Prescription Drug Information: PREGABALIN (Page 4 of 9)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of pregabalin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System Disorders – Headache

Gastrointestinal Disorders – Nausea, Diarrhea

Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement

In addition, there are postmarketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when pregabalin was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. There are also postmarketing reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications.

7 DRUG INTERACTIONS

Since pregabalin 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 pregabalin 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 pregabalin and commonly used antiepileptic drugs [see Clinical Pharmacology (12)].

Pharmacodynamics

Multiple oral doses of pregabalin 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 pregabalin was co-administered with these drugs. No clinically important effects on respiration were seen.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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 capsules 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 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Advise pregnant women of the potential risk to a fetus.

Data

Animal Data

When pregnant rats were given pregabalin (500, 1,250, or 2,500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1,250 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 pregabalin (250, 500, or 1,250 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 pregabalin (50, 100, 250, 1,250, or 2,500 mg/kg) throughout gestation and lactation, offspring growth was reduced at greater than or equal to 100 mg/kg and offspring survival was decreased at greater than or equal to 250 mg/kg. The effect on offspring survival was pronounced at doses greater than or equal to 1,250 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 1,250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD.

In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures greater than or equal to 50 times the mean human exposure (AUC (0–24) of 123 mcg∙hr/mL) at the MRD.

8.2 Lactation

Risk Summary

Small amounts of pregabalin have been detected in the milk of lactating women. A pharmacokinetic study in lactating women detected pregabalin in breast milk at average steady state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose [see Data]. The study did not evaluate the effects of 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.

8.3 Females and Males of Reproductive Potential

Infertility

Male

Effects on Spermatogenesis

In a randomized, double-blind, placebo-controlled non-inferiority study to assess the effect of pregabalin on sperm characteristics, healthy male subjects received pregabalin at a daily dose up to 600 mg (n=111) or placebo (n=109) for 13 weeks (one complete sperm cycle) followed by a 13-week washout period (off-drug). A total of 65 subjects in the pregabalin group (59%) and 62 subjects in the placebo group (57%) were included in the per protocol (PP) population. These subjects took study drug for at least 8 weeks, had appropriate timing of semen collections and did not have any significant protocol violations. Among these subjects, approximately 9% of the pregabalin group (6/65) vs. 3% in the placebo group (2/62) had greater than or equal to 50% reduction in mean sperm concentrations from baseline at Week 26 (the primary endpoint). The difference between pregabalin and placebo was within the pre-specified non-inferiority margin of 20%. There were no adverse effects of pregabalin on sperm morphology, sperm motility, serum FSH or serum testosterone levels as compared to placebo. In subjects in the PP population with greater than or equal to 50% reduction in sperm concentration from baseline, sperm concentrations were no longer reduced by greater than or equal to 50% in any affected subject after an additional 3 months off-drug. In one subject, however, subsequent semen analyses demonstrated reductions from baseline of greater than or equal to 50% at 9 and 12 months off-drug. The clinical relevance of these data is unknown.

In the animal fertility study with pregabalin in male rats, adverse reproductive and developmental effects were observed [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

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.

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.
Information describing a clinical study in which efficacy was not demonstrated in patients is approved for Pfizer Inc.’s Lyrica® (pregabalin) products. Additional pediatric use information is approved for Pfizer’s LYRICA (pregabalin) Capsules and Oral Solution products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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