Pregabalin

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Pregabalin quick reference

Pregabalin
Pregabalin general drug information
 Pronunciation pree GAB uh lin (.wav file)
 Trade Name(s) Lyrica
 How Supplied Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, 300 mg
 Generic Availability No generics available
 Patent Expiry Date March 6, 2018
 Classification analgesic, neurologic agent
 Schedule CV
 Pregnancy Category C
 Breast-feeding Consider alternative options. Use only if the benefit is greater than the risk.
Pregabalin chemical information
 IUPAC Name (S)-3-(aminomethyl)-5-methylhexanoic acid
 Empirical Formula C8H17NO2
 Molecular Weight 159.23 g/mol
pharmacokinetic information  |  pharmacogenomic information

Description

Pregabalin is a controlled substance which belongs to schedule V. It is currently FDA-approved for diabetic neuropathy, neuropathic pain, partial seizures and postherpetic neuralgia.[1] It is related to gabapentin in structure.[2] It is structurally derived from gamma-aminobutyric acid (GABA).[1][3] This drug has shown efficacy against placebo. Its pharmacokinetic interactions are limited; most of its drug-drug interactions are pharmacodynamic in nature. The largest side effect of pregabalin is that it can cause drowsiness and dizziness. Drowsiness and dizziness has been reported in 8-37% of patients taking this drug and is dose-dependent.

Pregabalin was approved for neuropathic pain associated with diabetic neuropathy and postherpetic neuralgia on December 31, 2004. It was subsequently approved on June 10, 2005 for the adjunctive treatment of partial seizures[4]

Mechanism of Action

Pregabalin binds to the alpha2-delta site in tissues of the central nervous system. It is unknown how pregabalin works exactly, however in vitro, it seems to impact calcium channel function by decreasing the calcium dependent discharge of some neurotransmitters.[1] Pregabalin is derived from GABA, however it does not bind to GABAA, GABAB, or to the benzodiazepine receptors.[3] When pregabalin is given for a long period of time to cultured neurons, the concentration of GABA transport protein increases as does the rate of GABA transport.[1]

Time Required for Therapeutic Response

  • Initial: pain alleviated/helped in as little as one week[1]

Pharmacokinetics

Absorption
Pregabalin is well-absorbed with a bioavailability of greater than 90%. The time to peak plasma concentration is 1.5 hours; this time is prolonged to 3 hours when pregabalin is given with food. The prolonged maximum concentrations do not appear to be clinically significant. The maximum plasma concentrations and AUC increase linearly from the following range of dosages 75 mg/day to 900 mg/day. Steady state is reached in 1-2 days.[1]

Distribution
Pregabalin does not bind to plasma proteins. Its volume of distribution is 0.5 L/kg. Pregabalin crosses the blood brain barrier in mice, rats and monkeys; human data is not yet available. Pregabalin is found in the milk of lactating rat.[1] The concentration in the body seems to range from 18-52 mmol/L.[3]

Metabolism
Pregabalin does not undergo much metabolism via the liver (less than 2%). 90% of pregabalin will be found in the urine as unchanged drug. The metabolite of pregabalin is the N-methylated derivative of pregabalin. 0.9% of the N-methylated derivative is found in the urine.[1]

Excretion
Pregabalin is eliminated principally via renal excretion. The mean half life is 6.3 hours with a renal clearance of 67.0 to 80.9 mL/min. This drug undergoes renal tubular reabsorption. Pregabalin’s excretion appears to be proportional to the creatinine clearance of the patient.[1]

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Special Population Pharmacokinetics

  • Renal insufficiency: The clearance of pregabalin is approximately proportional to the creatinine clearance of the patient, making dosage reduction in patients with renal insufficiency critical.[1]
  • Hepatic insufficiency: No pharmacokinetic differences noted.
  • Hemodialysis: Pregabalin is removed by hemodialysis. After 4 hours of hemodialysis, the plasma concentrations of pregabalin decrease by 50%.[1]
  • Geriatric: Clearance of pregabalin decreases with age because of normal age-related decreases in creatinine clearance. Thus dosage reduction is needed based on the patient’s renal function.[1][5]
  • Pediatric: Insufficient data.[1]
  • Gender: No pharmacokinetic differences noted.[1]

Indications and Dosages

FDA Approved Indications

Neuropathic pain associated with diabetic neuropathy[6][7][8][9]

  • Starting dose:
    • 50 mg TID
  • Maintenance dose:
    • 300-600 mg/day
  • Titration schedule: after one week, increase dose to 100 mg TID

Adjunctive therapy for partial seizures[10][11]

  • Starting dose:
    • 150 mg/day given in 2-3 divided doses
  • Maintenance dose:
    • up to 600 mg/day given in 2-3 divided doses
  • Titration schedule: increase to 600 mg/day, given in 2 or 3 divided doses, based on efficacy and tolerability.

Postherpatic neuralgia[12][13][14]

  • Starting dose:
    • 150 mg/day given in 2-3 divided doses
  • Maintenance dose:
    • 300 mg/day
  • Titration schedule: after one week, increase dose to 300 mg/day in 2-3 divided doses.

Fibromyalgia

  • Starting dose:
    • 75 mg/day BID
  • Maintenance dose:
    • 150-225 mg BID
  • Titration schedule: after one week, increase dose to 150 mg/day BID based on efficacy and tolerability.

Non-FDA Approved Indications

Dosage Adjustment

Renal insufficiency:

  • Creatinine clearance (CrCl) 30-60 mL/min:
    • Starting dose: 75 mg/day given in 2-3 divided doses
    • Titration schedule: increase to 150 mg/day, given in 2-3 divided doses, based on efficacy and tolerability
    • Maintenance dose: up to 300 mg/day in 2-3 divided doses
  • CrCl 15-30 mL/min:
    • Starting dose: 25-50 mg/day given in 1 or 2 doses
    • Titration schedule: increase to 75 mg/day, given in 1 or 2 doses, based on efficacy and tolerability
    • Maintenance dose: up to 150 mg/day in 1 or 2 doses
  • CrCl <15 mL/min:
    • Starting dose: 25 mg/day given once daily
    • Titration schedule: increase to 25-50 mg/day based on efficacy and tolerability
    • Maintenance dose: up to 75 mg/day

Hemodialysis:

  • Patients on 25 mg daily should take one supplemental dose of 25 mg or 50 mg after hemodialysis
  • Patients on 25-50 mg daily should take one supplemental dose of 50 mg or 75 mg after hemodialysis
  • Patients on 75 mg daily should take one supplemental dose of 100 mg or 150 mg after hemodialysis

Geriatric: dose-adjust based on CrCl.
Pediatric: May give up to 600 mg/day in children ≥12 years of age for treatment of seizures.

Dosage Limits

  • Adults: 300 mg/day for diabetic neuralgia; 600 mg/day for postherpetic neuralgia and seizures
  • Elderly: 300 mg/day for diabetic neuralgia
  • Adolescents and children ≥10 years: 600 mg/day for partial seizures
  • Children <10 years: has not been studied


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Administration

  • Route: Oral
  • Method:
    • May take with or without food. Swallow with a drink of water.

Monitoring Parameters

  • Creatinine clearance[1]

Contraindications/Precautions

Contraindications

  • Hypersensitivity to pregabalin or any of its components.[1]

Precautions

  • Tumorigenesis: in mice, there was found to be a higher than typical incidence of hemangiosarcoma.[1]
  • Known ophthalmologic problems: blurred vision typically resolves with continued use of pregabalin. It is recommended that more frequent eye testing be completed for patients with known ophthalmologic problems.[1]
  • Tapering/withdrawal of antiepileptic drugs: when pregabalin is to be discontinued, it should be stopped over a week. When patients stopped their pregabalin without tapering, they experienced insomnia, nausea, headache, and diarrhea. Pregabalin should be tapered to discontinuation over a week to decrease the chance of seizures in patients who are predisposed to seizures.[1]
  • Weight gain: weight gain is possible with pregabalin and seems to be associated with dose and length of therapy. Cardiovascular implications of the weight gain due to pregabalin are unknown.[1]
  • New York Heart Association class III or IV heart failure: peripheral edema is a possible side effect of pregabalin. In patients without cardiovascular morbidity, the edema appears to be benign, with no evidence of hypertension or heart failure. Use with caution in patients with heart failure.[1]
  • Creatinine kinase elevations: the increase in creatinine kinase for pregabalin was 60 units/liter and the increase in placebo treated patients was 28 units/liter. Patients should be instructed to report any muscle pain, for the risk of rhabdomyolysis is currently unknown with this agent.[1]
  • Decreased platelet count: patients taking pregabalin had a mean maximal decline in platelet count to 20,000/microliter. Patients taking placebo had a decrease in platelet count up to 11,000/microliter.[1]
  • Heart conduction abnormalities: mean PR interval prolongation was 3-6 sec when pregabalin was given at doses greater than or equal to 300mg/day. This does not appear to elevate the risk for second or third degree heart block.[1]

Pregnancy indications

Category C

In rats, pregabalin increased the risk of male-mediated teratogencity.[1]

Breast-feeding indications

Pregabalin is secreted into the breast milk of rats. Consider alternative options. Use only if the benefits are greater than the risks.

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Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

Adverse Reactions/Side Effects

Pregabalin is generally well-tolerated. It has been studied in over 10,000 patients. In clinical trials 14% discontinued use of pregabalin (7% discontinued who were taking placebo) mostly because of dizziness and somnolence. The most common adverse effects include dizziness, dry mouth, edema, blurred vision, weight gain, and difficulty concentrating.[1][20]

Pregabalin Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All Dizziness (11-37%), somnolence (8-25%), peripheral edema (4-16%), infection (3-14%), dry mouth (2-14%)
1-10% CNS Asthenia (2-7%), neuropathy (2-9%), ataxia (1-6%), vertigo (1-4%), confusion (1-3%), euphoria (2-3%), blurred vision (1-6%), headache (5-9%)
Cardiovascular Chest pain (1-4%)
GI Constipation (2-6%), flatulence (2-3%), vomiting (1-3%)
Neuromuscular/skeletal Pain (4-5%)
Respiratory Dyspnea (2-3%), bronchitis (1-3%)
Miscellaneous Weight gain (4-6%), edema (2-4%), hypoglycemia (1-3%)
<1% All Incoordination, thinking abnormal, tremor, abnormal gait, amnesia, nervousness, abnormal vision, urinary incontinence, allergic reaction, gastroenteritis, increased appetite, ecchymosis, arthralgia, leg cramps, pruritis, impotence

Overdosage Measures

There is not a lot of clinical experience with overdosage of pregabalin. There is a report of a patient who took 8000 mg, however, no adverse effects were noted.[1]
Treatment:

  • If clinically indicated, gastric lavage or emesis may be used.
  • Clinical support of the patient is essential.
  • If the patient’s clinical status is compromised, it may be prudent to use hemodialysis, though this has not been assayed clinically. This may be especially beneficial in patients with poor renal function. Hemodialysis removes 50% of the drug in 4 hours.[1]
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Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
25 mg capsule white/white capsule Pfizer/PGN 25
50 mg capsule white/black band capsule Pfizer/PGN 50
75 mg capsule red/white capsule Pfizer/PGN 75
100 mg capsule red/red capsule Pfizer/PGN 100
150 mg capsule white/white capsule Pfizer/PGN 150
200 mg capsule orange/orange capsule Pfizer/PGN 200
225 mg capsule red/white capsule Pfizer/PGN 225
300 mg capsule red/white capsule Pfizer/PGN 300
  • Inactive ingredients for capsules: cornstarch, gelatin, lactose monohydrate, talc, titanium dioxide

Patient Information

  • May be taken with or without food.
  • May cause dizziness, sleepiness and blurred vision. Use caution when driving or operating heavy machinery.
  • Call your prescriber right away if visual changes occur.
  • Do not stop taking pregabalin without taking to your prescriber. You need to be slowly weaned off of pregabalin to prevent side effects such as insomnia, nausea, headache, or diarrhea. If you are taking pregabalin for seizure control, abruptly stopping this medication may put you at risk for increased seizure activity.
  • Pregabalin may cause edema or weight gain; you may wish to monitor your weight while taking this drug.
  • Tell your prescriber and pharmacist all of the medications you are currently taking.
  • Call your prescriber or pharmacist right away if you have any muscle pain or weakness.
  • If you are taking a benzodiazepine or other CNS depressants, like opiates, you may experience more somnolence or other CNS effects with pregabalin.
  • Avoid alcohol.
  • Call your prescriber right away if you become pregnant or are planning on becoming pregnant or are breast feeding.
  • If a male is planning on fathering a child, contact your prescriber as this drug may be teratogenic.
  • If you are diabetic, please inspect your skin on a daily basis. Pregabalin may increase the risk for ulcerations.[1]
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References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 Pfizer Inc. Pregabalin (Lyrica) package insert. In: Distributed by Parke-Davis, editor. New York, NY: Pfizer; 2006.
  2. ↑ Guay DR. Pregabalin in neuropathic pain: a more "pharmaceutically elegant" gabapentin? American Journal Geriatric Pharmacotherapy. 2005 Dec;3(4):274-87.
  3. ↑ 3.0 3.1 3.2 Johannessen SI, Tomson T. Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed? Clinical Pharmacokinetics. 2006;45(11):1061-75.
  4. ↑ Pregabalin Monograph.Clinical Pharmacology (database on the internet) Available at www.clinicalpharmacolgy.com.
  5. ↑ Perucca E. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age. Clinical Pharmacokinetics. 2006;45(4):351-63.
  6. ↑ Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology. 2004 Dec 14;63(11):2104-10.
  7. ↑ Frampton JE, Scott LJ. Pregabalin: in the treatment of painful diabetic peripheral neuropathy. Drugs. 2004;64(24):2813-20; discussion 21.
  8. ↑ Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 2004 Aug;110(3):628-38.
  9. ↑ Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain. 2005 Jun;115(3):254-63.
  10. ↑ Warner G, Figgitt DP. Pregabalin: as adjunctive treatment of partial seizures. CNS Drugs. 2005;19(3):265-72; discussion 73-4.
  11. ↑ Beydoun A, Uthman BM, Kugler AR, Greiner MJ, Knapp LE, Garofalo EA, et al. Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy. Neurology. 2005 Feb 8;64(3):475-80.
  12. ↑ Frampton JE, Foster RH. Pregabalin: in the treatment of postherpetic neuralgia. Drugs. 2005;65(1):111-8; discussion 9-20.
  13. ↑ Sabatowski R, Galvez R, Cherry DA, Jacquot F, Vincent E, Maisonobe P, et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain. 2004 May;109(1-2):26-35.
  14. ↑ Dworkin RH, Corbin AE, Young JP, Jr., Sharma U, LaMoreaux L, Bockbrader H, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial.[see comment]. Neurology. 2003 Apr 22;60(8):1274-83.
  15. ↑ Montgomery SA. Pregabalin for the treatment of generalised anxiety disorder. Expert Opinion on Pharmacotherapy. 2006 Oct;7(15):2139-54.
  16. ↑ Frampton JE, Foster RH. Pregabalin: in the treatment of generalized anxiety disorder. CNS Drugs. 2006;20(8):685-93; discussion 94-5.
  17. ↑ Montgomery SA, Tobias K, Zornberg GL, Kasper S, Pande AC. Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine. Journal of Clinical Psychiatry. 2006 May;67(5):771-82.
  18. ↑ Knotkova H, Pappagallo M. Adjuvant analgesics. The Medical clinics of North America. 2007 Jan;91(1):113-24.
  19. ↑ Cottraux J. Recent developments in research and treatment for social phobia (social anxiety disorder). Current opinion in psychiatry. 2005 Jan;18(1):51-4.
  20. ↑ Hitiris N, Brodie MJ. Modern antiepileptic drugs: guidelines and beyond. Current Opinion in Neurology. 2006 Apr;19(2):175-80.

PUBMED References

Efficacy Trial Articles

  1. Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology. 2004 Dec 14;63(11):2104-10.
  2. Frampton JE, Scott LJ. Pregabalin: in the treatment of painful diabetic peripheral neuropathy. Drugs. 2004;64(24):2813-20; discussion 21.
  3. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 2004 Aug;110(3):628-38.
  4. Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M. Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain. 2005 Jun;115(3):254-63.
  5. Warner G, Figgitt DP. Pregabalin: as adjunctive treatment of partial seizures. CNS Drugs. 2005;19(3):265-72; discussion 73-4.
  6. Beydoun A, Uthman BM, Kugler AR, Greiner MJ, Knapp LE, Garofalo EA, et al. Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy. Neurology. 2005 Feb 8;64(3):475-80.
  7. Frampton JE, Foster RH. Pregabalin: in the treatment of postherpetic neuralgia. Drugs. 2005;65(1):111-8; discussion 9-20.
  8. Sabatowski R, Galvez R, Cherry DA, Jacquot F, Vincent E, Maisonobe P, et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain. 2004 May;109(1-2):26-35.
  9. Dworkin RH, Corbin AE, Young JP, Jr., Sharma U, LaMoreaux L, Bockbrader H, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial.see comment. Neurology. 2003 Apr 22;60(8):1274-83.
  10. Montgomery SA. Pregabalin for the treatment of generalised anxiety disorder. Expert Opinion on Pharmacotherapy. 2006 Oct;7(15):2139-54.
  11. Frampton JE, Foster RH. Pregabalin: in the treatment of generalised anxiety disorder. CNS Drugs. 2006;20(8):685-93; discussion 94-5.
  12. Montgomery SA, Tobias K, Zornberg GL, Kasper S, Pande AC. Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine. Journal of Clinical Psychiatry. 2006 May;67(5):771-82.
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Therapeutic Class Comparison Articles

  1. Zaccara G, Messori A, Cincotta M, Burchini G. Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from long-term studies? Acta Neurol Scand. 2006 Sep;114(3):157-68.
  2. Gidal BE. New and emerging treatment options for neuropathic pain. The American journal of managed care. 2006 Jun;12(9 Suppl):S269-78.
  3. Hempenstall K, Nurmikko TJ, Johnson RW, A'Hern RP, Rice AS. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS medicine. 2005 Jul;2(7):e164.

Pharmacokinetics Articles

  1. Guay DR. Pregabalin in neuropathic pain: a more "pharmaceutically elegant" gabapentin? American Journal Geriatric Pharmacotherapy. 2005 Dec;3(4):274-87.
  2. Johannessen SI, Tomson T. Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed? Clinical Pharmacokinetics. 2006;45(11):1061-75.
  3. Perucca E. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age. Clinical Pharmacokinetics. 2006;45(4):351-63.
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Drug Interaction Articles

  1. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. British Journal of Clinical Pharmacology. 2006 Mar;61(3):246-55.
  2. Hitiris N, Brodie MJ. Modern antiepileptic drugs: guidelines and beyond. Current Opinion in Neurology. 2006 Apr;19(2):175-80.

Adverse Effects Articles

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Compliance Articles

Pharmacoeconomic Articles

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External Links

Clinical treatment guidelines

Patient information pages

Other resources

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