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FDA Alerts
Special Alerts:
[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: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Antiepileptic and http://www.fda.gov/cder/drug/InfoSheets/HCP/antiepilepticsHCP.htm.
Closely monitor for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression. (See Suicidality Risk under Cautions.)
If pregabalin discontinued, gradually taper dosage over ≥1 week. (See Discontinuance, Abuse Potential, and Dependence under Cautions.)
Administration
Oral Administration
Administer orally without regard to meals.
Dosage
Adults
Seizure Disorders
Partial Seizures
Oral
Initially, 75 mg twice daily or 50 mg 3 times daily (initial dosage not to exceed 150 mg daily). Increase dosage up to a maximum of 600 mg daily, based on individual patient response and tolerability.
Effective maintenance dosage is 150–600 mg daily, administered in 2 or 3 divided doses.
Efficacy and adverse effects dose related, although effect of dosage escalation rate on tolerability not studied.
Dosage recommendations for use of pregabalin in conjunction with gabapentin not available, since such regimens not evaluated in controlled clinical studies.
Neuropathic Pain
Postherpetic Neuralgia
Oral
Initially, 150 mg daily (75 mg twice daily or 50 mg 3 times daily). Increase dosage to 300 mg daily within 1 week based on efficacy and tolerability.
Recommended maintenance dosage is 150–300 mg daily in 2 or 3 divided doses.
May increase dosage up to 600 mg daily (administered in 2 or 3 divided doses) in those who tolerate the drug but do not experience adequate pain relief following 2–4 weeks of treatment with pregabalin 300 mg daily.
Because of risk for dose-dependent adverse effects and higher rates of treatment discontinuance secondary to adverse effects, reserve dosages exceeding 300 mg daily for those who have continuing pain and are tolerating the 300-mg daily dosage.
Diabetic Neuropathy
Oral
Initially, 150 mg daily in 3 divided doses (50 mg 3 times daily); increase dosage within 1 week up to a maximum of 300 mg daily (administered in 3 divided doses), based on efficacy and tolerability.
Higher pregabalin dosages (i.e., 600 mg daily) provide no additional benefit, but may increase risk of adverse effects.
Fibromyalgia
Oral
Initially, 150 mg daily (75 mg twice daily). Increase dosage to 300 mg daily (150 mg twice daily) within 1 week based on efficacy and tolerability.
Recommended maintenance dosage is 300–450 mg daily.
May increase dosage up to a maximum of 450 mg daily (225 mg twice daily) in those who do not experience adequate benefit with pregabalin 300 mg daily.
Higher pregabalin dosages (i.e., 600 mg daily) provide no additional benefit, but may increase risk of adverse effects.
Prescribing Limits
Adults
Seizure Disorders and Neuropathic Pain
Oral
Maximum 600 mg daily.
Fibromyalgia
Oral
Maximum 450 mg daily.
Special Populations
Renal Impairment
Modify dosage of pregabalin in adults with renal impairment (Clcr <60 mL/minute) based on Clcr.
Table 1: Pregabalin Dosage Adjustment in Patients with Renal Impairment
Usual Dosage Regimen (for Patients with Clcr of ≥60 mL/min)
Clcr (mL/min)
Adjusted Dosage Regimen
150 mg daily given in 2 or 3 divided doses
30–60
75 mg daily given in 2 or 3 divided doses
15–30
25–50 mg daily given as a single dose or in 2 divided doses
<15
25 mg once daily
300 mg daily given in 2 or 3 divided doses
30–60
150 mg daily given in 2 or 3 divided doses
15–30
75 mg daily given as a single dose or in 2 divided doses
<15
25–50 mg once daily
450 mg daily given in 2 or 3 divided doses
30–60
225 mg daily given in 2 or 3 divided doses
15–30
100–150 mg daily given as a single dose or in 2 divided doses
<15
50–75 mg once daily
600 mg daily given in 2 or 3 divided doses
30–60
300 mg daily given in 2 or 3 divided doses
15–30
150 mg daily given as a single dose or in 2 divided doses
<15
75 mg once daily
Patients undergoing hemodialysis should receive a supplemental dose immediately following each 4-hour dialysis session. Individuals receiving the 25-mg once-daily dosage regimen should receive a supplemental dose of 25 or 50 mg, those receiving the 25- to 50-mg once-daily dosage regimen should receive a supplemental dose of 50 or 75 mg, those receiving the 50- to 75-mg once daily dosage regimen should receive a supplemental dose of 75 or 100 mg, and those receiving the 75-mg once-daily dosage regimen should receive a supplemental dose of 100 or 150 mg.
Geriatric Patients
Adjust dosage for geriatric patients with renal impairment. (See Dosage Adjustment in Patients with Renal Impairment under Dosage and Administration.)
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