WARNINGS AND PRECAUTIONS
Angioedema
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.
LYRICA should be discontinued immediately in patients with these symptoms.
Caution should be exercised when prescribing LYRICA 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 angioedema.
Hypersensitivity
There have been postmarketing reports of hypersensitivity in patients shortly after
initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters,
hives, rash, dyspnea, and wheezing. LYRICA should be discontinued immediately in
patients with these symptoms.
Withdrawal of Antiepileptic Drugs (AEDs)
As with all AEDs, LYRICA should be withdrawn gradually to minimize the potential
of increased seizure frequency in patients with seizure disorders. If LYRICA is
discontinued this should be done gradually over a minimum of 1 week.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts
or behavior in patients taking these drugs for any indication. Patients treated with
any AED for any indication should be monitored for the emergence or worsening of
depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
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 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2 Risk by indication for antiepileptic drugs in the pooled analysis
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 or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and 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.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised 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. Behaviors of concern should be reported
immediately to healthcare providers.
Peripheral Edema
LYRICA 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 the incidence of peripheral edema was 6% in the LYRICA
group compared with 2% in the placebo group. In controlled clinical trials, 0.5%
of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema.
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, care should
be taken when co-administering LYRICA 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, LYRICA should be used with
caution in these patients.
Dizziness and Somnolence
LYRICA may cause dizziness and somnolence. Patients should be informed that LYRICA-related
dizziness and somnolence may impair their ability to perform tasks such as driving
or operating machinery (see Patient Counseling Information).
In the LYRICA controlled trials, dizziness was experienced by 31% of LYRICA-treated
patients compared to 9% of placebo-treated patients; somnolence was experienced
by 22% of LYRICA-treated patients compared to 7% of placebo-treated patients. Dizziness
and somnolence generally began shortly after the initiation of LYRICA therapy and
occurred more frequently at higher doses. Dizziness and somnolence were the adverse
reactions most frequently leading to withdrawal (4% each) from 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.
Weight Gain
LYRICA treatment may cause weight gain. 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. LYRICA associated
weight gain was related to 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 Warnings and Precautions).
Although weight gain was not associated with clinically important changes in blood
pressure in short-term controlled studies, the long-term cardiovascular effects
of LYRICA-associated weight gain are unknown.
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 LYRICA-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 HbA1C).
Abrupt or Rapid Discontinuation
Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms
including insomnia, nausea, headache, and diarrhea. LYRICA should be tapered gradually
over a minimum of 1 week rather than discontinued abruptly.
Tumorigenic Potential
In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA,
an unexpectedly high incidence of hemangiosarcoma was identified in two different
strains of mice (see Nonclinical Toxicology). The clinical significance of
this finding is unknown. Clinical experience during LYRICA's premarketing development
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 >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 LYRICA, it is impossible to know
whether the incidence seen in these cohorts is or is not affected by treatment.
Ophthalmological Effects
In controlled studies, a higher proportion of patients treated with LYRICA reported
blurred vision (7%) than did patients treated with placebo (2%), which resolved
in a majority of cases with continued dosing. Less than 1% of patients discontinued
LYRICA treatment due to vision-related events (primarily blurred vision).
Prospectively planned ophthalmologic testing, 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 patients treated
with LYRICA, 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 placebo-treated patients.
Although the clinical significance of the ophthalmologic findings is unknown, patients
should be informed that if changes in vision occur, they should notify their physician.
If visual disturbance persists, further assessment should be considered. More frequent
assessment should be considered for patients who are already routinely monitored
for ocular conditions (see Patient Counseling Information).
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 three 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. Prescribers should instruct patients to promptly report unexplained
muscle pain, tenderness, or weakness, particularly if these muscle symptoms are
accompanied by malaise or fever. LYRICA treatment should be discontinued if myopathy
is diagnosed or suspected or if markedly elevated creatine kinase levels occur.
Decreased Platelet Count
LYRICA treatment was associated with a decrease in platelet count. LYRICA-treated
subjects experienced a mean maximal decrease in platelet count of 20 × 103/µL,
compared to 11 × 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 <150 × 103/µL. A single
LYRICA treated subject developed severe thrombocytopenia with a platelet count less
than 20 × 103/μL. In randomized controlled trials, LYRICA
was 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 LYRICA
doses ≥300 mg/day. This mean change difference was not associated with an increased
risk of PR increase ≥25% from baseline, an increased percentage of subjects with
on-treatment PR >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.
DRUG INTERACTIONS
Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible
metabolism in humans (<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 LYRICA 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 LYRICA and commonly used
antiepileptic drugs (see Clinical Pharmacology).
Pharmacodynamics
Multiple oral doses of LYRICA 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 LYRICA was co-administered
with these drugs. No clinically important effects on respiration were seen.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. Increased incidences of fetal structural abnormalities and
other manifestations of developmental toxicity, including lethality, growth retardation,
and nervous and reproductive system functional impairment, were observed in the
offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced
plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended
dose (MRD) of 600 mg/day.
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 ≥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 LYRICA (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 LYRICA (50, 100, 250, 1250, or 2500
mg/kg) throughout gestation and lactation, offspring growth was reduced at
≥ 100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring
survival was pronounced at doses ≥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 ≥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.
There are no adequate and well-controlled studies in pregnant women. LYRICA should
be used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
To provide information regarding the effects of in utero exposure to LYRICA, physicians
are advised to recommend that pregnant patients taking LYRICA 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/.
Labor and Delivery
The effects of LYRICA on labor and delivery in pregnant women are unknown. In the
prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia
at exposures ≥50 times the mean human exposure (AUC(0-24)
of 123 µg•hr/mL) at the maximum recommended clinical dose of 600 mg/day.
Nursing Mothers
It is not known if pregabalin is excreted in human milk; it is, however, present
in the milk of rats. Because many drugs are excreted in human milk, and because
of the potential for tumorigenicity shown for pregabalin in animal studies, a decision
should be made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.
Pediatric Use
The safety and efficacy of pregabalin in pediatric patients have not been established.
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 ≥50 mg/kg. The neurobehavioral changes of acoustic startle
persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥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.
Geriatric Use
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 controlled clinical studies of LYRICA 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 LYRICA 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.
LYRICA is known to be substantially excreted by the kidney, and the
risk of toxic reactions to LYRICA may be greater in patients with
impaired renal function. Because LYRICA is eliminated primarily by
renal excretion, the dose should be adjusted for elderly patients
with renal impairment (see Dosage and Administration).
PATIENT COUNSELING INFORMATION
Medication Guide
Patients should be informed of the availability of a Medication Guide,
and they should be instructed to read the Medication Guide prior to taking LYRICA. Patients should be instructed to take LYRICA only as prescribed.
Angioedema
Patients should be advised that LYRICA 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.
Patients should be instructed to discontinue LYRICA and immediately
seek medical care if they experience these symptoms (see Warnings and
Precautions).
Hypersensitivity
Patients should be advised that LYRICA has been associated with hypersensitivity
reactions such as wheezing, dyspnea, rash, hives, and blisters. Patients should
be instructed to discontinue LYRICA and immediately seek medical care if they experience
these symptoms (see Warnings and Precautions).
Suicidal Thinking and Behavior
Patients, their caregivers, and families should be counseled that AEDs, including LYRICA,
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. Behaviors of concern should be reported immediately to healthcare providers
(see Warnings and Precautions).
Dizziness and Somnolence
Patients should be counseled that LYRICA may cause dizziness, somnolence, blurred
vision and other CNS signs and symptoms. Accordingly, they should be advised not
to drive, operate complex machinery, or engage in other hazardous activities until
they have gained sufficient experience on LYRICA to gauge whether or not it affects
their mental, visual, and/or motor performance adversely. (see Warnings and Precautions).
Weight Gain and Edema
Patients should be counseled that LYRICA may cause edema and weight gain. Patients
should be advised that concomitant treatment with LYRICA and a thiazolidinedione
antidiabetic agent may lead to an additive effect on edema and weight gain. For
patients with preexisting cardiac conditions, this may increase the risk of heart
failure. (see Warnings and Precautions).
Abrupt or Rapid Discontinuation
Patients should be advised to take LYRICA as prescribed. Abrupt or rapid discontinuation
may result in insomnia, nausea, headache, or diarrhea. (see Warnings and Precautions).
Ophthalmological Effects
Patients should be counseled that LYRICA may cause visual disturbances. Patients
should be informed that if changes in vision occur, they should notify their physician
(see Warnings and Precautions).
Creatine Kinase Elevations
Patients should be instructed to promptly report unexplained muscle pain, tenderness,
or weakness, particularly if accompanied by malaise or fever. (see Warnings and Precautions).
CNS Depressants
Patients who require concomitant treatment with central nervous system depressants
such as opiates or benzodiazepines should be informed that they may experience additive
CNS side effects, such as somnolence.
Alcohol
Patients should be told to avoid consuming alcohol while taking LYRICA, as LYRICA
may potentiate the impairment of motor skills and sedating effects of alcohol.
Use in Pregnancy
Patients should be instructed to notify their physician if they become pregnant
or intend to become pregnant during therapy, and to notify their physician if they
are breast feeding or intend to breast feed during therapy (see Use In Specific Populations).
Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become
pregnant. This registry is collecting information about the safety of antiepileptic
drugs during pregnancy. To enroll, patients can call the toll free number
1-888-233-2334 (see Use In Specific Populations).
Male Fertility
Men being treated with LYRICA who plan to father a child should be informed of the
potential risk of male-mediated teratogenicity. In preclinical studies in rats,
pregabalin was associated with an increased risk of male-mediated teratogenicity.
The clinical significance of this finding is uncertain (see Nonclinical Toxicology).
Dermatopathy
Diabetic patients should be instructed to pay particular attention to skin integrity
while being treated with LYRICA. Some animals treated with pregabalin developed
skin ulcerations, although no increased incidence of skin lesions associated with
LYRICA was observed in clinical trials (see Nonclinical Toxicology).