Included as part of the PRECAUTIONS section.
There have been postmarketing reports of angioedema in
patients during initial and chronic treatment with LYRICA. Specific symptoms
included swelling of the face, mouth (tongue, lips, and gums), and neck (throat
and larynx). There were reports of life-threatening angioedema with respiratory
compromise requiring emergency treatment. Discontinue LYRICA CR immediately in
patients with these symptoms.
Exercise caution when prescribing LYRICA CR to patients
who have had a previous episode of angioedema. In addition, patients who are
taking other drugs associated with angioedema (e.g., angiotensin converting
enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing
There have been postmarketing reports of hypersensitivity
reactions in patients shortly after initiation of treatment with LYRICA.
Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and
wheezing. Discontinue LYRICA CR immediately in patients with these symptoms.
Suicidal Behavior And Ideation
Antiepileptic drugs (AEDs), including pregabalin, the
active ingredient in LYRICA CR, increase the risk of suicidal thoughts or
behavior in patients taking these drugs for any indication. Monitor patients
treated with any AED for any indication for the emergence or worsening of
depression, suicidal thoughts or behavior, and/or any unusual changes in mood
Pooled analyses of 199 placebo-controlled clinical trials
(mono-and adjunctive therapy) of 11 different AEDs showed that patients
randomized to one of the AEDs had approximately twice the risk (adjusted
Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared
to patients randomized to placebo. In these trials, which had a median
treatment duration of 12 weeks, the estimated incidence rate of suicidal
behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to
0.24% among 16,029 placebo-treated patients, representing an increase of
approximately one case of suicidal thinking or behavior for every 530 patients
treated. There were four suicides in drug-treated patients in the trials and
none in placebo-treated patients, but the number is too small to allow any
conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with
AEDs was observed as early as one week after starting drug treatment with AEDs
and persisted for the duration of treatment assessed. Because most trials
included in the analysis did not extend beyond 24 weeks, the risk of suicidal
thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally
consistent among drugs in the data analyzed. The finding of increased risk with
AEDs of varying mechanisms of action and across a range of indications suggests
that the risk applies to all AEDs used for any indication. The risk did not vary
substantially by age (5-100 years) in the clinical trials analyzed.
Table 3 shows absolute and relative risk by indication
for all evaluated AEDs.
Table 3: Risk by Indication for Antiepileptic Drugs in
the Pooled Analysis
||Placebo Patients With Events per 1000 Patients
||Drug Patients With Events per 1000 Patients
||Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients
||Risk Difference: Additional Drug Patients With Events per 1000 Patients
The relative risk for suicidal thoughts or behavior was
higher in clinical trials for epilepsy than in clinical trials for psychiatric
or other conditions, but the absolute risk differences were similar for the
epilepsy and psychiatric indications.
Anyone considering prescribing LYRICA CR must balance the
risk of suicidal thoughts or behavior with the risk of untreated illness. Many
other illnesses for which AEDs are prescribed are themselves associated with
morbidity and mortality and an increased risk of suicidal thoughts and
behavior. Should suicidal thoughts and behavior emerge during treatment, the
prescriber needs to consider whether the emergence of these symptoms in any
given patient may be related to the illness being treated.
Inform patients, their caregivers, and families that
LYRICA CR can increase the risk of suicidal thoughts and behavior and advise
them of the need to be alert for the emergence or worsening of the signs and
symptoms of depression, any unusual changes in mood or behavior, or the
emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report
behaviors of concern immediately to healthcare providers.
LYRICA CR treatment may cause peripheral edema. In
short-term trials of patients without clinically significant heart or
peripheral vascular disease, there was no apparent association between
peripheral edema and cardiovascular complications such as hypertension or
congestive heart failure. Peripheral edema was not associated with laboratory
changes suggestive of deterioration in renal or hepatic function.
In controlled clinical trials for pain indications, the
incidence of peripheral edema for patients receiving LYRICA CR in the
single-blind phase was 5.3% of patients. In controlled clinical trials for pain
indications, 0.8% of LYRICA CR patients withdrew due to peripheral edema during
the single-blind phase.
Higher frequencies of weight gain and peripheral edema
were observed in patients taking both LYRICA and a thiazolidinedione
antidiabetic agent compared to patients taking either drug alone. The majority
of patients using thiazolidinedione antidiabetic agents in the overall safety
database were participants in studies of pain associated with diabetic
peripheral neuropathy. In this population, peripheral edema was reported in 3%
(2/60) of patients who were using thiazolidinedione antidiabetic agents only,
8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of
patients who were on both LYRICA and thiazolidinedione antidiabetic agents.
Similarly, weight gain was reported in 0% (0/60) of patients on
thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5%
(9/120) of patients on both drugs.
As the thiazolidinedione class of antidiabetic drugs can
cause weight gain and/or fluid retention, possibly exacerbating or leading to
heart failure, monitor patients for the development of edema when co-administering
LYRICA CR and these agents.
Because there are limited data on congestive heart
failure patients with New York Heart Association (NYHA) Class III or IV cardiac
status, monitor these patients for possible exacerbation of congestive heart
failure symptoms when using LYRICA CR.
Dizziness And Somnolence
LYRICA CR may cause dizziness and somnolence. Inform
patients that LYRICA CR-related dizziness and somnolence may impair their
ability to perform tasks such as driving or operating machinery. Concomitant
use of LYRICA CR with other central nervous system (CNS) depressants may
exacerbate these effects [see DRUG INTERACTIONS].
In the LYRICA CR controlled trials for pain indications,
dizziness was experienced by 24% of LYRICA CR-treated patients during the
single-blind phase; somnolence was experienced by 15.8% of LYRICA CR-treated
patients. Dizziness and somnolence generally began shortly after the initiation
of LYRICA CR therapy and occurred more frequently at higher doses. Dizziness
and somnolence were the adverse reactions most frequently leading to withdrawal
(2.4%, 1.2% each) during the single-blind phase of the controlled studies. In LYRICA-treated patients reporting these adverse
reactions in short-term, controlled studies, dizziness persisted until the last
dose in 30% and somnolence persisted until the last dose in 42% of patients.
LYRICA CR treatment may cause weight gain. In LYRICA CR
controlled trials for pain indications, weight gain was experienced by 4% of
LYRICA CR-treated patients during the single-blind phase. Adverse events of
weight gain were observed in 3.7% of LYRICA CR-treated patients and 1% of
placebo-treated patients during the double-blind phase.
In LYRICA controlled clinical trials of up to 14 weeks a
gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated
patients and 2% of placebo-treated patients. Few patients treated with LYRICA
(0.3%) withdrew from controlled trials due to weight gain. In studies with
LYRICA, associated weight gain was related to pregabalin dose and duration of
exposure, but did not appear to be associated with baseline BMI, gender, or
age. Weight gain was not limited to patients with edema [see Peripheral Edema].
Although weight gain was not associated with clinically
important changes in blood pressure in short-term controlled studies with LYRICA,
the long-term cardiovascular effects of pregabalin-associated weight gain are
Among diabetic patients, LYRICA-treated patients gained
an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg
(range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333
diabetic patients who received LYRICA for at least 2 years, the average weight
gain was 5.2 kg.
While the effects of pregabalin-associated weight gain on
glycemic control have not been systematically assessed, in controlled and
longer-term open-label clinical trials with diabetic patients, LYRICA treatment
did not appear to be associated with loss of glycemic control (as measured by
Risks Associated With Abrupt Or Rapid Discontinuation
Following abrupt or rapid discontinuation of LYRICA CR,
some patients reported symptoms including, insomnia, nausea, headache, anxiety,
and diarrhea. Increased seizure frequency may occur in patients with seizure
disorders taking LYRICA CR for pain if LYRICA CR is rapidly discontinued. Taper
LYRICA CR gradually over a minimum of 1 week rather than discontinuing the drug
abruptly. The efficacy of LYRICA CR as adjunctive therapy for adult patients
with partial onset seizures has not been established.
In standard preclinical in vivo lifetime carcinogenicity
studies of pregabalin, an unexpectedly high incidence of hemangiosarcoma was
identified in 2 different strains of mice [see Nonclinical Toxicology].
The clinical significance of this finding is unknown. Clinical experience
during premarketing development of LYRICA provides no direct means to assess
its potential for inducing tumors in humans.
In clinical studies across various patient populations,
comprising 6396 patient-years of exposure in patients greater than 12 years of
age, new or worsening-preexisting tumors were reported in 57 patients. Without
knowledge of the background incidence and recurrence in similar populations not
treated with pregabalin, it is impossible to know whether the incidence seen in
these cohorts is or is not affected by treatment.
In controlled studies for pain indications, 4.8% of
patients treated with LYRICA CR in the single-blind phase reported blurred
vision, which resolved in a majority of cases with continued dosing. Less than
1% of patients discontinued LYRICA CR treatment due to vision-related events
(primarily blurred vision). Additionally, 0.7% of LYRICA CR-treated patients as
compared to no placebo-treated patients experienced blurred vision in the
Prospectively planned ophthalmologic testing during the
premarketing development of pregabalin, including visual acuity testing, formal
visual field testing and dilated funduscopic examination, was performed in over
3600 patients. In these patients, visual acuity was reduced in 7% of
LYRICA-treated patients and 5% of placebo-treated patients. Visual field
changes were detected in 13% of LYRICA-treated and 12% of placebo-treated
patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of
Although the clinical significance of the ophthalmologic
findings is unknown, inform patients to notify their physician if changes in
vision occur. If visual disturbance persists, consider further assessment.
Consider more frequent assessment for patients who are already routinely
monitored for ocular conditions.
Creatine Kinase Elevations
LYRICA treatment was associated with creatine kinase
elevations. Mean changes in creatine kinase from baseline to the maximum value
were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In
all controlled trials across multiple patient populations, 1.5% of patients on LYRICA
and 0.7% of placebo patients had a value of creatine kinase at least 3 times
the upper limit of normal. Three LYRICA-treated subjects had events reported as
rhabdomyolysis in premarketing clinical trials. The relationship between these
myopathy events and LYRICA is not completely understood because the cases had
documented factors that may have caused or contributed to these events.
Instruct patients to promptly report unexplained muscle pain, tenderness, or
weakness, particularly if these muscle symptoms are accompanied by malaise or
fever. Discontinue treatment with LYRICA CR if myopathy is diagnosed or
suspected or if markedly elevated creatine kinase levels occur.
Decreased Platelet Count
Both LYRICA CR and LYRICA treatment were associated with
a decrease in platelet count. In the double-blind phase of controlled studies
for pain indication, LYRICA CR-treated patients experienced a median change
from baseline in platelet count of 11 x 103/mm² (for the PHN population) and 14
x 103/mm² (for the FM population) as compared to 1 x 103/mm² in placebo-treated
patients (for both populations). LYRICA-treated patients experienced a mean
maximal decrease in platelet count of 20 x 103/μL, compared to 11 x 103/μL
in placebo patients. In the overall database of controlled trials, 2% of
placebo patients and 3% of LYRICA patients experienced a potentially clinically
significant decrease in platelets, defined as 20% below baseline value and less
than 150 x 103/μL. A single LYRICA-treated subject developed severe
thrombocytopenia with a platelet count less than 20 x 103/μL. In
randomized controlled trials, LYRICA or LYRICA CR were not associated with an
increase in bleeding-related adverse reactions.
PR Interval Prolongation
LYRICA treatment was associated with PR interval
prolongation. In analyses of clinical trial ECG data, the mean PR interval
increase was 3–6 msec at pregabalin doses greater than or equal to 300 mg/day.
This mean change difference was not associated with an increased risk of PR
increase greater than or equal to 25% from baseline, an increased percentage of
subjects with on-treatment PR greater than 200 msec, or an increased risk of
adverse reactions of second or third degree AV block.
Subgroup analyses did not identify an increased risk of
PR prolongation in patients with baseline PR prolongation or in patients taking
other PR prolonging medications. However, these analyses cannot be considered
definitive because of the limited number of patients in these categories.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Advise patients that LYRICA CR may cause angioedema, with
swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx)
that can lead to life-threatening respiratory compromise. Instruct patients to
discontinue LYRICA CR and immediately seek medical care if they experience
these symptoms [see WARNINGS AND PRECAUTIONS].
Advise patients that LYRICA CR has been associated with
hypersensitivity reactions such as skin redness, blisters, hives, rash,
dyspnea, and wheezing. Instruct patients to discontinue LYRICA CR and
immediately seek medical care if they experience these symptoms [see WARNINGS
Suicidal Thinking And Behavior
Counsel patients, their caregivers, and families that
AEDs, including pregabalin, the active ingredient in LYRICA CR, may increase
the risk of suicidal thoughts and behavior and should be advised of the need to
be alert for the emergence or worsening of symptoms of depression, any unusual
changes in mood or behavior, or the emergence of suicidal thoughts, behavior,
or thoughts about self-harm. Instruct patients, caregivers, and families to
report behaviors of concern immediately to a healthcare provider [see WARNINGS
Dizziness And Somnolence
Inform patients that LYRICA CR may cause dizziness,
somnolence, blurred vision, and other CNS signs and symptoms. Accordingly,
advise patients not to drive, operate complex machinery, or engage in other
hazardous activities until they have gained sufficient experience on LYRICA CR
to gauge whether or not it affects their mental, visual, and/or motor
performance adversely [see WARNINGS AND PRECAUTIONS].
Weight Gain And Edema
Inform patients that LYRICA CR may cause edema and weight
gain. Advise patients that concomitant treatment with LYRICA CR and a
thiazolidinedione antidiabetic agent may lead to an additive effect on edema
and weight gain. Advise patients with preexisting cardiac conditions that this
may increase the risk of heart failure [see WARNINGS AND PRECAUTIONS].
Abrupt Or Rapid Discontinuation
Advise patients to take LYRICA CR as prescribed. Abrupt
or rapid discontinuation may result in insomnia, nausea, headache, anxiety, or
diarrhea. Advise patients with seizure disorders that abrupt or rapid
discontinuation may increase seizure frequency [see WARNINGS AND PRECAUTIONS].
Counsel patients that LYRICA CR may cause visual
disturbances. Inform patients that if changes in vision occur, they should
notify their physician [see WARNINGS AND PRECAUTIONS].
Creatine Kinase Elevations
Instruct patients to promptly report unexplained muscle
pain, tenderness, or weakness, particularly if accompanied by malaise or fever [see
WARNINGS AND PRECAUTIONS].
Inform patients who require concomitant treatment with
central nervous system depressants such as opiates or benzodiazepines that they
may experience additive CNS side effects, such as somnolence and dizziness [seeDRUG INTERACTIONS].
Advise patients to avoid consuming alcohol while taking
LYRICA CR, as LYRICA CR may potentiate the impairment of motor skills and
sedating effects of alcohol [see DRUG INTERACTIONS].
Use In Pregnancy
Advise pregnant patients to enroll in the North American
Antiepileptic Drug (NAAED) Pregnancy Registry [see Use In Specific
Instruct patients that if they miss taking their dose of
LYRICA CR after an evening meal, then they should take their usual dose of
LYRICA CR prior to bedtime following a snack. If they miss taking the dose of
LYRICA CR prior to bedtime, then they should take their usual dose of LYRICA CR
following a morning meal. If they miss taking the dose of LYRICA CR following
the morning meal, then they should take their usual dose of LYRICA CR at the
usual time that evening following an evening meal.
Advise nursing mothers that breastfeeding is not
recommended during treatment with LYRICA CR [see Use In Specific Populations].
Inform men being treated with LYRICA CR who plan to
father a child of the potential risk of male-mediated teratogenicity [see Nonclinical
Toxicology and Use In Specific Populations].
Instruct diabetic patients to pay particular attention to
skin integrity while being treated with LYRICA CR [see Nonclinical
This product's label may have been updated. For current
full prescribing information, please visit www.pfizer.com.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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, 1000, 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, 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 15 and 26 times, respectively, human exposure
at the MRD.
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 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 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, 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 10
times that in humans receiving the MRD. A no-effect dose for female
reproductive toxicity in rats was not established.
Use In Specific Populations
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 LYRICA CR, physicians
are advised to recommend that pregnant patients taking LYRICA CR 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/.
There are no adequate and well-controlled studies with
LYRICA CR 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 18 times
human exposure at the maximum recommended dose (MRD) of 660 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.
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 18 times human exposure at the MRD of 660 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 17 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
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]. 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]. Because of the potential risk of tumorigenicity, breastfeeding
is not recommended during treatment with LYRICA CR.
A pharmacokinetic study in ten lactating women, who were
at least 12 weeks postpartum, evaluated the concentrations of pregabalin in
plasma and breast milk. LYRICA 150 mg oral capsule was given every 12 hours
(300 mg daily dose) for a total of 4 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 breastfed infant were not
Females And Males Of Reproductive Potential
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 (1 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 1
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
The safety and effectiveness of LYRICA CR in pediatric
patients have not been established.
Juvenile Animal Toxicity 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 660 mg/day. A no-effect dose was not established.
In controlled clinical studies of LYRICA in neuropathic
pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74
years of age, and 73 patients were 75 years of age or older.
In controlled clinical studies of LYRICA in neuropathic
pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years
of age, and 379 patients were 75 years of age or older.
In the LYRICA CR neuropathic pain associated with
postherpetic neuralgia study, 422 patients 65 years of age and older received
No overall differences in safety and effectiveness were
observed between these patients and younger patients, and other reported
clinical experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out.
Pregabalin is known to be substantially excreted by the
kidney, and the risk of adverse reactions to this drug may be greater in
patients with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose selection, and
it may be useful to monitor renal function. See DOSAGE AND ADMINISTRATION
for recommendations for dosing in patients with renal impairment.