Lyrica

Lake Erie Medical & Surgical Supply DBA Quality Care Products LLC

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use LYRICA safely and effectively. See full prescribing information for LYRICA. LYRICA (pregabalin) Capsules, CV LYRICA (pregabalin) Oral Solution, CV Initial U.S. Approval: 2004RECENT MAJOR CHANGESRECENT MAJOR CHANGES Dosage and Administration, Oral Solution Concentration and Dispensing (2.6) INDICATIONS AND USAGEINDICATIONS AND USAGE LYRICA is indicated for:- Neuropathic pain associated with diabetic peripheral neuropathy (DPN) (1.1) - Post herpetic neuralgia (PHN) (1.2) - Adjunctive therapy for adult patients with partial onset seizures (1.3) - Fibromyalgia (1.4) DOSAGE AND ADMINISTRATIONDOSAGE AND ADMINISTRATION DPN Pain (2.1):- Administer in 3 divided doses per day - Begin dosing at 150 mg/day - May be increased to a maximum of 300 mg/day within 1 week. PHN (2.2):- Administer in 2 or 3 divided doses per day - Begin dosing at 150 mg/day - May be increased to 300 mg/day within 1 week - Maximum dose of 600 mg/day. Adjunctive Therapy for Adult Patients with Partial Onset Seizures (2.3):- Administer in 2 or 3 divided doses per day - Begin dosing at 150 mg/day - Maximum dose of 600 mg/day. Fibromyalgia (2.4):- Administer in 2 divided doses per day - Begin dosing at 150 mg/day - May be increased to 300 mg/day within 1 week - Maximum dose of 450 mg/day. Dose should be adjusted in patients with reduced renal function. (2.5) Oral Solution Concentration and Dispensing (2.6) DOSAGE FORMS AND STRENGTHSDOSAGE FORMS AND STRENGTHS - Capsules: 25mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg. (3) - Oral Solution: 20 mg/ mL. (3) CONTRAINDICATIONSCONTRAINDICATIONS - Known hypersensitivity to pregabalin or any of its components. (4) WARNINGS AND PRECAUTIONSWARNINGS AND PRECAUTIONS - Angioedema (e.g. swelling of the throat, head and neck) can occur, and may be associated with life-threatening respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in these cases. (5.1) - Hypersensitivity reactions (e.g. hives, dyspnea, and wheezing) can occur. Discontinue LYRICA immediately in these patients. (5.2) - Increased seizure frequency may occur in patients with seizure disorders if LYRICA is rapidly discontinued. Withdraw LYRICA gradually over a minimum of 1 week. (5.3) - Antiepileptic drugs, including LYRICA, increase the risk of suicidal thoughts or behavior. (5.4) - LYRICA may cause peripheral edema. Exercise caution when co-administering LYRICA and thiazolidinedione antidiabetic agents. (5.5) - LYRICA may cause dizziness and somnolence and impair patients' ability to drive or operate machinery.(5.6) Side EffectsADVERSE REACTIONS Most common adverse reactions (greater than or equal to 5% and twice placebo) are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and thinking abnormal (primarily difficulty with concentration/attention). (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at (800) 438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch USE IN SPECIFIC POPULATIONSUSE IN SPECIFIC POPULATIONS To enroll in the North American Antiepileptic Drug Pregnancy Registry call 1-888-233-2334 (toll free). ( 8.1 ) See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication Guide

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1.1 Management of neuropathic pain associated with diabetic peripheral neuropathy 1.2 Management of postherpetic neuralgia 1.3 Adjunctive therapy for adult patients with partial onset seizures 1.4 Management of fibromyalgia
• 2.1 Neuropathic pain associated with diabetic peripheral neuropathy 2.2 Postherpetic neuralgia 2.3 Adjunctive therapy for adult patients with partial onset seizures 2.4 Management of Fibromyalgia 2.5 Patients with Renal Impairment 2.6 Oral Solution Concen
• 3 DOSAGE FORMS AND STRENGTHS
• 4 LYRICA CONTRAINDICATIONS
• 5.1 Angioedema 5.2 Hypersensitivity 5.3 Withdrawal of Antiepileptic Drugs (AEDs) 5.4 Suicidal Behavior and Ideation 5.5 Peripheral Edema 5.6 Dizziness and Somnolence 5.7 Weight Gain 5.8 Abrupt or Rapid Discontinuation 5.9 Tumorigenic Potential 5.10 Ophtha
• 6.1 Clinical Trials Experience 6.2 Post-marketing Experience
• 7 DRUG INTERACTIONS
• 8.1 Pregnancy
• 8.2 Labor and Delivery
• 8.3 Nursing Mothers
• 8.4 Pediatric Use
• 8.5 Geriatric Use
• 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence
• 10 OVERDOSAGE
• 11 LYRICA DESCRIPTION
• 12.1 Mechanism of Action
• 12.3 Pharmacokinetics 12.4 Pharmacokinetics in Special Populations
• 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 13.2 Animal Toxicology and/or Pharmacology
• 14.1 Neuropathic pain associated with diabetic peripheral neuropathy 14.2 Postherpetic Neuralgia 14.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures 14.4 Management of Fibromyalgia 1 2
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17.1 Medication Guide 17.2 Angioedema 17.3 Hypersensitivity 17.4 Suicidal Thinking and Behavior 17.5 Dizziness and Somnolence 17.6 Weight Gain and Edema 17.7 Abrupt or Rapid Discontinuation 17.8 Ophthalmological Effects 17.9 Creatine Kinase Elevations 17
• Image of 100 mg Label

FULL PRESCRIBING INFORMATION

Uses

1.1 Management of neuropathic pain associated with diabetic peripheral neuropathy 1.2 Management of postherpetic neuralgia 1.3 Adjunctive therapy for adult patients with partial onset seizures 1.4 Management of fibromyalgia

1 INDICATIONS AND USAGE
LYRICA is indicated for:

1.1 Management of neuropathic pain associated with diabetic peripheral neuropathy

1.2 Management of postherpetic neuralgia

1.3 Adjunctive therapy for adult patients with partial onset seizures

1.4 Management of fibromyalgia

2.1 Neuropathic pain associated with diabetic peripheral neuropathy 2.2 Postherpetic neuralgia 2.3 Adjunctive therapy for adult patients with partial onset seizures 2.4 Management of Fibromyalgia 2.5 Patients with Renal Impairment 2.6 Oral Solution Concen

2 DOSAGE AND ADMINISTRATION

LYRICA is given orally with or without food.

When discontinuing LYRICA, taper gradually over a minimum of 1 week.

2.1 Neuropathic pain associated with diabetic peripheral neuropathy

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. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see    Dosage and Administration (2.5)].

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)].

2.2 Postherpetic neuralgia

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. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.5)].

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)].

2.3 Adjunctive therapy for adult patients with partial onset seizures

LYRICA at doses of 150 to 600 mg/day has been shown to be effective as adjunctive therapy in the treatment of partial onset seizures in adults. Both the efficacy and adverse event profiles of LYRICA have been shown to be dose-related. Administer the total daily dose in two or three divided doses. In general, it is recommended that patients be started on a total daily dose no greater than 150 mg/day (75 mg two times a day, or 50 mg three times a day). Based on individual patient response and tolerability, the dose may be increased to a maximum dose of 600 mg/day.

Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.5)].

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

The efficacy of add-on 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.

2.4 Management of Fibromyalgia

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)]. Because LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function [see Dosage and Administration (2.5)].

2.5 Patients with Renal Impairment

In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. 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 1 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 1).
 

2.6 Oral Solution Concentration and Dispensing

The oral solution is 20 mg pregabalin per milliliter (mL) and prescriptions should be written in milligrams (mg). The pharmacist will calculate the applicable dose in mL for dispensing (e.g., 150 mg equals 7.5 mL oral solution).

3 DOSAGE FORMS AND STRENGTHS

3 DOSAGE FORMS AND STRENGTHS

Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg
Oral Solution: 20 mg/mL
[see Description (11) and How Supplied/Storage and Handling (16)].

4 CONTRAINDICATIONS

4 CONTRAINDICATIONS

LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy.

5.1 Angioedema 5.2 Hypersensitivity 5.3 Withdrawal of Antiepileptic Drugs (AEDs) 5.4 Suicidal Behavior and Ideation 5.5 Peripheral Edema 5.6 Dizziness and Somnolence 5.7 Weight Gain 5.8 Abrupt or Rapid Discontinuation 5.9 Tumorigenic Potential 5.10 Ophtha

6.1 Clinical Trials Experience 6.2 Post-marketing Experience

7 DRUG INTERACTIONS

7 DRUG INTERACTIONS
Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (less than 2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs [see Clinical Pharmacology (12)].

Pharmacodynamics

Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen.

8.1 Pregnancy

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day.

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 ≥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 ≥ 100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥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.

There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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/.

8.2 Labor and Delivery

8.2 Labor and Delivery

The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures greater  than or eqaul to 50 times the mean human exposure (AUC (0–24) of 123 µg - hr/mL) at the maximum recommended clinical dose of 600 mg/day.

8.3 Nursing Mothers

8.3 Nursing Mothers

It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

8.4 Pediatric Use

The safety and efficacy of pregabalin in pediatric patients have not been established.

In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established.

8.5 Geriatric Use

8.5 Geriatric Use

In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older.

In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older.

In controlled clinical studies of LYRICA in epilepsy, there were only 10 patients 65 to 74 years of age, and 2 patients who were 75 years of age or older.

No overall differences in safety and efficacy were observed between these patients and younger patients.

In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy.

LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment [see Dosage and Administration (2.5)].

9.1 Controlled Substance 9.2 Abuse 9.3 Dependence

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

LYRICA is a Schedule V controlled substance.

LYRICA is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).

9.2 Abuse
In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450mg, single dose) received subjective ratings of "good drug effect,""high" and "liking" to a degree that was similar to diazepam (30mg, single dose). In controlled clinical studies in over 5500 patients, 4 % of LYRICA-treated patients and 1 % of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%.

9.3 Dependence
In clinical studies, following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions (5.8)], suggestive of physical dependence.

10 OVERDOSAGE

10 OVERDOSAGE

Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans

There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences.

Treatment or Management of Overdose

There is no specific antidote for overdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA.

Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient's clinical state or in patients with significant renal impairment. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).

11 DESCRIPTION

11 DESCRIPTION

Pregabalin is described chemically as (S)-3-(aminomethyl)-5-methylhexanoic acid. The molecular formula is C8H17NO2 and the molecular weight is 159.23. The chemical structure of pregabalin is:

Pregabalin is a white to off-white, crystalline solid with a pKa1 of 4.2 and a pKa2 of 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.

12.1 Mechanism of Action

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

LYRICA (pregabalin) binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's antinociceptive and antiseizure effects in animals. In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha2-delta containing-calcium channel trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord.

While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABAA, GABAB, or benzodiazepine receptors, does not augment GABAA responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. However, in cultured neurons prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport. Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.

12.3 Pharmacokinetics 12.4 Pharmacokinetics in Special Populations

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD.

Mutagenesis

Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes.

Impairment of Fertility

In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day.

In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD.

In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established.

Human Data

In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalin-treated subjects in mean percent sperm with normal motility was less than 4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied.

13.2 Animal Toxicology and/or Pharmacology

13.2 Animal Toxicology and/or Pharmacology

Dermatopathy

Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies.

Ocular Lesions

Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) greater than or equal to 2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year.

14.1 Neuropathic pain associated with diabetic peripheral neuropathy 14.2 Postherpetic Neuralgia 14.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures 14.4 Management of Fibromyalgia 1 2

14 CLINICAL STUDIES

14.1 Neuropathic pain associated with diabetic peripheral neuropathy
The efficacy of the maximum recommended dose of LYRICA for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in three double-blind, placebo-controlled, multicenter studies with three times a day dosing, two of which studied the maximum recommended dose. Patients were enrolled with either Type 1 or Type 2 diabetes mellitus and a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for 1 to 5 years. A total of 89% of patients completed Studies DPN 1 and DPN 2. The patients had a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). The baseline mean pain scores across the two studies ranged from 6.1 to 6.7. Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin. Patients recorded their pain daily in a diary.

Study DPN 1: This 5-week study compared LYRICA 25, 100, or 200 mg three times a day with placebo. Treatment with LYRICA 100 and 200 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. There was no evidence of a greater effect on pain scores of the 200 mg three times a day dose than the 100 mg three times a day dose, but there was evidence of dose dependent adverse reactions [see Adverse Reactions (6.1)]. For a range of degrees of improvement in pain from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
 
Figure 1: Patients Achieving Various Levels of Pain Relief – Study DPN 1

Study DPN 2: This 8-week study compared LYRICA 100 mg three times a day with placebo. Treatment with LYRICA 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figure 2 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
 
Figure 2: Patients Achieving Various Levels of Pain Relief – Study DPN 2

14.2 Postherpetic Neuralgia
The efficacy of LYRICA for the management of postherpetic neuralgia was established in three double-blind, placebo-controlled, multicenter studies. These studies enrolled patients with neuralgia persisting for at least 3 months following healing of herpes zoster rash and a minimum baseline score of ≥4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). Seventy-three percent of patients completed the studies. The baseline mean pain scores across the 3 studies ranged from 6 to 7. Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin. Patients recorded their pain daily in a diary.

Study PHN 1: This 13-week study compared LYRICA 75, 150, and 300 mg twice daily with placebo. Patients with creatinine clearance (CLcr) between 30 to 60 mL/min were randomized to 75 mg, 150 mg, or placebo twice daily. Patients with creatinine clearance greater than 60 mL/min were randomized to 75 mg, 150 mg, 300 mg or placebo twice daily. In patients with creatinine clearance greater than 60 mL/min treatment with all doses of LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Despite differences in dosing based on renal function, patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by higher rates of discontinuation due to adverse reactions. For various degrees of improvement in pain from baseline to study endpoint, Figure 3 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.

Figure 3: Patients Achieving Various Levels of Pain Relief – Study PHN 1

Study PHN 2: This 8-week study compared LYRICA 100 or 200 mg three times a day with placebo, with doses assigned based on creatinine clearance. Patients with creatinine clearance between 30 to 60 mL/min were treated with 100 mg three times a day, and patients with creatinine clearance greater than 60 mL/min were treated with 200 mg three times daily. Treatment with LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figure 4 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
 

Figure 4: Patients Achieving Various Levels of Pain Relief – Study PHN 2

Study PHN 3: This 8-week study compared LYRICA 50 or 100 mg three times a day with placebo with doses assigned regardless of creatinine clearance. Treatment with LYRICA 50 and 100 mg three times a day statistically significantly improved the endpain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by markedly higher rates of discontinuation due to adverse reactions. For various degrees of improvement in pain from baseline to study endpoint, Figure 5 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
 
Figure 5: Patients Achieving Various Levels of Pain Relief – Study PHN 3

14.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures
The efficacy of LYRICA as adjunctive therapy in partial onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies in adult patients. Patients were enrolled who had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant antiepileptic drugs (AEDs). Patients taking gabapentin were required to discontinue gabapentin treatment 1 week prior to entering baseline. During an 8-week baseline period, patients had to experience at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks. The mean duration of epilepsy was 25 years in these 3 studies and the mean and median baseline seizure frequencies were 22.5 and 10 seizures per month, respectively. Approximately half of the patients were taking 2 concurrent AEDs at baseline. Among the LYRICA-treated patients, 80% completed the double-blind phase of the studies.

Table 7 shows median baseline seizure rates and median percent reduction in seizure frequency by dose.

16 HOW SUPPLIED/STORAGE AND HANDLING

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

17.1 Medication Guide 17.2 Angioedema 17.3 Hypersensitivity 17.4 Suicidal Thinking and Behavior 17.5 Dizziness and Somnolence 17.6 Weight Gain and Edema 17.7 Abrupt or Rapid Discontinuation 17.8 Ophthalmological Effects 17.9 Creatine Kinase Elevations 17

17 PATIENT COUNSELING INFORMATION

See the FDA-approved Medication Guide.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking PROZAC as monotherapy or in combination with olanzapine. When using PROZAC and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.

17.1 General Information

Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with fluoxetine capsules and to reread it each time the prescription is renewed.

Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluoxetine capsules and should counsel them in its appropriate use. Healthcare providers should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking PROZAC.

When using PROZAC and olanzapine in combination, also refer to the Medication Guide for Symbyax.

17.2 Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Box Warning and Warnings and Precautions ( 5.1)].

17.3 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions

Patients should be cautioned about the risk of serotonin syndrome or NMS-like reactions with the concomitant use of fluoxetine and triptans, tramadol, or other serotonergic agents [see Warnings and Precautions ( 5.2) and Drug Interactions ( 7.3)].

Patients should be advised of the signs and symptoms associated with serotonin syndrome or NMS-like reactions that may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, in which the symptoms may include hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be cautioned to seek medical care immediately if they experience these symptoms.

17.4 Allergic Reactions and Rash

Patients should be advised to notify their physician if they develop a rash or hives [see Warnings and Precautions ( 5.3)]. Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms.

17.5 Abnormal Bleeding

Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding [see Warnings and Precautions ( 5.7) and Drug Interactions ( 7.6)]. Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking PROZAC.

17.6 Hyponatremia

Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including PROZAC. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death [see Warnings and Precautions ( 5.8)].

17.7 Potential for Cognitive and Motor Impairment

PROZAC may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected [see Warnings and Precautions ( 5.11)].

17.8 Use of Concomitant Medications

Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including Symbyax®, Sarafem®, or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while on PROZAC.

17.9 Discontinuation of Treatment

Patients should be advised to take PROZAC exactly as prescribed, and to continue taking fluoxetine as prescribed even after their symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking PROZAC without consulting their physician [see Warnings and Precautions ( 5.13)]. Patients should be advised to consult with their healthcare provider if their symptoms do not improve with PROZAC.

17.10 Use in Specific Populations

Pregnancy — Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations ( 8.1)].

Nursing Mothers — Patients should be advised to notify their physician if they intend to breast-feed an infant during therapy. Because PROZAC is excreted in human milk, nursing while taking fluoxetine is not recommended [see Use in Specific Populations ( 8.3)].

Pediatric Use — PROZAC is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions ( 5.1)]. Limited evidence is available concerning the longer-term effects of fluoxetine on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving fluoxetine.Safety and effectiveness of PROZAC and olanzapine in combination in patients less than 18 years of age have not been established [see Warnings and Precautions ( 5.6) and Use in Specific Populations ( 8.4)].

Literature revised October 29, 2009

Eli Lilly and Company, Indianapolis, IN 46285, USA

Copyright © 1987, 2009, Eli Lilly and Company. All rights reserved.

PV 7430 DPP

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