediated Synaptic Transmission in the Hippocampus In Vitro,” Synapse, 2005, 55(4):262-9.

Fischer JH, Barr AN, Rogers SL, et al, “Lack of Serious Toxicity Following Gabapentin Overdose,” Neurology, 1994, 44(5):982-3.

Goa KL and Sorkin EM, “Gabapentin: A Review of Its Pharmacological Properties and Clinical Potential in Epilepsy,” Drugs, 1993, 46(3):409-27.

Khurana DS, Riviello J, Helmers S, et al, “Efficacy of Gabapentin Therapy in Children With Refractory Partial Seizures,” J Pediatr, 1996, 128(6):829-33.

Lee DO, Steingard RJ, Cesena M, et al, “Behavioral Side Effects of Gabapentin in Children,” Epilepsia, 1996, 37(1):87-90.

Leiderman D, Garofalo E, and LaMoreaux L, “Gabapentin Patients With Absence Seizures: Two Double-Blind, Placebo Controlled Studies,” Epilepsia, 1993, 34(Suppl 6):45.

Mellick LB and Mellick GA, “Successful Treatment of Reflex Sympathetic Dystrophy With Gabapentin,” Am J Emerg Med, 1995, 13(1):96.

Pande AC, Crockatt JG, Janney CA, et al, “Gabapentin in Bipolar Disorder: A Placebo-Controlled Trial of Adjunctive Therapy. Gabapentin Bipolar Disorder Study Group,” Bipolar Disord, 2000, 2(3):249-55.

Short C and Cooke L, “Hypomania Induced by Gabapentin,” Br J Psychiatry, 1995, 166(5):679-80.

Sills GJ, “The Mechanisms of Action of Gabapentin and Pregabalin,” Curr Opin Pharmacol, 2006, 6(1):108-13.

International Brand Names

• Bapex (MX)
• Blugat (MX)
• Dineurin (CN)
• Engaba (PK)
• Epiven (ID)
• Epleptin (ZA)
• Gaba-Act (KP)
• Gabadin (PY)
• Gabahexal (AU)
• Gabalep (KP)
• Gabantin (MX)
• Gabapenin (KP)
• Gabatin (CH, KP)
• Gabatine (AU)
• Gabax (PL)
• Gabexol (ID)
• Gabietal (EC)
• Ganin (ID)
• Gantin (AU)
• Gapridol (MX)
• Kaptin (CO)
• Nepatic (ID)
• Neuril (DK)
• Neurontin (AE, AR, AT, AU, BE, BG, BH, BO, BR, CH, CN, CO, CR, CY, CZ, DE, DO, EC, EE, EG, ES, FI, FR, GB, GR, GT, HK, HN, HU, ID, IE, IL, IN, IQ, IR, IT, JO, KE, KP, KW, LB, LY, MX, MY, NI, NL, NO, OM, PA, PE, PH, PL, PR, PT, PY, QA, SA, SE, SG, SV, SY, TH, TW, UY, VE, YE, ZA)
• Nopatic (MX)
• Nupentin (AU)
• Pendine (AU)
• Pengatine (KP)

Lexi-Comp.com

Last full review/revision August 2008