Generic Name: pregabalin

Brand Names: Lyrica

Uses

Seizure Disorders

Management (in combination with other anticonvulsants) of partial seizures in adults.

Neuropathic Pain

Management of postherpetic neuralgia in adults.

Management of pain associated with diabetic peripheral neuropathy in adults.

Fibromyalgia

Management of fibromyalgia in adults.

Dosage and Administration

General

• 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 (Cl_cr <60 mL/minute) based on Cl_cr.

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.)

Cautions

Contraindications

• Hypersensitivity to pregabalin or any ingredient in the formulation.

Warnings/Precautions

Suicidality Risk

Possible increased risk of suicidal behavior or ideation (suicidality) reported in patients receiving anticonvulsants, including pregabalin, compared with those receiving placebo. Increased suicidality risk observed ≥1 week after beginning therapy and continued through 24 weeks. Although patients treated for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, relative suicidality risk was higher for patients with epilepsy compared to those receiving anticonvulsants for other conditions.

Closely monitor patients receiving pregabalin for suicidality and other unusual changes in behavior. Symptoms such as anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality. Balance suicidality risk with the clinical need for the drug. (See Advice to Patients.)

Angioedema

Angioedema, including life-threatening angioedema with respiratory compromise requiring emergency treatment, reported during postmarketing surveillance in patients receiving initial and chronic pregabalin therapy. Specific symptoms included swelling of the face, mouth (e.g., tongue, lips, gums), and neck (e.g., throat, larynx). Discontinue pregabalin immediately in patients with these symptoms.

Use with caution in patients who have had a previous episode of angioedema.

Patients receiving other drugs associated with angioedema (e.g., ACE inhibitors) may be at increased risk of developing angioedema.

Hypersensitivity Reactions

Hypersensitivity reactions (i.e., skin redness, blisters, hives, rash, dyspnea, wheezing) reported during postmarketing surveillance in patients shortly after initiation of pregabalin therapy. Discontinue pregabalin immediately in patients with these symptoms.

Discontinuance, Abuse Potential, and Dependence

Abrupt withdrawal may result in increased seizure frequency; withdraw pregabalin gradually and reduce dosage slowly over ≥1 week.

Following abrupt withdrawal, possible insomnia, nausea, headache, or diarrhea; suggestive of physical dependence.

Possible euphoria.

Although pregabalin is not known to be active at receptor sites associated with drugs of abuse, the Drug Enforcement Administration (DEA) placed the drug into schedule V of the Federal Controlled Substances Act (CSA) of 1970 subsequent to a recommendation for control from the Department of Health and Human Services (DHHS).

Evaluate patients for history of drug abuse and observe them for signs of pregabalin misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).

Peripheral Edema

Risk of edema (mainly peripheral edema). Peripheral edema not associated with deterioration of renal or hepatic function.

No apparent association between peripheral edema and cardiovascular complications (e.g., hypertension, CHF) in patients without clinically important heart or peripheral vascular disease.

Use with caution in patients with NYHA class III or IV CHF.

Dizziness and Somnolence

Risk of dizziness and somnolence during pregabalin treatment.

Weight Gain

Possible weight gain related to dosage and duration of exposure to pregabalin, but not related to baseline body mass index (BMI), gender, age, or existing edema.

Weight gain not associated with clinically important short-term changes in BP, but long-term cardiovascular effects not known.

Pregabalin therapy does not appear to be associated with loss of glycemic control.

Tumorigenic Potential

Carcinogenicity (e.g., hemangiosarcoma) demonstrated in animals.

New or worsening of preexisting tumors reported in humans; causal relationship not established.

Ocular Effects

Possible blurred vision, decreased visual acuity, visual field changes, and funduscopic changes. Clinical importance not known.

If visual disturbance persists, consider further or more frequent ocular assessment in those already monitored for ocular conditions.

Creatine Kinase Elevations

Possible increases in CPK concentrations (≥ 3 times the ULN) and rhabdomyolysis; causal relationship not established.

Discontinue pregabalin if myopathy is diagnosed or suspected or if markedly elevated CPK concentrations occur.

Thrombocytopenia

Risk of thrombocytopenia, although increased bleeding not reported.

PR Interval Prolongation

Risk of prolongation of the PR interval (mean increase: 3–6 msec) in those receiving daily pregabalin dosages of ≥ 300 mg. It appears that patients with preexisting PR prolongation at baseline or those receiving drugs that prolong the PR interval are not at increased risk for developing prolongation of the PR interval.

Specific Populations

Pregnancy

Category C.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing or the drug because of potential risk to nursing infants.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out. Neurologic adverse reactions including dizziness, blurred vision, balance disorder, tremor, confusional state, abnormal coordination, and lethargy occurred more frequently in patients ≥65 years of age than in younger adults in controlled clinical studies of patients with fibromyalgia.

Substantially eliminated by kidneys; risk of increased severe adverse reactions in those with impaired renal function.

Adjust dosage in those with renal impairment. (See Dosage Adjustment in Patients with Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Concomitant use of pregabalin with other anticonvulsants for partial seizures: Dizziness, somnolence, ataxia, abnormal thinking, tremor, confusion, twitching, myoclonus, amnesia, speech disorder, incoordination, abnormal gait, dry mouth, constipation, increased appetite, weight gain, peripheral edema, blurred vision, diplopia, abnormal vision, accidental injury, pain.

Management of postherpetic neuralgia: Dizziness, somnolence, headache, confusion, abnormal thinking, ataxia, incoordination, amnesia, abnormal gait, dry mouth, constipation, flatulence, vomiting, weight gain, peripheral edema, edema, facial edema, blurry vision, diplopia, abnormal vision, infection, flu syndrome, accidental injury, pain.

Management of pain associated with diabetic peripheral neuropathy: Dizziness, somnolence, asthenia, neuropathy, ataxia, vertigo, abnormal thinking, confusion, euphoria, incoordination, dry mouth, constipation, flatulence, weight gain, peripheral edema, edema, hypoglycemia, accidental injury, back pain, chest pain, blurry vision, dyspnea.

Management of fibromyalgia: Dizziness, somnolence, headache, euphoric mood, attention disturbance, balance disorder, memory impairment, confusional state, abnormal coordination, hypoesthesia, lethargy, tremor, anxiety, disorientation, depression, dry mouth, constipation, vomiting, flatulence, abdominal distention, weight gain, fatigue, peripheral edema, chest pain, abnormal feeling, edema, fluid retention, drunk feeling, increased appetite, blurred vision, sinusitis, vertigo, pharyngolaryngeal pain, arthralgia, muscle spasms, back pain.

Interactions

Does not appear to inhibit CYP isoenzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 or induce CYP1A2 or 3A4.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Since pregabalin undergoes negligible metabolism in humans, pharmacokinetics unlikely to be affected by other agents through metabolic interactions.

Increased metabolism of concomitantly administered CYP1A2 substrates (e.g., caffeine, theophylline) or CYP3A4 substrates (e.g., midazolam, testosterone) not anticipated.

Protein-bound Drugs

Does not bind to plasma proteins; pharmacokinetic interaction with drugs that are highly protein bound unlikely.

Specific Drugs

Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration, with peak plasma concentrations attained within 1.5 hours.

Oral bioavailability is ≥90% and independent of dose.

Food

Food reduces peak plasma concentration by about 25–30% and delays time to peak plasma concentration by about 3 hours, but does not affect extent of absorption.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Crosses the placenta in rats; not known whether crosses the placenta in humans.

Distributed into CSF in animals.

Elimination

Metabolism

Negligibly metabolized.

Elimination Route

Primarily excreted in urine, mainly as unchanged drug (90%).

Half-life

Mean: 6.3 hours.

Special Populations

Pregabalin clearance tends to decrease with increasing age. (See Geriatric Use under Cautions and see Renal Impairment under Dosage and Administration.)

Removed by hemodialysis; dosage adjustment is necessary. (See Renal Impairment under Dosage and Administration.)

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).

Actions

• Exact mechanism of anticonvulsant and analgesic action unknown; may be related to binding with high affinity to the α₂-δ subunit (an auxiliary subunit of voltage-gated calcium channels) in CNS tissues.
• In vitro, reduces calcium-dependent release of several neurotransmitters, including glutamate, norepinephrine, calcitonin gene-related peptide, and substance P, possibly by modulation of calcium channel function.
• Does not bind directly to GABA_A, GABA_B, or benzodiazepine receptors; does not augment GABA_A responses in cultured neurons; and does not alter brain concentrations of GABA in rats or affect GABA uptake or degradation. In cultured neurons, prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport.

• Does not block sodium channels; not active at opiate receptors; does not alter cyclooxygenase activity.
• Inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.

Advice to Patients

• Advise patients, family members, and caregivers that anticonvulsants may increase the risk of suicidal thoughts or actions. Advise them to pay close attention to any day-to-day changes in mood, behavior, and actions; these changes can happen very quickly. Advise of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions) and of need to contact clinician immediately if these or any new and worrisome behaviors occur.
• Risk of angioedema and other hypersensitivity reactions; importance of discontinuing the drug and reporting suggestive manifestations (e.g., edema of face, eyes, lips, or tongue; swallowing or breathing with difficulty) to a clinician.
• Risk of dizziness, somnolence, blurred vision, and other neuropsychiatric effects. Avoid driving or operating machinery or engaging in other hazardous activities while taking pregabalin until experienced with the drug’s effects.
• Avoid alcohol-containing beverages or products; drug may potentiate impairment of motor skills and sedation associated with ingestion of alcohol.
• Risk of visual disturbances. Importance of informing clinician if changes in vision occur.
• Importance of adhering to prescribed directions for use and not altering the drug regimen without first consulting with the clinician. Provide copy of manufacturer’s patient information; importance of reading this information prior to initiating therapy with pregabalin.
• Importance of not discontinuing pregabalin abruptly, since insomnia, nausea, headache, or diarrhea may occur.
• Risk of edema and weight gain; concomitant administration with a thiazolidinedione antidiabetic agent may increase such risk. In patients with preexisting cardiac conditions, risk of heart failure may be increased.
• Importance of patients promptly informing clinicians of any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
• Advise diabetic patients to watch for skin damage while receiving pregabalin therapy, since increased risk of skin ulcerations associated with pregabalin therapy has been observed in animal studies.
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
• Advise patients of male-mediated teratogenicity. Importance of men informing clinicians if they plan to father a child.
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses. Potential for additive CNS effects if used concomitantly with other CNS depressants (e.g., opiates, benzodiazepines).
• 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.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule V (C-V) drug. (See Discontinuance, Abuse Potential, and Dependence under Cautions.)

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.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions August 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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.