PREGABALIN capsule

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

PREGABALIN (UNII: 55JG375S6M) (PREGABALIN - UNII:55JG375S6M)

Available from:

Alembic Pharmaceuticals Inc.

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Pregabalin capsule is indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy • Management of postherpetic neuralgia • Adjunctive therapy for the treatment of partial-onset seizures in patients 1 month of age and older • Management of fibromyalgia • Management of neuropathic pain associated with spinal cord injury  Pregabalin 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 [see Warnings and Precautions (5.2)]. 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 Observational studies on the use of pregabalin during pregnancy suggest a possible small increase in the rate of overall major birth defects, but there was no consistent or specific pattern of major birth defects identified (see Data). Available postmarketing data on miscarriage and other maternal, fetal, and long term developmental adverse effects were insufficient to identify risk associated with pregabalin. 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 Human Data One database study, which included over 2,700 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 3,063,251 pregnancies unexposed to antiepileptics demonstrated prevalence ratios for major malformations overall of 1.14 (CI 95% 0.96 to 1.35) for pregabalin, 1.29 (CI 95% 1.01 to 1.65) for lamotrigine, 1.39 (CI 95% 1.07 to 1.82) for duloxetine, and 1.24 (CI 95% 1 to 1.54) for exposure to either lamotrigine or duloxetine. Important study limitations include uncertainty of whether women who filled a prescription took the medication and inability to adequately control for the underlying disease and other potential confounders. A published study included results from two separate databases. One database, which included 353 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 368,489 pregnancies unexposed to antiepileptics, showed no increase in risk of major birth defects; adjusted relative risk 0.87 (CI 95% 0.53 to 1.42). The second database, which included 118 pregnancies exposed to pregabalin (monotherapy) during the first trimester compared to 380,347 pregnancies unexposed to antiepileptics, suggested a small increase in risk of major birth defects; adjusted relative risk 1.26 (CI 95% 0.64 to 2.49). The risk estimates crossed the null, and the study had limitations similar to the prior study. Other published epidemiologic studies reported inconsistent findings. No specific pattern of birth defects was identified across studies. All of the studies had limitations due to their retrospective design. Animal Data When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given pregabalin (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 pregabalin (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at greater than or equal to 100 mg/kg and offspring survival was decreased at greater than or equal to 250 mg/kg. The effect on offspring survival was pronounced at doses greater than or equal to 1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at greater than or equal to 250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures greater than or equal to 50 times the mean human exposure (AUC (0-24) of 123 µg∙hr/mL) at the MRD. 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 (5.9)] . 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 Males 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)]. 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 to 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. 4 to Less Than 17 Years of Age with Partial-Onset Seizures The safety and effectiveness of pregabalin as adjunctive treatment for partial-onset seizures in pediatric patients 4 to less than 17 years of age have been established in a 12-week, double-blind, placebo-controlled study (n=295) [see Clinical Studies (14.3)]. Patients treated with pregabalin 10 mg/kg/day had, on average, a 21.0% greater reduction in partial-onset seizures than patients treated with placebo (p=0.0185). Patients treated with pregabalin 2.5 mg/kg/day had, on average, a 10.5% greater reduction in partial-onset seizures than patients treated with placebo, but the difference was not statistically significant (p=0.2577). Responder rates (50% or greater reduction in partial-onset seizure frequency) were a key secondary efficacy parameter and showed numerical improvement with pregabalin compared with placebo: the responder rates were 40.6%, 29.1%, and 22.6%, for pregabalin 10 mg/kg/day, pregabalin 2.5 mg/kg/day, and placebo, respectively. The most common adverse reactions (≥5%) with pregabalin in this study were somnolence, weight increased, and increased appetite [see Adverse Reactions (6.1)]. The use of pregabalin 2.5 mg/kg/day in pediatric patients is further supported by evidence from adequate and well-controlled studies in adults with partial-onset seizures and pharmacokinetic data from adult and pediatric patients [see Clinical Pharmacology (12.3)] . 1 Month to Less than 4 Years of Age with Partial-Onset Seizures The safety and effectiveness of pregabalin as adjunctive treatment for partial-onset seizures in pediatric patients 1 month to less than 4 years of age have been established in a 14-day double-blind, placebo-controlled study (N=175) [see Clinical Studies (14.3)] . The youngest subject evaluated was 3 months of age; use in patients 1 month to less than 3 months of age is supported by additional pharmacokinetic analyses. Patients treated with pregabalin 14 mg/kg/day had, on average, 43.9% greater reduction in partial-onset seizures than patients treated with placebo (p=0.0223). In addition, pediatric patients treated with pregabalin 14 mg/kg/day showed numerical improvement in responder rates (≥50% reduction in partial-onset seizure frequency) compared with placebo (53.6% versus 41.5%). Patients treated with pregabalin 7 mg/kg/day did not show improvement relative to placebo for either endpoint. The most common dose-related adverse reactions (≥5%) with pregabalin in this study were somnolence, pneumonia, and viral infection [see Adverse Reactions (6.1)] . 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. In controlled clinical studies of pregabalin 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 pregabalin 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 pregabalin 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 pregabalin 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. Pregabalin is known to be substantially excreted by the kidney, and the risk of toxic reactions to pregabalin may be greater in patients with impaired renal function. Because pregabalin is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment [see Dosage and Administration (2.7)] . Pregabalin is eliminated primarily by renal excretion and dose adjustment is recommended for adult patients with renal impairment [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)]. The use of pregabalin in pediatric patients with compromised renal function has not been studied. Pregabalin is a Schedule V controlled substance. Pregabalin 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 pregabalin misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior). In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, pregabalin (450 mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4 % of pregabalin-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%. In clinical studies, following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions (5.6)] , consistent with physical dependence. In the postmarketing experience, in addition to these reported symptoms there have also been reported cases of anxiety and hyperhidrosis.

Product summary:

Pregabalin Capsules are available containing 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg and 300 mg of pregabalin, USP. 25 mg capsules are opaque white/opaque white, size ‘4’, hard gelatin capsules, radially imprinted with ‘A’ on Cap and ‘140’ on body with black ink, filled with white to off-white powder. NDC 62332-119-30                bottle of 30 capsules NDC 62332-119-90                bottle of 90 capsules NDC 62332-119-91                bottle of 1000 capsules NDC 62332-119-10                carton of 100 (10 x 10) unit-dose capsules 50 mg capsules are   opaque white/opaque orange, size ‘2’, hard gelatin capsules, radially imprinted with ‘A’ on Cap and ‘141’ on body with black ink, filled with white to off-white powder. NDC 62332-120-30                bottle of 30 capsules NDC 62332-120-90                bottle of 90 capsules NDC 62332-120-91                bottle of 1000 capsules NDC 62332-120-10                carton of 100 (10 x 10) unit-dose capsules 75 mg capsules are  opaque white/orange opaque, size ‘4’, hard gelatin capsules, radially imprinted with ‘A’ on Cap and ‘142’ on body with black ink, filled with white to off-white powder. NDC 62332-121-30                bottle of 30 capsules NDC 62332-121-90                bottle of 90 capsules NDC 62332-121-91                bottle of 1000 capsules NDC 62332-121-10                carton of 100 (10 x 10) unit-dose capsules   100 mg capsules are  orange opaque/orange opaque, size ‘3’, hard gelatin capsules, radially imprinted with ‘A’ on Cap and ‘143’ on body with black ink, filled with white to off-white powder. NDC 62332-122-30                bottle of 30 capsules NDC 62332-122-90                bottle of 90 capsules NDC 62332-122-91                bottle of 1000 capsules NDC 62332-122-10                carton of 100 (10 x 10) unit-dose capsules  150 mg capsules are   opaque white/opaque white, size ‘2’, hard gelatin capsules, radially imprinted with ‘A’ on Cap and ‘144’ on body with black ink, filled with white to off-white powder. NDC 62332-123-30                bottle of 30 capsules NDC 62332-123-90                bottle of 90 capsules NDC 62332-123-91                bottle of 1000 capsules NDC 62332-123-10                carton of 100 (10 x 10) unit-dose capsules 200 mg capsules are  orange/orange, size ‘1’, hard gelatin capsules, radially imprinted with ‘A’ on Cap and ‘145’ on body with black ink, filled with white to off-white powder. NDC 62332-124-30                bottle of 30 capsules NDC 62332-124-90                bottle of 90 capsules NDC 62332-124-91                bottle of 1000 capsules NDC 62332-124-10                carton of 100 (10 x 10) unit-dose capsules 225 mg capsules are  opaque white/light orange, size ‘1’, hard gelatin capsules, radially imprinted with ‘A’ on Cap and ‘146’ on body with black ink, filled with white to off-white powder. NDC 62332-125-30                bottle of 30 capsules NDC 62332-125-90                bottle of 90 capsules NDC 62332-125-91                bottle of 1000 capsules NDC 62332-125-10                carton of 100 (10 x 10) unit-dose capsules 300 mg capsules are   opaque white/orange, size ‘0’, hard gelatin capsules, radially imprinted with ‘A’ on Cap and ‘147’ on body with black ink, filled with white to off-white powder. NDC 62332-126-30                bottle of 30 capsules NDC 62332-126-90                bottle of 90 capsules NDC 62332-126-71                bottle of 500 capsules NDC 62332-126-10                carton of 100 (10 x 10) unit-dose capsules Storage and Handling Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature).  

Authorization status:

Abbreviated New Drug Application

Patient Information leaflet

Alembic Pharmaceuticals Inc.
----------
Medication Guide
Pregabalin(pree gab’ a lin)
Capsules, CV
Read this Medication Guide before you start taking pregabalin and each
time you get a refill.
There may be new information. This information does not take the place
of talking to your
healthcare provider about your medical condition or treatment. If you
have any questions about
pregabalin,
ask
your
healthcare
provider
or
pharmacist.
What
is
the
most
important
information
I
should
know
about
pregabalin?
Pregabalin
may
cause
serious
side
effects
including:
• serious, even life-threatening, allergic reactions • swelling of
your hands, legs and feet
• suicidal
thoughts
or
actions
• dizziness
and
sleepiness
• serious
breathing
problems
These
serious
side
effects
are
described
below:
•
Serious,
even
life-threatening,
allergic
reactions.
Stop taking pregabalin and call your healthcare provider right away if
you have any of these
signs
of
a
serious
allergic
reaction:
o
swelling
of
your
face,
mouth,
lips,
gums,
tongue,
throat
or
neck
o
trouble
breathing
o
rash,
hives
(raised
bumps)
or
blisters
•Like other antiepileptic drugs, pregabalin may cause suicidal
thoughts or actions in a very
small number of people, about 1 in 500. Call a healthcare provider
right away if you have any
of
these
symptoms,
especially
if
they
are
new,
worse,
or
worry
you:
o thoughts
about
suicide
or
dying
o trouble
sleeping
(insomnia)
o attempts
to
commit
suicide
o new
or
worse
irritability
o new
or
worse
depression o acting
aggressive,
being
angry,
or
violent
o new
or
worse
anxiety o acting
on
dangerous
impulses
o feeling agitated or restless o an extreme increase in activity and
talking (mania)
o panic
attacks o other
unusual
changes
in
behavior
or
mood
If you have suicidal thoughts or actions, do not stop pregabalin
without first talking to a
healthcare
provider.
o
Stopping
pregabalin
suddenly
can
cause
serious
problems.
o Suicidal thoughts or actions can be caused by things other than
medicines. If you have
suicidal thoughts or action

Summary of Product characteristics

PREGABALIN - PREGABALIN CAPSULE
ALEMBIC PHARMACEUTICALS INC.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
PREGABALIN CAPSULES
SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR
PREGABALIN CAPSULES.
PREGABALIN CAPSULES, FOR ORAL USE, CV
INITIAL U.S. APPROVAL: 2004
INDICATIONS AND USAGE
Pregabalin capsule is indicated for:
• Neuropathic pain associated with diabetic peripheral neuropathy
(DPN) (1)
• Postherpetic neuralgia (PHN) (1)
• Adjunctive therapy for the treatment of partial-onset seizures in
patients 1 month of age and older (1)
• Fibromyalgia (1)
• Neuropathic pain associated with spinal cord injury (1) (1)
DOSAGE AND ADMINISTRATION
• For adult indications, begin dosing at 150 mg/day. For
partial-onset seizure dosing in pediatric patients 1
month of age and older, refer to section 2.4.(2.2, 2.3, 2.4, 2.5, 2.6)
• Dosing recommendations: (2)
INDICATION
DOSING
REGIMEN
MAXIMUM DOSE
DPN Pain (2.2)
3 divided doses
per day
300 mg/day within 1
week
PHN (2.3)
2 or 3 divided
doses per day
300 mg/day within 1
week.
Maximum dose of
600 mg/day.
Adjunctive Therapy for Partial-Onset Seizures in Pediatric and
Adult Patients Weighing 30 kg or More (2.4)
2 or 3 divided
doses per day
Maximum dose of
600 mg/day.
Adjunctive Therapy for Partial-Onset Seizures in Pediatric Patients
Weighing Less than 30 kg (2.4)
_1 month to less_
_than 4 years:_
3 divided doses
per day
_4 years and older: _
2 or 3 divided
doses per day
14 mg/kg/day.
Fibromyalgia (2.5)
2 divided doses
per day
300 mg/day within 1
week.
Maximum dose of
450 mg/day.
Neuropathic Pain Associated with Spinal Cord Injury (2.6)
2 divided doses
per day
300 mg/day within 1
week.
Maximum dose of
600 mg/day.
•Dose should be adjusted in adult patients with reduced renal
function. (2.7) (2)
DOSAGE FORMS AND STRENGTHS
•Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and
300 mg. (3) (3)
CONTRAINDICATIONS
Known hypersensitivity to pregabalin or any of its components. (4)