Pregabalin Extended Release 330 mg Tablet, Film Coated, Extended Release, 30-count — NDC 50228-464-30 (Billing 50228-0464-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Pregabalin binds with high affinity to the alpha 2 -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 alpha 2 -delta subunit may be involved in pregabalin's anti-nociceptive 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 alpha 2 -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 GABA A , GABA B , or benzodiazepine receptors, does not augment GABA A 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.

12.3Pharmacokinetics Pregabalin extended-release tablets has linear pharmacokinetics with dose-proportional increases in maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) from 82.5 mg/day to 660 mg/day. Following repeated administration, steady state is achieved within approximately 48 to 72 hours. Pregabalin extended-release tablets administered once daily following an evening meal has equivalent AUC and lower C max relative to a comparative dose of LYRICA administered without food twice daily (Table 5).

Variability in C max and AUC for pregabalin extended-release tablets is less than or equal to 25%. Table 5. Steady-State Pharmacokinetics for pregabalin extended-release tablets 165 mg Once Daily and LYRICA 75 mg Twice Daily Pregabalin extended-release tablets Once Daily LYRICA BID Note: Geometric mean (%CV) for AUC 24 , C max , C min ; median (range) for T max .

Abbreviations: AUC 24 =area under the curve over 24 hours; BID=every 12 hours; C max =peak concentrations; C min =minimum concentrations; N=Number of subjects ; T max =time to peak concentrations N 24 24 C max (mcg/mL) 2.0 (17) 3.2 (21) T max (h) 8.0 (5.0 – 12.0) 0.7 (0.7 – 1.5) AUC 24 (mcg.h/mL) 29.4 (17) 31.5 (18) C min (mcg/mL) 0.44 (24) 0.59 (25) Absorption Pregabalin is absorbed from the small intestine and proximal colon. Pregabalin extended-release tablets absorption is linear and dose proportional. The bioavailability of pregabalin extended-release tablets is reduced if taken on an empty stomach.

The AUC is approximately 30% lower when pregabalin extended-release tablets is administered fasted relative to following an evening meal. When pregabalin extended-release tablets is administered following a 600 to 750 calorie (50% carbohydrates, 20% protein, 30% fat) evening meal, peak plasma concentrations occur within approximately 8 to 10 hours and AUC is approximately 93% to 97% relative to a comparative dose of LYRICA. The rate and extent of pregabalin extended-release tablets absorption is similar when administered following a 400 to 500 calorie, 30% fat or an 800 to 1000 calorie, 15%, 30%, or… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Pregabalin binds with high affinity to the alpha 2 -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 alpha 2 -delta subunit may be involved in pregabalin's anti-nociceptive 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 alpha 2 -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 GABA A , GABA B , or benzodiazepine receptors, does not augment GABA A 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.

12.3Pharmacokinetics Pregabalin extended-release tablets has linear pharmacokinetics with dose-proportional increases in maximum plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) from 82.5 mg/day to 660 mg/day. Following repeated administration, steady state is achieved within approximately 48 to 72 hours. Pregabalin extended-release tablets administered once daily following an evening meal has equivalent AUC and lower C max relative to a comparative dose of LYRICA administered without food twice daily (Table 5).

Variability in C max and AUC for pregabalin extended-release tablets is less than or equal to 25%. Table 5. Steady-State Pharmacokinetics for pregabalin extended-release tablets 165 mg Once Daily and LYRICA 75 mg Twice Daily Pregabalin extended-release tablets Once Daily LYRICA BID Note: Geometric mean (%CV) for AUC 24 , C max , C min ; median (range) for T max .

Abbreviations: AUC 24 =area under the curve over 24 hours; BID=every 12 hours; C max =peak concentrations; C min =minimum concentrations; N=Number of subjects ; T max =time to peak concentrations N 24 24 C max (mcg/mL) 2.0 (17) 3.2 (21) T max (h) 8.0 (5.0 – 12.0) 0.7 (0.7 – 1.5) AUC 24 (mcg.h/mL) 29.4 (17) 31.5 (18) C min (mcg/mL) 0.44 (24) 0.59 (25) Absorption Pregabalin is absorbed from the small intestine and proximal colon. Pregabalin extended-release tablets absorption is linear and dose proportional. The bioavailability of pregabalin extended-release tablets is reduced if taken on an empty stomach.

The AUC is approximately 30% lower when pregabalin extended-release tablets is administered fasted relative to following an evening meal. When pregabalin extended-release tablets is administered following a 600 to 750 calorie (50% carbohydrates, 20% protein, 30% fat) evening meal, peak plasma concentrations occur within approximately 8 to 10 hours and AUC is approximately 93% to 97% relative to a comparative dose of LYRICA. The rate and extent of pregabalin extended-release tablets absorption is similar when administered following a 400 to 500 calorie, 30% fat or an 800 to 1000 calorie, 15%, 30%, or 50% fat evening meal.

When pregabalin extended-release tablets is administered following an 800 to 1000 calorie (50% carbohydrates, 20% protein, 30% fat) morning meal, peak plasma concentrations occur within approximately 12 hours and AUC is 99% relative to a comparative dose of LYRICA. AUC decreases approximately 13% to 25% when pregabalin extended-release tablets is administered following a 400 to 500 calorie or 600 to 750 calorie (50% carbohydrates, 20% protein, 30% fat) morning meal relative to the 800 to 1000 calorie meal, while C max remains the same.

Distribution Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately

0.5L/kg. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys.

In addition, pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. Elimination Metabolism Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 90% of the administered dose was recovered in the urine as unchanged pregabalin.

The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, pregabalin (S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys. Excretion Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hours in subjects with normal renal function.

Mean renal clearance was estimated to be 67.0 to 80.9 mL/min in young… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Management of Postherpetic Neuralgia (Study PHN CR) Support for efficacy of pregabalin extended-release tablets for the management of PHN and diabetic peripheral neuropathy (DPN) was based on the efficacy of LYRICA for these indications along with an adequate and well-controlled study in adults with PHN. This 19-week randomized withdrawal study compared daily doses of pregabalin extended-release tablets 82.5 mg, 165 mg, 247.5 mg, 330 mg, 495 mg, or 660 mg with placebo. Those enrolled were required to have pain present for more than 3 months after healing of the herpes zoster skin rash and a baseline pain score of greater than or equal to 4 on the numeric rating scale (NRS)-Pain (assessed over a 1 week recall period).

The baseline mean pain scores were 6.83 for pregabalin extended-release tablets-treated patients vs. 6.85 for placebo-treated patients. A total of 82.4% of patients completed the single-blind phase of the study.

Patients were considered responders if they had at least a 50% reduction in pain in the single-blind phase. Those who responded to treatment were then randomized in the double-blind phase to treatment with either the pregabalin extended-release tablets dose achieved in the single-blind phase or placebo. Patients were treated for up to 3 months following randomization.

A total of 87.5% of pregabalin extended-release tablets-treated patients and 78% of placebo-treated patients completed the double-blind phase of the study. Pregabalin extended-release tablets treatment demonstrated statistically significant improvement in the endpoint change in mean pain score from baseline compared to placebo. For a range of levels of improvement in pain intensity 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. In the pregabalin extended-release tablets group, 79.8% of subjects achieved at least a 30% improvement and 73.6% at least 50% improvement in pain intensity.

In the placebo group, 64.9% of subjects achieved at least a 30% improvement and 54.6% at least a 50% improvement in pain intensity. Figure 1. Percent of Patients Achieving Various Levels of Improvement in Pain Intensity (N=413) PRINCIPAL DISPLAY PANEL - 50 mg/500 mg Tablet Bottle Label

14.2Management of Fibromyalgia (Study FM CR) A double-blind, placebo-controlled, randomized withdrawal trial of pregabalin extended-release tablets in adults with fibromyalgia failed to demonstrate efficacy.

14.3Adjunctive Therapy for Adult Patients with Partial Onset Seizures A double-blind, placebo-controlled, randomized trial of pregabalin extended-release tablets as adjunctive therapy in adults with partial onset seizures failed to demonstrate efficacy.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in 2 strains of mice (B6C3F1 and CD-1) given pregabalin (200 mg/kg, 1000 mg/kg, or 5000 mg/kg) in the diet for 2 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 human dose (MRD) of 660 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established.

No evidence of carcinogenicity was seen in 2 studies in Wistar rats following dietary administration of pregabalin for 2 years at doses (50 mg/kg, 150 mg/kg, or 450 mg/kg in males and 100 mg/kg, 300 mg/kg, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 15 and 26 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 mg/kg 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 to 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 4 times human exposure at the MRD of 660 mg/day. In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 mg/kg to 1250 mg/kg) in general toxicology studies of 4 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 10 times human exposure at the MRD.

In a fertility study in which female rats were given pregabalin (500 mg/kg, 1250 mg/kg, 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 10 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established.

13.2Animal 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 MRD of 660 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 2 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 660 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in 2 stra… [Excerpted — this section continues on DailyMed.]