Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies

In premarketing controlled trials of all adult populations combined, 14% of patients treated with pregabalin and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and less than 1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the pregabalin group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each).

Most Common Adverse Reactions in All Controlled Clinical Studies in Adults

In premarketing controlled trials of all adult patient populations combined (including DPN, PHN, and adult patients with partial-onset seizures), dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and "thinking abnormal" (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with pregabalin than by subjects treated with placebo (greater than or equal to 5% and twice the rate of that seen in placebo).

Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy

Controlled Studies in Postherpetic Neuralgia

Controlled Studies of Adjunctive Therapy for Partial-Onset Seizures in Adult Patients

Controlled Study of Adjunctive Therapy for Partial-Onset Seizures in Patients 4 to Less Than 17 Years of Age

Controlled Study of Adjunctive Therapy for Partial-Onset Seizures in Patients 1 Month to Less Than 4 Years of Age

Controlled Studies with Fibromyalgia

Controlled Studies in Neuropathic Pain Associated with Spinal Cord Injury

Other Adverse Reactions Observed During the Clinical Studies of Pregabalin

Following is a list of treatment-emergent adverse reactions reported by patients treated with pregabalin during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening.

Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section (5).

Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever, Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction, Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock

Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation

Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess

Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia, Alanine aminotransferase increased, Aspartate aminotransferase increased

Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria

Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm

Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypoesthesia, Libido decreased, Nystagmus, Paresthesia, Sedation, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus

Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn

Skin and Appendages – Frequent: Pruritus, Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule

Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis

Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis

Comparison of Gender and Race

The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to pregabalin during pregnancy. To provide information regarding the effects of in utero exposure to pregabalin, physicians are advised to recommend that pregnant patients taking pregabalin 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 pregabalin 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

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 pregabalin on milk production or the effects of pregabalin 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 (5.8)]. Because of the potential risk of tumorigenicity, breastfeeding is not recommended during treatment with pregabalin.

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. Pregabalin 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 pregabalin on milk production. Infants did not receive breast milk obtained during the dosing period, therefore, the effects of pregabalin on the breast fed infant were not evaluated.

Infertility

Neuropathic Pain Associated with Diabetic Peripheral Neuropathy, Postherpetic Neuralgia, and Neuropathic Pain Associated with Spinal Cord Injury

Safety and effectiveness in pediatric patients have not been established.

Fibromyalgia

Safety and effectiveness in pediatric patients have not been established.

A 15-week, placebo-controlled trial was conducted with 107 pediatric patients with fibromyalgia, ages 12 through 17 years, at pregabalin total daily doses of 75–450 mg per day. The primary efficacy endpoint of change from baseline to Week 15 in mean pain intensity (derived from an 11-point numeric rating scale) showed numerically greater improvement for the pregabalin-treated patients compared to placebo-treated patients, but did not reach statistical significance. The most frequently observed adverse reactions in the clinical trial included dizziness, nausea, headache, weight increased, and fatigue. The overall safety profile in adolescents was similar to that observed in adults with fibromyalgia.

Adjunctive Therapy for Partial-Onset Seizures

Safety and effectiveness in pediatric patients below the age of 1 month have not been established.

Juvenile Animal Data

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 greater than or equal to 50 mg/kg. The neurobehavioral changes of acoustic startle persisted at greater than or equal to 250 mg/kg and locomotor activity and water maze performance at greater than or equal to 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.

Absorption and Distribution

Following oral administration of pregabalin capsules under fasting conditions, peak plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is greater than or equal to 90% and is independent of dose. Following single- (25 to 300 mg) and multiple-dose (75 to 900 mg/day) administration, maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) values increase linearly. Following repeated administration, steady state is achieved within 24 to 48 hours. Multiple-dose pharmacokinetics can be predicted from single-dose data.

The rate of pregabalin absorption is decreased when given with food, resulting in a decrease in Cmax of approximately 25% to 30% and an increase in Tmax to approximately 3 hours. However, administration of pregabalin with food has no clinically relevant effect on the total absorption of pregabalin. Therefore, pregabalin can be taken with or without food.

Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/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.

Metabolism and Elimination

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.

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 healthy subjects. Because pregabalin is not bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin elimination is nearly proportional to creatinine clearance (CLcr) [see Dosage and Administration (2.7)].

Pharmacokinetics in Specific Populations

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.

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.

Study DPN 1: This 5-week study compared pregabalin 25, 100, or 200 mg three times a day with placebo. Treatment with pregabalin 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 levels of improvement in pain intensity from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that level 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 Improvement in Pain Intensity – Study DPN 1

Study DPN 2: This 8-week study compared pregabalin 100 mg three times a day with placebo. Treatment with pregabalin 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 levels of improvement in pain intensity from baseline to study endpoint, Figure 2 shows the fraction of patients achieving that level 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 Improvement in Pain Intensity– Study DPN 2

Study PHN 1: This 13-week study compared pregabalin 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 pregabalin 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 pregabalin 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 levels of improvement in pain intensity from baseline to study endpoint, Figure 3 shows the fraction of patients achieving that level 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 Improvement in Pain Intensity– Study PHN 1

Study PHN 2: This 8-week study compared pregabalin 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 pregabalin 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 levels of improvement in pain intensity from baseline to study endpoint, Figure 4 shows the fraction of patients achieving those levels 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 Improvement in Pain Intensity – Study PHN 2

Study PHN 3: This 8-week study compared pregabalin 50 or 100 mg three times a day with placebo with doses assigned regardless of creatinine clearance. Treatment with pregabalin 50 and 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. Patients with creatinine clearance between 30 to 60 mL/min tolerated pregabalin 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 levels of improvement in pain intensity from baseline to study endpoint, Figure 5 shows the fraction of patients achieving that level 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 Improvement in Pain Intensity– Study PHN 3

Adjunctive Therapy for Partial-Onset Seizures in Adult Patients

The efficacy of pregabalin as adjunctive therapy for partial-onset seizures in adult patients was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies. 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 pregabalin-treated patients, 80% completed the double-blind phase of the studies.

Table 11 shows median baseline seizure rates and median percent reduction in seizure frequency by dose.

In the first study (E1), there was evidence of a dose-response relationship for total daily doses of pregabalin between 150 and 600 mg/day; a dose of 50 mg/day was not effective. In the first study (E1), each daily dose was divided into two equal doses (twice a day dosing). In the second study (E2), each daily dose was divided into three equal doses (three times a day dosing). In the third study (E3), the same total daily dose was divided into two equal doses for one group (twice a day dosing) and three equal doses for another group (three times a day dosing). While the three times a day dosing group in Study E3 performed numerically better than the twice a day dosing group, this difference was small and not statistically significant.

A secondary outcome measure included the responder rate (proportion of patients with greater than or equal to 50% reduction from baseline in partial seizure frequency). The following figure displays responder rate by dose for two of the studies.

Figure 6: Responder Rate by Adjunctive Epilepsy Study

Figure 7: Seizure Reduction by Dose (All Partial-Onset Seizures) for Studies E1, E2, and E3

Subset evaluations of the antiseizure efficacy of pregabalin showed no clinically important differences as a function of age, gender, or race.

Adjunctive Therapy for Partial-Onset Seizures in Pediatric Patients 4 to Less Than 17 Years of Age

The efficacy of pregabalin as adjunctive therapy in partial-onset seizures was established in a 12-week, randomized, double-blind, placebo-controlled, multicenter study in pediatric patients 4 years to less than 17 years of age with partial-onset seizures with or without secondary generalization. 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 6 years and the mean and median baseline seizure frequencies were 57 and 18 seizures per month, respectively. Approximately 74% of the patients were taking 2 to 3 concurrent AEDs at baseline. Among the pregabalin-treated patients, 87% completed the double-blind phase of the study.

In this study, pregabalin 2.5 mg/kg/day (maximum 150 mg/day) and 10 mg/kg/day (maximum 600 mg/day) were compared to placebo. Administration of each daily dose was divided into two equal doses (twice a day dosing). Because of higher weight-normalized clearance in patients with body weight less than 30 kg [see Clinical Pharmacology (12.3)], the pregabalin dose was increased by 40% to 3.5 mg/kg/day for patients weighing less than 30 kg randomized to the 2.5 mg/kg/day group or to 14 mg/kg/day for patients randomized to the 10 mg/kg/day group.

Table 12 shows median baseline seizure rates, median percent change from baseline in seizure rates, and percent difference relative to placebo (derived from the primary analysis model) by dose.

There was evidence of a dose-response relationship for total daily doses of pregabalin between 2.5 mg/kg/day and 10 mg/kg/day. A significant improvement in seizure rate was observed for pregabalin 10 mg/kg/day group compared with placebo. While the 2.5 mg/kg/day group performed numerically better than placebo, this difference was not statistically significant.

A key secondary efficacy measure, the responder rate (proportion of patients with greater than or equal to 50% reduction from baseline in partial seizure frequency) showed improvements for pregabalin groups compared with placebo. The following figure displays responder rate by dose:

Figure 8: Responder Rate (Greater than or Equal to 50% Reduction)

Adjunctive Therapy for Partial-Onset Seizures in Pediatric Patients 1 Month to Less Than 4 Years of Age

The efficacy of pregabalin as adjunctive therapy in partial-onset seizures was established in a 14-day, randomized, double-blind, placebo-controlled, multicenter study in children 1 month to less than 4 years of age with partial-onset seizures with or without secondary generalization. The youngest patient evaluated was 3 months of age. During a 48- to 72-hour baseline video electroencephalogram (EEG), patients had to experience at least 2 partial-onset seizures. The mean duration of epilepsy at baseline was 1.6 years and the mean and median baseline seizure frequencies were 12.2 and 4.4 seizures per day, respectively. Approximately 33%, 50%, and 17% of patients were taking 1, 2, or 3 concurrent AEDs at baseline, respectively. Among the pregabalin-treated patients, 97% completed the double-blind phase of the study.

In this study, pregabalin 7 mg/kg/day and 14 mg/kg/day were compared to placebo. Administration of each daily dose was divided into three equal doses (three times a day dosing). The primary endpoint was the 24-hour partial-onset seizure rate based on the comparison of the baseline video EEG to a repeat 48–72 hour video EEG performed at the end of 14 days of double-blind treatment.

Table 13 shows median baseline seizure rates, median percent change from baseline in seizure rates, and percent difference relative to placebo (derived from the primary analysis model) by dose.

A significant improvement in partial-onset seizure rate was observed for pregabalin 14 mg/kg/day group compared with placebo. Patients treated with pregabalin 7 mg/kg/day did not show improvement relative to placebo.

Responder rates (≥50% or greater reduction in partial-onset seizure frequency) were a secondary efficacy parameter; patients treated with pregabalin 14 mg/kg/day showed numerical improvement compared with placebo, while patients treated with pregabalin 7 mg/kg/day did not show improvement relative to placebo: the responder rates were 53.6%, 30.5%, and 41.5% for pregabalin 14 mg/kg/day, pregabalin 7 mg/kg/day, and placebo, respectively.

Study F1: This 14-week study compared pregabalin total daily doses of 300 mg, 450 mg and 600 mg with placebo. Patients were enrolled with a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numeric pain rating scale and a score of greater than or equal to 40 mm on the 100 mm pain visual analog scale (VAS). The baseline mean pain score in this trial was 6.7. Responders to placebo in an initial one-week run-in phase were not randomized into subsequent phases of the study. A total of 64% of patients randomized to pregabalin completed the study. There was no evidence of a greater effect on pain scores of the 600 mg daily dose than the 450 mg daily dose, but there was evidence of dose--dependent adverse reactions [see Adverse Reactions (6.1)]. Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study. The results are summarized in Figure 9 and Table 14.

For various levels of improvement in pain intensity from baseline to study endpoint, Figure 9 shows the fraction of patients achieving that level of improvement. The figure is cumulative. 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 9: Patients Achieving Various Levels of Improvement in Pain Intensity – Fibromyalgia Study F1

Study F2: This randomized withdrawal study compared pregabalin with placebo. Patients were titrated during a 6-week open-label dose optimization phase to a total daily dose of 300 mg, 450 mg, or 600 mg. Patients were considered to be responders if they had both: 1) at least a 50% reduction in pain (VAS) and, 2) rated their overall improvement on the PGIC as "much improved" or "very much improved." Those who responded to treatment were then randomized in the double-blind treatment phase to either the dose achieved in the open-label phase or to placebo. Patients were treated for up to 6 months following randomization. Efficacy was assessed by time to loss of therapeutic response, defined as 1) less than 30% reduction in pain (VAS) from open-label baseline during two consecutive visits of the double-blind phase, or 2) worsening of FM symptoms necessitating an alternative treatment. Fifty-four percent of patients were able to titrate to an effective and tolerable dose of pregabalin during the 6-week open-label phase. Of the patients entering the randomized treatment phase assigned to remain on pregabalin, 38% of patients completed 26 weeks of treatment versus 19% of placebo-treated patients.

When considering return of pain or withdrawal due to adverse events as loss of response (LTR), treatment with pregabalin resulted in a longer time to loss of therapeutic response than treatment with placebo. Fifty-three percent of the pregabalin-treated subjects compared to 33% of placebo patients remained on study drug and maintained a therapeutic response to Week 26 of the study. Treatment with pregabalin also resulted in a longer time to loss of response based on the FIQ1, and longer time to loss of overall assessment of patient status, as measured by the PGIC2.

Figure 10: Time to Loss of Therapeutic Response, Fibromyalgia Study F2 (Kaplan-Meier Analysis)

1

Time to worsening of the FIQ was defined as the time to a 1-point increase from double-blind baseline in each of the subscales, and a 5-point increase from double-blind baseline evaluation for the FIQ total score.

2

Time to PGIC lack of improvement was defined as time to PGIC assessments indicating less improvement than "much improvement."

Study SCI 1: This 12-week, randomized, double-blind, parallel-group, multicenter, flexible dose (150–600 mg/day) study compared pregabalin with placebo. The 12-week study consisted of a 3-week dose adjustment phase and a 9-week dose maintenance phase. Treatment with pregabalin 150–600 mg/day statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline. The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 12 is presented in Figure 11. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.

Figure 11: Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 1

Study SCI 2: This 16-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, flexible dose (150–600 mg/day, in increments of 150 mg) study compared the efficacy, safety and tolerability of pregabalin with placebo. The 16-week study consisted of a 4-week dose adjustment phase and a 12-week dose maintenance phase. Treatment with pregabalin statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline. The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 16 is presented in Figure 12. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.

Figure 12: Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 2