Lyrica (Pregabalin)

LYRICA is indicated for:

• •
  Management of neuropathic pain associated with diabetic peripheral neuropathy
• •
  Management of postherpetic neuralgia
• •
  Adjunctive therapy for the treatment of partial-onset seizures in patients 1 month of age and older
• •
  Management of fibromyalgia
• •
  Management of neuropathic pain associated with spinal cord injury

• •For adult indications, begin dosing at 150 mg/day. For partial-onset seizure dosing in pediatric patients 1 month of age and older, refer to section 2.4. (
  2.2 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy in Adults

  The maximum recommended dose of LYRICA is 100 mg three times a day (300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability.

  Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional significant benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 300 mg/day is not recommended

  [see Adverse Reactions (6.1)]

  .
  ,
  2.3 Postherpetic Neuralgia in Adults

  The recommended dose of LYRICA is 75 to 150 mg two times a day, or 50 to 100 mg three times a day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 75 mg two times a day, or 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability.

  Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 300 mg/day, and who are able to tolerate LYRICA, may be treated with up to 300 mg two times a day, or 200 mg three times a day (600 mg/day). In view of the dose-dependent adverse reactions and the higher rate of treatment discontinuation due to adverse reactions, reserve dosing above 300 mg/day for those patients who have on-going pain and are tolerating 300 mg daily

  [see Adverse Reactions (6.1)]

  .
  ,
  2.4 Adjunctive Therapy for Partial-Onset Seizures in Patients 1 Month of Age and Older

  The recommended dosages for adults and pediatric patients 1 month of age and older are included in Table 1. Administer the total daily dosage orally in two or three divided doses as indicated in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon body weight. Based on clinical response and tolerability, dosage may be increased, approximately weekly.

  Table 1. Recommended Dosage for Adults and Pediatric Patients 1 Month and Older

  Age and Body Weight	Recommended Initial Dosage	Recommended Maximum Dosage	Frequency of Administration
  Adults (17 years and older)	150 mg/day	600 mg/day	2 or 3 divided doses
  Pediatric patients weighing 30 kg or more	2.5 mg/kg/day	10 mg/kg/day (not to exceed 600 mg/day)	2 or 3 divided doses
  Pediatric patients weighing less than 30 kg	3.5 mg/kg/day	14 mg/kg/day	1 month to less than 4 years of age: 3 divided doses 4 years of age and older: 2 or 3 divided doses

  Both the efficacy and adverse event profiles of LYRICA have been shown to be dose-related.

  The effect of dose escalation rate on the tolerability of LYRICA has not been formally studied.

  The efficacy of adjunctive LYRICA in patients taking gabapentin has not been evaluated in controlled trials. Consequently, dosing recommendations for the use of LYRICA with gabapentin cannot be offered.
  ,
  2.5 Management of Fibromyalgia in Adults

  The recommended dose of LYRICA for fibromyalgia is 300 to 450 mg/day. Begin dosing at 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day). Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional benefit and this dose was less well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 450 mg/day is not recommended

  [see Adverse Reactions (6.1)]

  .
  ,
  2.6 Neuropathic Pain Associated with Spinal Cord Injury in Adults

  The recommended dose range of LYRICA for the treatment of neuropathic pain associated with spinal cord injury is 150 to 600 mg/day. The recommended starting dose is 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient pain relief after 2 to 3 weeks of treatment with 150 mg two times a day and who tolerate LYRICA may be treated with up to 300 mg two times a day

  [see Clinical Studies (14.5)]

  .
  )
• •Dosing recommendations:

• •Dose should be adjusted in adult patients with reduced renal function. (
  2.7 Dosing for Adult Patients with Renal Impairment

  In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in adult patients with reduced renal function. The use of LYRICA in pediatric patients with compromised renal function has not been studied.

  Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 2. To use this dosing table, an estimate of the patient's CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation:

  

  Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr greater than or equal to 60 mL/min). Then refer to Table 2 to determine the corresponding renal adjusted dose.

  (For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr greater than or equal to 60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.)

  For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 2).

  Table 2. Pregabalin Dosage Adjustment Based on Renal Function

  Creatinine Clearance (CLcr) (mL/min)	Total Pregabalin Daily Dose (mg/day) Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose.				Dose Regimen
  TID= Three divided doses; BID = Two divided doses; QD = Single daily dose.
  Greater than or equal to 60	150	300	450	600	BID or TID
  30–60	75	150	225	300	BID or TID
  15–30	25–50	75	100–150	150	QD or BID
  Less than 15	25	25–50	50–75	75	QD
  Supplementary dosage following hemodialysis (mg)Supplementary dose is a single additional dose.
  Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg
  Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg
  Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg
  Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg

  

  )

Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg

Oral Solution: 20 mg/mL

[see

11 DESCRIPTION

Pregabalin is described chemically as (

S

)-3-(aminomethyl)-5-methylhexanoic acid. The molecular formula is C₈H₁₇NO₂and the molecular weight is 159.23. The chemical structure of pregabalin is:

Pregabalin is a white to off-white, crystalline solid with a pK_a1of 4.2 and a pK_a2of 10.6. It is freely soluble in water and both basic and acidic aqueous solutions. The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is – 1.35.

LYRICA (pregabalin) Capsules are administered orally and are supplied as imprinted hard-shell capsules containing 25, 50, 75, 100, 150, 200, 225, and 300 mg of pregabalin, along with lactose monohydrate, cornstarch, and talc as inactive ingredients. The capsule shells contain gelatin and titanium dioxide. In addition, the orange capsule shells contain red iron oxide and the white capsule shells contain sodium lauryl sulfate and colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells. The imprinting ink contains shellac, black iron oxide, propylene glycol, and potassium hydroxide.

LYRICA (pregabalin) oral solution, 20 mg/mL, is administered orally and is supplied as a clear, colorless solution contained in a 16 fluid ounce white HDPE bottle with a polyethylene-lined closure. The oral solution contains 20 mg/mL of pregabalin, along with methylparaben, propylparaben, monobasic sodium phosphate anhydrous, dibasic sodium phosphate anhydrous, sucralose, artificial strawberry #11545 and purified water as inactive ingredients.

and

16 HOW SUPPLIED/STORAGE AND HANDLING

25 mg capsules:

White, hard-gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 25" on the body; available in:

Bottles of 90:

NDC 0071-1012-68

50 mg capsules:

White, hard-gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 50" and an ink band on the body, available in:

Bottles of 90:	NDC 0071-1013-68
Unit-Dose Blister Packages of 100:	NDC 0071-1013-41

75 mg capsules:

White/orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 75" on the body; available in:

Bottles of 90:	NDC 0071-1014-68
Unit-Dose Blister Packages of 100:	NDC 0071-1014-41

100 mg capsules:

Orange, hard-gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 100" on the body, available in:

Bottles of 90:	NDC 0071-1015-68
Unit-Dose Blister Packages of 100:	NDC 0071-1015-41

150 mg capsules:

White hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 150" on the body, available in:

Bottles of 90:	NDC 0071-1016-68
Unit-Dose Blister Packages of 100:	NDC 0071-1016-41

200 mg capsules:

Light orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 200" on the body, available in:

Bottles of 90:

NDC 0071-1017-68

225 mg capsules:

White/light orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 225" on the body; available in:

Bottles of 90:

NDC 0071-1019-68

300 mg capsules:

White/orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 300" on the body, available in:

Bottles of 90:

NDC 0071-1018-68

20 mg/mL oral solution:

16 fluid ounce white high density polyethylene (HDPE) bottle with a polyethylene-lined closure:

16 fluid ounce bottle

NDC 0071-1020-01

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature).

]

• •Pregnancy: May cause fetal harm. Advise of potential risk to the fetus. (
  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYRICA during pregnancy. To provide information regarding the effects of

  in utero

  exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/

  .

  Risk Summary

  There are no adequate and well-controlled studies with LYRICA in pregnant women.

  However, in animal reproduction studies, increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including skeletal malformations, retarded ossification, and decreased fetal body weight were observed in the offspring of rats and rabbits given pregabalin orally during organogenesis, at doses that produced plasma pregabalin exposures (AUC) greater than or equal to 16 times human exposure at the maximum recommended dose (MRD) of 600 mg/day

  [see Data]

  . In an animal development study, lethality, growth retardation, and nervous and reproductive system functional impairment were observed in the offspring of rats given pregabalin during gestation and lactation. The no-effect dose for developmental toxicity was approximately twice the human exposure at MRD. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2–4% and of miscarriage is 15–20% of clinically recognized pregnancies. Advise pregnant women of the potential risk to a fetus.

  Data

  Animal Data

  When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established.

  When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD.

  In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at greater than or equal to 100 mg/kg and offspring survival was decreased at greater than or equal to 250 mg/kg. The effect on offspring survival was pronounced at doses greater than or equal to 1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at greater than or equal to 250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD.

  In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures greater than or equal to 50 times the mean human exposure (AUC_(0–24)of 123 µg∙hr/mL) at the MRD.
  )
• •Lactation: Breastfeeding is not recommended. (
  8.2 Lactation

  Risk Summary

  Small amounts of pregabalin have been detected in the milk of lactating women. A pharmacokinetic study in lactating women detected pregabalin in breast milk at average steady state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose

  [see Data]

  . The study did not evaluate the effects of LYRICA on milk production or the effects of LYRICA on the breastfed infant.

  Based on animal studies, there is a potential risk of tumorigenicity with pregabalin exposure via breast milk to the breastfed infant

  [see Nonclinical Toxicology (13.1)]

  . Available clinical study data in patients greater than 12 years of age do not provide a clear conclusion about the potential risk of tumorigenicity with pregabalin

  [see Warnings and Precautions (5.9)]

  . Because of the potential risk of tumorigenicity, breastfeeding is not recommended during treatment with LYRICA.

  Data

  A pharmacokinetic study in ten lactating women, who were at least 12 weeks postpartum, evaluated the concentrations of pregabalin in plasma and breast milk. LYRICA 150 mg oral capsule was given every 12 hours (300 mg daily dose) for a total of four doses. Pregabalin was detected in breast milk at average steady-state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose. The study did not evaluate the effects of LYRICA on milk production. Infants did not receive breast milk obtained during the dosing period, therefore, the effects of LYRICA on the breast fed infant were not evaluated.
  )