Pfizer Canada Inc. 17300 Trans-Canada Highway Kirkland, Quebec H9J 2M5 Submission Control No: 103320 TM C.P. Pharmaceuticals International C.V. Pfizer Canada Inc., licensee (c) Pfizer Canada Inc., 2007 Date of Revision: November 8, 2007
LYRICA has been approved under the Notice of Compliance with Conditions (NOC/c) policy for one of its indicated uses.
What is a Notice of Compliance with Conditions (NOC/c)?
An NOC/c is a form of market approval granted to a product on the basis of promising evidence of clinical effectiveness following review of the submission by Health Canada. Products approved under Health Canada's NOC/c policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness. They have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, they either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies. Health Canada has provided access to this product on the condition that sponsors carry out additional clinical trials to verify the anticipated benefit within an agreed upon time frame.
What will be different about this Product Monograph?
The following Product Monograph will contain boxed text at the beginning of each major section clearly stating the nature of the market authorization. Sections for which NOC/c status holds particular significance will be identified in the left margin by the symbol NOC/c. These sections may include, but are not limited to, the following:
Indications and Clinical Uses;
Action;
Warnings and Precautions;
Adverse Reactions;
Dosage and Administration; and
Clinical Trials.
Adverse Drug Reaction Reporting and Re-Issuance of the Product Monograph
Health care providers are encouraged to report Adverse Drug Reactions associated with normal use of these and all drug products to Health Canada's Health Product Safety Information Division at 1-866-234-2345. The Product Monograph will be re-issued in the event of serious safety concerns previously unidentified or at such time as the sponsor provides the additional data in support of the product's clinical benefit. Once the latter has occurred, and in accordance with the NOC/c policy, the conditions associated with market authorization will be removed.
Table of Contents
SUMMARY PRODUCT INFORMATION 4 INDICATIONS AND CLINICAL USE 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 14 DRUG INTERACTIONS 28 DOSAGE AND ADMINISTRATION 30 OVERDOSAGE 32 ACTION AND CLINICAL PHARMACOLOGY 33 STORAGE AND STABILITY 36 DOSAGE FORMS, COMPOSITION AND PACKAGING 37
PHARMACEUTICAL INFORMATION 38 CLINICAL TRIALS 39 DETAILED PHARMACOLOGY 43 TOXICOLOGY 45 REFERENCES 48
pregabalin
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Capsules, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, 300 mg | Lactose monohydrate For a complete listing see Dosage Forms, Composition and Packaging section. |
Adults
LYRICA (pregabalin) is indicated for the management of neuropathic pain associated with:
NOC/c
Diabetic peripheral neuropathy and
Postherpetic neuralgia
LYRICA may be useful in the management of central neuropathic pain.
Geriatrics (>65 years of age): Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in creatinine clearance. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function. (see WARNINGS AND PRECAUTIONS,
Geriatrics (>65 years of age)) Pediatrics (<18 years of age): The safety and efficacy of pregabalin in pediatric patients (<18 years of age) have not been established and its use in this patient population is not recommended. (see WARNINGS AND PRECAUTIONS, Pediatrics)
Patients who are hypersensitive to pregabalin or to any ingredient in the formulation or component of the container.
Tumorigenic Potential
In standard preclinical in vivo lifetime carcinogenicity studies of pregabalin, a high incidence of hemangiosarcoma was identified in two different strains of mice. (see Preclinical Toxicology) The clinical significance of this finding is uncertain. Clinical experience during pregabalin'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 8666 patients ranging in age from 12 to 100 years, new or worsening-preexisting tumors were reported in 57 patients. The most common malignant tumor diagnosed was skin carcinoma (17 patients) followed by breast carcinoma (8 patients), prostatic carcinoma (6 patients), carcinoma not otherwise specified (6 patients), and bladder carcinoma (4 patients). Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA (pregabalin), it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment.
Ophthalmological Effects
In controlled studies, pregabalin treatment was associated with vision-related adverse events such as blurred vision (amblyopia) [6% pregabalin and 2% placebo] and diplopia (2% pregabalin and 0.5% placebo). Approximately 1% of pregabalin-treated patients discontinued treatment due to vision-related adverse events (primarily blurred vision). Of the patients who did not withdraw, the blurred vision resolved with continued dosing in approximately half of the cases. (see Post-Marketing Adverse Drug Reactions) 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 pregabalin, and 5% of placebo-treated patients. Visual field changes were detected in 13% of pregabalin-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of pregabalin-treated and 2% of placebo-treated patients. At this time, 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, including discontinuation of pregabalin, should be considered. More frequent assessments should be considered for patients who are already routinely monitored for ocular conditions.
Peripheral Edema
In controlled clinical trials pregabalin treatment caused peripheral edema in 6% of patients (336/5508) compared with 2% of patients (42/2384) in the placebo group. In these studies, 0.5% (28/5508) of pregabalin patients and 0.2% (4/2384) of placebo patients withdrew due to peripheral edema (see ADVERSE REACTIONS, Peripheral Edema). In controlled clinical trials of up to 13 weeks in duration 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. In the same trials, peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA (pregabalin) 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 pregabalin only, and 19% (23/120) of patients who were on both pregabalin and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on pregabalin 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.
Congestive Heart Failure
In controlled clinical studies, events of congestive heart failure were reported at an infrequent rate (between 0.1% and 1%; see ADVERSE REACTIONS, Less Common Clinical Trial
Adverse Reactions).
There have been post-marketing reports of congestive heart failure in some patients receiving pregabalin (see ADVERSE REACTIONS, Post-marketing Adverse Drug Reactions). These reactions are mostly seen in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic pain indication. Pregabalin should be used with caution in these patients. Discontinuation of pregabalin may resolve the reaction.
Weight Gain
Pregabalin treatment was associated with weight gain. In pregabalin controlled clinical trials of up to 13 weeks, a gain of 7% or more over baseline weight was observed in 8% of pregabalin-treated patients and 2% of placebo-treated patients. Few patients treated with pregabalin (0.2%) withdrew from controlled trials due to weight gain (see ADVERSE REACTIONS, Weight Gain). Pregabalin 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 - Peripheral Edema). Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of pregabalin-associated weight gain are unknown. Among diabetic patients, pregabalin-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 pregabalin 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, pregabalin treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C).
Dizziness and Somnolence
In controlled neuropathic pain studies, pregabalin caused dizziness in 23% of patients (424/1831) compared to 7% in placebo (58/857). Somnolence was experienced by 14% (256/1831) and 4% (33/857) of the patients treated with pregabalin and placebo, respectively. These events begin shortly after the initiation of therapy and generally occur more frequently at higher doses. In these studies, dizziness and somnolence led to withdrawal of 3.5% and 2.6% of the pregabalin-treated patients, respectively. For the remaining patients (359 and 208, respectively) who experienced these events, dizziness and somnolence persisted until the last dose of pregabalin in 43% and 58% of the patients, respectively (see ADVERSE REACTIONS, Tables 2 and 4, and Post-Marketing Adverse Drug Reactions). Accordingly, patients should be advised not to drive or operate complex machinery or engage in other hazardous activities until they have gained sufficient experience on pregabalin to gauge whether or not it affects their mental and/or motor performance adversely (see Product Monograph Part III: CONSUMER INFORMATION).
Abrupt or Rapid Discontinuation
Following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, and diarrhea. Pregabalin should be tapered gradually over a minimum of one week rather than discontinued abruptly. (See ADVERSE REACTIONS, Adverse Events Following Abrupt or Rapid Discontinuation).
Sexual Function/Reproduction
Impairment of Male Fertility
Preclinical Data
In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3-4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse effects on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established. The clinical significance of female fertility findings in animals is unknown.
Human Data
In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin 600 mg/day for 3 months (one complete sperm cycle). Pregabalin did not exhibit significant detrimental effects on the reproductive function of healthy male subjects, as measured by semen analysis, when compared with placebo (n = 16). However, due to the small sample size and short-term exposure to pregabalin (only one complete sperm cycle), no conclusions can be made regarding possible reproductive effects of pregabalin during long-term exposure. Effects on other male reproductive parameters in humans have not been adequately studied.
Special Populations
Renal
Because pregabalin is eliminated primarily by renal excretion, the dose of pregabalin should be adjusted as noted for elderly patients with renal impairment (see ACTION AND CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Adjustment of Dose in Renally-Impaired Patients
In patients with a medical history of significant renal insufficiency, daily dosages should be reduced accordingly (see Table in DOSAGE AND ADMINISTRATION, Dosing Considerations).
Preclinical Data
Pregabalin was not teratogenic in mice, rats, or rabbits. Pregabalin induced fetal toxicity in rats and rabbits at >= 39 times the mean human exposure at the maximum recommended clinical dose of 600 mg/day [AUC(0-24) of 123 mg *hr/mL]. In the prenatal-postnatal toxicity study, pregabalin induced offspring developmental toxicity in rats at >= 5 times the maximum recommended human exposure. No developmental effects occurred at 2 times the maximum recommended human exposure (see TOXICOLOGY).
Human Data
Pregnant Women
There are no adequate and well-controlled studies in pregnant women. Pregabalin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labour and Delivery
The effects of pregabalin on labour and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures >= 47 times the mean human exposure [AUC(0-24) of 123 mg *hr/mL] at the maximum recommended clinical dose of 600 mg/day (see TOXICOLOGY).
Nursing Women
It is not known if pregabalin is excreted in human breast milk; however, it is present in the milk of rats. Because of the potential for adverse reactions in nursing infants from pregabalin, 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 (see TOXICOLOGY).
Pediatrics (<18 years of age)
The safety and efficacy of pregabalin in pediatric patients (<18 years of age) have not been established.
Geriatrics (> 65 years of age)
Of the 1831 patients who received pregabalin in neuropathic pain studies, 528 were 65 to 74 years of age, and 452 were 75 years of age or older. No significant differences in efficacy were observed between these patients and younger patients. Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in creatinine clearance. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function. In general, the incidence of adverse events did not increase with age.
Creatine Kinase Elevations
Pregabalin treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for pregabalin-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 2% of patients on pregabalin and 1% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three pregabalin-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and pregabalin 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. Pregabalin treatment should be discontinued if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur.
Laboratory Changes, Decreased Platelet Count
Pregabalin treatment was associated with a decrease in platelet count. Pregabalin-treated subjects experienced a mean maximal decrease in platelet count of 20 x 103/mL, compared to 11 x 103/mL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of pregabalin patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and < 150 x 103/mL. In randomized controlled trials, pregabalin was not associated with an increase in bleeding related adverse events.
ECG Changes, PR Interval Prolongation
Pregabalin treatment was associated with mild PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3-6 msec at pregabalin 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 events of second or third degree AV block.
Information for Patients
Patients should be counseled that LYRICA (pregabalin) 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 pregabalin to gauge whether or not it affects their mental, visual, and/or motor performance adversely.
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, Ophthalmologic Effects).
Patients should be advised to take LYRICA as prescribed. Abrupt or rapid discontinuation may result in insomnia, nausea, headache, or diarrhea.
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.
Patients should be instructed to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
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. Patients should be told to avoid consuming alcohol while taking LYRICA, as LYRICA may potentiate the impairment of motor skills and sedation of alcohol.
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.
In preclinical studies in rats, pregabalin was associated with an increased risk of male-mediated teratogenicity. (see WARNINGS AND PRECAUTIONS - Sexual Function/Reproduction) The clinical significance of this finding is uncertain; however, men being treated with LYRICA who plan to father a child should be informed of the potential risk of male-mediated teratogenicity.
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 WARNINGS AND PRECAUTIONS - Preclinical Toxicology). Patients should be informed of the availability of a patient information leaflet, and they should be instructed to read the leaflet prior to taking LYRICA.
Preclinical Toxicology
Carcinogenesis
A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. In an investigative study in female B6C3F1 mice, chronic treatment (24 months) with pregabalin at 1000 mg/kg caused an increased incidence of hemangiosarcoma, consistent with previous studies, but not at 50 or 200 mg/kg. Discontinuation of treatment after 12 months at 1000 mg/kg did not significantly reduce the incidence of hemangiosarcoma at 24 months. Evidence of carcinogenicity was not seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. The clinical significance in humans of this finding in mice is unknown.
Mutagenesis
Pregabalin is not genotoxic based on results of a battery of in vitro and in vivo tests. 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.
Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies.
Ocular lesions (characterized by retinal atrophy (including loss of photoreceptor cells) and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) >= 2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year. The clinical significance of this finding in rats is unknown.
Monitoring and Laboratory Tests
Routine therapeutic drug monitoring or clinical laboratory testing is not required for patients treated with LYRICA (pregabalin) (see ADVERSE REACTIONS).
Adverse Drug Reaction Overview
Clinical Trial Adverse Drug Reactions
In all controlled and uncontrolled trials during the pre-marketing development of pregabalin, more than 8666 patients have received LYRICA (pregabalin), with 83% of exposure at dosages of 300 mg/day or above and 32% at dosages of 600 mg/day or higher. Approximately 4010 patients had at least 6 months of exposure, 2415 had at least 1 year of exposure, and 939 had at least 2 years of exposure to pregabalin. In controlled trials, 1831 patients with neuropathic pain received pregabalin.
NOC/c
In a controlled study of central neuropathic pain due to spinal cord injury, 137 patients were randomized to receive placebo (N=67) or escalating doses (150-600 mg/day) of pregabalin, (N=70). The controlled study was followed by an open-label trial in which 103 patients received pregabalin (150-600 mg/day). The median duration of therapy across the double-blind and open-label studies for those subjects treated in the open-label extension was 608 days (range 14-1248). Sixty-nine (67%) subjects received at least 1 year of open-label pregabalin and 31 (30.1%) received at least 2 years of open-label pregabalin.
Most Common Adverse Events in All Pre-marketing Controlled Clinical Studies of Peripheral Neuropathic Pain
The most commonly observed adverse events (>= 5% and twice the rate of that seen in placebo) in pregabalin-treated patients in pre-marketing studies were: dizziness, somnolence, peripheral edema, and dry mouth. Adverse events were usually mild to moderate in intensity.
Discontinuation Due to Adverse Events in Pre-marketing Controlled Clinical Studies
In all pre-marketing controlled studies, the discontinuation rate due to adverse events was 14% for patients receiving pregabalin and 7% for patients receiving placebo. The most common reasons for discontinuation due to adverse events (>= 2%) in the pregabalin treatment groups were dizziness and somnolence. Other adverse events that led to withdrawal more frequently in the pregabalin group than the placebo group were ataxia (1%), and asthenia, confusion, headache and nausea (<1% each). In pre-marketing controlled neuropathic pain studies, the discontinuation rate due to adverse events was 11% for pregabalin and 5% for placebo. The most common reasons for discontinuation due to adverse events (>= 2%) in the pregabalin treatment groups were dizziness and somnolence. Other adverse events that led to withdrawal more frequently in the pregabalin group than the placebo group were confusion (1%) and asthenia, peripheral edema and ataxia (<1% each).
Incidence of Adverse Events in Pre-marketing Controlled Clinical Studies of Neuropathic Pain
In summaries of adverse events, investigator's terms for individual adverse events have been grouped into a smaller number of standardized categories using the COSTART IV dictionary. The prescriber should be aware that the percentages in Table 1 through Table 8 cannot be used to predict the frequency of adverse events in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.
Adverse Events From Pre-marketing Controlled Clinical Studies of Neuropathic Pain
Diabetic Peripheral Neuropathy
Table 1 lists all adverse events, regardless of causality, occurring in >= 2% of patients with neuropathic pain associated with diabetic peripheral neuropathy receiving pregabalin for at least one of the pregabalin groups, and for which the incidence was greater than in the placebo group. A majority of pregabalin-treated patients in these studies had adverse events with a maximum intensity of mild or moderate. In these studies, 979 patients received pregabalin and 459 patients received placebo for up to 13 weeks.
Table 1. Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled Studies in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy (Events in at Least 2% of Patients Receiving Pregabalin and More Frequent Than in Placebo- Treated Patients) | ||||||
|---|---|---|---|---|---|---|
| Body System Preferred Term | Placebo (N = 459) % | Pregabalin (mg/day) | ||||
| 75 | 150 | 300 | 600 | |||
| (N =77) | (N = 212) | (N = 321) | (N = 369) | |||
| % | % | % | % | |||
| Body as a whole | ||||||
| Infection | 6.1 | 3.9 | 7.5 | 8.4 | 4.6 | |
| Asthenia | 2.4 | 3.9 | 1.9 | 4.4 | 7.3 | |
| Pain | 3.9 | 5.2 | 4.2 | 2.5 | 4.9 | |
| Accidental injury | 2.8 | 5.2 | 2.4 | 2.2 | 5.7 | |
| Back pain | 0.4 | 0.0 | 2.4 | 1.2 | 1.9 | |
| Chest pain | 1.1 | 3.9 | 1.4 | 1.2 | 1.6 | |
| Face edema | 0.4 | 0.0 | 0.9 | 0.9 | 2.2 | |
| Digestive system | ||||||
| Dry mouth | 1.1 | 2.6 | 1.9 | 4.7 | 6.5 | |
| Constipation | 1.5 | 0.0 | 2.4 | 3.7 | 6.0 | |
| Diarrhea | 4.8 | 5.2 | 2.8 | 1.9 | 3.0 | |
| Flatulence | 1.3 | 2.6 | 0 | 2.2 | 2.7 | |
| Vomiting | 1.5 | 1.3 | 0.9 | 2.2 | 1.1 | |
| Hemic and lymphatic system | ||||||
| Ecchymosis | 0.2 | 2.6 | 0.5 | 0.6 | 0.3 | |
| Metabolic and nutritional disorders | ||||||
| Peripheral edema | 2.4 | 3.9 | 6.1 | 9.3 | 12.5 | |
| Weight gain | 0.4 | 0.0 | 4.2 | 3.7 | 6.2 | |
| Edema | 0.0 | 0.0 | 1.9 | 4.0 | 1.9 | |
| Hypoglycemia | 1.1 | 1.3 | 3.3 | 1.6 | 1.1 | |
| Nervous system | ||||||
| Dizziness | 4.6 | 7.8 | 9.0 | 23.1 | 29.0 | |
| Somnolence | 2.6 | 3.9 | 6.1 | 13.1 | 16.3 | |
| Neuropathy | 3.5 | 9.1 | 1.9 | 2.2 | 5.4 | |
| Ataxia | 1.3 | 6.5 | 0.9 | 2.2 | 4.3 | |
| Vertigo | 1.1 | 1.3 | 1.9 | 2.5 | 3.5 | |
| Confusion | 0.7 | 0.0 | 1.4 | 2.2 | 3.3 | |
| Euphoria | 0.0 | 0.0 | 0.5 | 3.4 | 1.6 | |
| Thinking abnormal a | 0.0 | 1.3 | 0.0 | 0.9 | 3.0 | |
| Abnormal gait | 0.0 | 1.3 | 0.0 | 0.6 | 2.7 | |
| Reflexes decreased | 1.7 | 3.9 | 0.5 | 1.2 | 1.4 | |
| Amnesia | 0.2 | 2.6 | 0.9 | 0.0 | 2.2 | |
| Hypesthesia | 0.7 | 2.6 | 0.0 | 0.0 | 0.8 | |
| Hyperalgesia | 0.2 | 2.6 | 0.0 | 0.0 | 0.3 | |
| Respiratory system | ||||||
| Dyspnea | 0.7 | 2.6 | 0.0 | 1.9 | 1.9 | |
| Skin and appendages | ||||||
| Pruritus | 1.3 | 2.6 | 0.0 | 0.9 | 0.0 | |
| Special senses | ||||||
| Blurred vision b | 1.5 | 2.6 | 1.4 | 2.8 | 5.7 | |
| Conjunctivitis | 0.2 | 2.6 | 1.4 | 0.6 | 0.3 | |
a
Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slow thinking.
b
Investigator term; summary level term is amblyopia.
Discontinuation in Controlled Clinical Studies of Diabetic Peripheral Neuropathy
Approximately 9% of patients receiving pregabalin and 4% receiving placebo discontinued from controlled diabetic peripheral neuropathy studies due to adverse events. The adverse events most commonly leading to discontinuation are presented in Table 2.
Table 2. Adverse Events Most Frequently (>=2% of patients) Leading to Discontinuation in Placebo-Controlled Studies in Patients With Neuropathic Pain Associated with Diabetic Peripheral Neuropathy | |||||
|---|---|---|---|---|---|
| Number (%) of Patients | |||||
| COSTART Preferred Term | Placebo (N = 459) | Pregabalin (mg/day) | |||
| 75 (N =77) | 150 (N = 212) | 300 (N = 321) | 600 (N = 369) | ||
| Dizziness | 2 (0.4) | 0 (0.0) | 3 (1.4) | 6 (1.9) | 21 (5.7) |
| Somnolence | 0 (0.0) | 0 (0.0) | 0 (0.0) | 5 (1.6) | 15 (4.1) |
Postherpetic Neuralgia
Table 3 lists all adverse events, regardless of causality, occurring in >= 2% of patients with neuropathic pain associated with postherpetic neuralgia receiving pregabalin for at least one of the pregabalin groups, and for which the incidence was greater than in the placebo group. A majority of pregabalin-treated patients in these studies had adverse events with a maximum intensity of mild or moderate. In these studies, 852 patients received pregabalin and 398 patients received placebo for up to 13 weeks.
Table 3. Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled Studies in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 2% of Patients Receiving Pregabalin and More Frequent Than in Placebo-Treated Patients) | ||||||
|---|---|---|---|---|---|---|
| Body System Preferred Term | Placebo (N = 398) % | Pregabalin (mg/day) | ||||
| 75 | 150 | 300 | 600 | |||
| (N =84) | (N = 302) | (N = 312) | (N = 154) | |||
| % | % | % | % | |||
| Body as a whole | ||||||
| Infection | 3.5 | 14.3 | 8.3 | 6.4 | 2.6 | |
| Headache | 5.3 | 4.8 | 8.9 | 4.5 | 8.4 | |
| Pain | 3.8 | 4.8 | 4.3 | 5.4 | 4.5 | |
| Asthenia | 4.0 | 3.6 | 5.0 | 2.6 | 5.2 | |
| Accidental injury | 1.5 | 3.6 | 2.6 | 3.2 | 5.2 | |
| Flu syndrome | 1.3 | 1.2 | 1.7 | 2.2 | 1.3 | |
| Face edema | 0.8 | 0.0 | 1.7 | 1.3 | 3.2 | |
| Malaise | 1.0 | 2.4 | 0.3 | 0.6 | 0.0 | |
| Cardiovascular system | ||||||
| Vasodilatation | 1.3 | 2.4 | 1.0 | 0.6 | 0.0 | |
| Digestive system | ||||||
| Dry mouth | 2.8 | 7.1 | 7.0 | 6.1 | 14.9 | |
| Constipation | 2.3 | 3.6 | 4.6 | 5.4 | 5.2 | |
| Diarrhea | 4.0 | 2.4 | 4.3 | 3.5 | 4.5 | |
| Flatulence | 1.0 | 2.4 | 1.3 | 1.6 | 3.2 | |
| Vomiting | 0.8 | 1.2 | 0.7 | 2.9 | 2.6 | |
Table 3. Incidence (%) of Treatment-Emergent Adverse Events in Placebo-Controlled Studies in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 2% of Patients Receiving Pregabalin and More Frequent Than in Placebo-Treated Patients) | ||||||
|---|---|---|---|---|---|---|
| Body System Preferred Term | Placebo (N = 398) % | Pregabalin (mg/day) | ||||
| 75 | 150 | 300 | 600 | |||
| (N =84) | (N = 302) | (N = 312) | (N = 154) | |||
| % | % | % | % | |||
| Metabolic and nutritional disorders | ||||||
| Peripheral edema | 3.5 | 0.0 | 7.9 | 15.7 | 16.2 | |
| Weight gain | 0.3 | 1.2 | 1.7 | 5.4 | 6.5 | |
| Edema | 1.3 | 0.0 | 1.0 | 2.2 | 5.8 | |
| Hyperglycemia | 0.8 | 2.4 | 0.3 | 0.0 | 0.0 | |
| Nervous system | ||||||
| Dizziness | 9.3 | 10.7 | 17.9 | 31.4 | 37.0 | |
| Somnolence | 5.3 | 8.3 | 12.3 | 17.9 | 24.7 | |
| Ataxia | 0.5 | 1.2 | 2.0 | 5.4 | 9.1 | |
| Abnormal gait | 0.5 | 0.0 | 2.0 | 3.8 | 7.8 | |
| Confusion | 0.3 | 1.2 | 2.3 | 2.9 | 6.5 | |
| Thinking abnormal a | 1.5 | 0.0 | 1.7 | 1.3 | 5.8 | |
| Incoordination | 0.0 | 2.4 | 1.7 | 1.3 | 2.6 | |
| Amnesia | 0.0 | 0.0 | 1.0 | 1.3 | 3.9 | |
| Speech disorder | 0.0 | 0.0 | 0.3 | 1.3 | 3.2 | |
| Insomnia | 1.8 | 0.0 | 0.7 | 2.2 | 0.0 | |
| Euphoria | 0.0 | 2.4 | 0.0 | 1.3 | 1.3 | |
| Nervousness | 0.5 | 0.0 | 1.0 | 0.3 | 2.6 | |
| Tremor | 1.5 | 1.2 | 0.0 | 1.0 | 2.6 | |
| Hallucinations | 0.0 | 0.0 | 0.3 | 0.3 | 3.2 | |
| Hyperesthesia | 0.3 | 2.4 | 0.3 | 0.0 | 1.3 | |
| Respiratory system | ||||||
| Bronchitis | 0.8 | 0.0 | 1.3 | 1.0 | 2.6 | |
| Pharyngitis | 0.8 | 0.0 | 2.6 | 0.6 | 0.6 | |
| Rhinitis | 1.8 | 1.2 | 0.7 | 0.6 | 3.2 | |
| Skin and appendages | ||||||
| Rash | 3.0 | 2.4 | 2.0 | 2.9 | 5.2 | |
| Special senses | ||||||
| Blurred vision b | 2.5 | 1.2 | 5.0 | 5.1 | 9.1 | |
| Diplopia | 0.0 | 0.0 | 1.7 | 1.9 | 3.9 | |
| Abnormal vision | 0.3 | 0.0 | 1.0 | 1.6 | 5.2 | |
| Urogenital system | ||||||
| Urinary tract infection | 1.5 | 0.0 | 2.3 | 1.6 | 3.2 | |
a
Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slow thinking.
b
Investigator term; summary level term is amblyopia.
Discontinuation in Controlled Clinical Studies of Postherpetic Neuralgia
Approximately 14% of patients receiving pregabalin and 7% receiving placebo discontinued from controlled postherpetic neuralgia studies due to adverse events. The adverse events most commonly leading to discontinuation are presented in Table 4.
Table 4. Adverse Events Most Frequently (>=2% of patients) Leading to Discontinuation in Placebo-Controlled Studies in Patients With Neuropathic Pain Associated with Postherpetic Neuralgia | |||||
|---|---|---|---|---|---|
| Number (%) of Patients | |||||
| COSTART Preferred Term | Placebo (N = 398) | Pregabalin (mg/day) | |||
| 75 (N =84) | 150 (N = 302) | 300 (N = 312) | 600 (N = 154) | ||
| Dizziness | 3 (0.8) | 0 (0.0) | 11 (3.6) | 12 (3.8) | 12 (7.8) |
| Somnolence | 1 (0.3) | 0 (0.0) | 6 (2.0) | 12 (3.8) | 10 (6.5) |
| Confusion | 1 (0.3) | 0 (0.0) | 2 (0.7) | 5 (1.6) | 8 (5.2) |
| Peripheral edema | 1 (0.3) | 0 (0.0) | 2 (0.7) | 5 (1.6) | 5 (3.2) |
| Ataxia | 0 (0.0) | 0 (0.0) | 1 (0.3) | 5 (1.6) | 4 (2.6) |
| Abnormal gait | 0 (0.0) | 0 (0.0) | 0 (0.0) | 4 (1.3) | 4 (2.6) |
| Hallucinations | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) | 4 (2.6) |
| Dry mouth | 1 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 4 (2.6) |
Incidence of Most Common Dose-Related Treatment-Emergent Adverse Events
Most common dose-related treatment-emergent adverse events are presented in Table 5 (diabetic peripheral neuropathy) and Table 6 (post-herpetic neuralgia).
Table 5. Incidence (%) of Most Common Dose-Related Treatment-Emergent Adverse Events in Placebo-Controlled Studies in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy | |||||
|---|---|---|---|---|---|
| Adverse Event Preferred Term | Placebo (N = 459) % | Pregabalin (mg/day) | |||
| 75 | 150 | 300 | 600 | ||
| (N =77) | (N = 212) | (N = 321) | (N = 369) | ||
| % | % | % | % | ||
| Dizziness | 4.6 | 7.8 | 9.0 | 23.1 | 29.0 |
| Somnolence | 2.6 | 3.9 | 6.1 | 13.1 | 16.3 |
| Peripheral edema | 2.4 | 3.9 | 6.1 | 9.3 | 12.5 |
| Asthenia | 2.4 | 3.9 | 1.9 | 4.4 | 7.3 |
| Dry mouth | 1.1 | 2.6 | 1.9 | 4.7 | 6.5 |
| Weight gain | 0.4 | 0.0 | 4.2 | 3.7 | 6.2 |
| Constipation | 1.5 | 0.0 | 2.4 | 3.7 | 6.0 |
| Blurred vision a | 1.5 | 2.6 | 1.4 | 2.8 | 5.7 |
a
Investigator term; summary level term is amblyopia.
Table 6. Incidence (%) of Most Common Dose-Related Treatment-Emergent Adverse Events in Placebo-Controlled Studies in Neuropathic Pain Associated with Postherpetic Neuralgia | |||||
|---|---|---|---|---|---|
| Adverse Event Preferred Term | Placebo (N = 398) % | Pregabalin (mg/day) | |||
| 75 | 150 | 300 | 600 | ||
| (N =84) | (N = 302) | (N = 312) | (N = 154) | ||
| % | % | % | % | ||
| Dizziness | 9.3 | 10.7 | 17.9 | 31.4 | 37.0 |
| Somnolence | 5.3 | 8.3 | 12.3 | 17.9 | 24.7 |
| Peripheral edema | 3.5 | 0.0 | 7.9 | 15.7 | 16.2 |
| Dry mouth | 2.8 | 7.1 | 7.0 | 6.1 | 14.9 |
| Blurred vision a | 2.5 | 1.2 | 5.0 | 5.1 | 9.1 |
| Ataxia | 0.5 | 1.2 | 2.0 | 5.4 | 9.1 |
| Weight gain | 0.3 | 1.2 | 1.7 | 5.4 | 6.5 |
| Abnormal gait | 0.5 | 0.0 | 2.0 | 3.8 | 7.8 |
a
Investigator term; summary level term is amblyopia.
NOC/c
Adverse Events From a Controlled Clinical Study in Central Neuropathic Pain Associated With Spinal Cord Injury
The most commonly observed treatment-related adverse events (>= 5% and twice the rate of that seen in placebo) in pregabalin-treated patients were: somnolence, dizziness, asthenia, dry mouth, edema, myasthenia, constipation, thinking abnormal, amblyopia, and amnesia. Adverse events were usually mild to moderate in intensity. Table 7 lists all adverse events, regardless of causality, occurring in >= 2% of patients receiving pregabalin and for which the incidence was greater than in the placebo group. A majority of pregabalin-treated patients had adverse events with a maximum intensity of mild or moderate. In this study, 70 patients received pregabalin and 67 patients received placebo for up to 12 weeks.
NOC/c
Table 7. Incidence (%) of Treatment-Emergent Adverse Events in a Placebo-Controlled Study in Central Neuropathic Pain Associated With Spinal Cord Injury (Events in at Least 2% of Patients Receiving Pregabalin and More Frequent Than in Placebo-Treated Patients)
| Body System Preferred Term | Placebo N = 67 % | Pregabalin (150 - 600 mg/day) N = 70 % |
| Body as a whole | ||
| Asthenia | 6.0 | 15.7 |
| Infection | 6.0 | 8.6 |
| Abdomen enlarged | 0.0 | 4.3 |
| Pain | 1.5 | 4.3 |
| Back pain | 1.5 | 2.9 |
| Cellulitis | 0.0 | 2.9 |
| Flu syndrome | 1.5 | 2.9 |
| Neck pain | 1.5 | 2.9 |
| Cardiovascular System | ||
| Hypotension | 0.0 | 2.9 |
| Digestive system | ||
| Dry mouth | 3.0 | 15.7 |
| Constipation | 6.0 | 12.9 |
| Gastroenteritis | 0.0 | 2.9 |
| Increased appetite | 0.0 | 2.9 |
| Metabolic and nutritional disorders | ||
| Edema | 0.0 | 12.9 |
| Peripheral edema | 6.0 | 10.0 |
| Weight gain | 0.0 | 4.3 |
| Musculoskeletal System | ||
| Myasthenia | 4.5 | 8.6 |
| Joint disorder | 0.0 | 2.9 |
| Nervous system | ||
| Somnolence | 9.0 | 41.4 |
| Dizziness | 9.0 | 24.3 |
| Amnesia | 3.0 | 10.0 |
| Thinking abnormal a | 1.5 | 8.6 |
| Paresthesia | 1.5 | 5.7 |
| Euphoria | 0.0 | 4.3 |
| Speech disorder | 1.5 | 4.3 |
| Twitching | 0.0 | 4.3 |
| Withdrawal syndrome | 0.0 | 4.3 |
| Skin and appendages | ||
| Skin ulcer | 1.5 | 4.3 |
| Alopecia | 0.0 | 2.9 |
| Vesiculobullous rash | 0.0 | 2.9 |
| Special senses | ||
| Blurred vision b | 3.0 | 8.6 |
| Diplopia | 1.5 | 2.9 |
| Tinnitus | 0.0 | 2.9 |
| Urogenital System | ||
| Urinary incontinence | 3.0 | 5.7 |
| a Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slow thinking. b Investigator term; summary level term is amblyopia. | ||
NOC/c
Discontinuation in a Controlled Clinical Study in Central Neuropathic Pain Associated With Spinal Cord Injury
Approximately 21% of patients receiving pregabalin and 13% receiving placebo discontinued due to adverse events. The adverse events most commonly leading to discontinuation are presented in Table 8.
Table 8. Adverse Events Most Frequently (>=2% of patients) Leading to Discontinuation in a Placebo-Controlled Study in Patients With Central Neuropathic Pain Associated with Spinal Cord Injury
| Number (%) of Patients | ||
| COSTART Preferred Term | Placebo (N = 67) | Pregabalin (N = 70) 150 - 600 mg/day |
| Somnolence | 0 (0.0) | 4 (5.7) |
| Edema | 0 (0.0) | 4 (5.7) |
| Asthenia | 0 (0.0) | 3 (4.3) |
Overall, the most frequent treatment-related adverse events in the open-label study were related to the nervous system and included: somnolence (18.4%), dizziness (16.5%), and insomnia (10.7%). Other frequent treatment-related adverse events included: asthenia (12.6%), nausea (11.7%), and constipation (10.7%).
Adverse Events Following Abrupt or Rapid Discontinuation
Following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache, and diarrhea. Pregabalin should be tapered gradually over a minimum of one week rather than discontinued abruptly [see WARNINGS AND PRECAUTIONS, Abrupt or Rapid Discontinuation].
Other Events Observed During the Premarketing Evaluation of LYRICA
Following is a list of treatment-emergent adverse events reported during premarketing assessment of LYRICA in clinical trials (over 8600 adult subjects) except those already listed in the previous tables or elsewhere in labeling. In the tabulations that follow, a COSTART-based dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the over 8600 adult individuals exposed to multiple doses of LYRICA who experienced an event of the type cited on at least 1 occasion while receiving LYRICA. It is important to emphasize that although the events reported occurred during treatment with LYRICA, they were not necessarily caused by it.
Less Common Clinical Trial Adverse Drug Reactions (<2%)
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. | |
|---|---|
| Body System | Adverse Events |
| Body as a whole | |
| Frequent | Flu syndrome, back pain, allergic reaction, fever, generalized edema |
| Infrequent | Neck pain, neoplasm, cellulitis, cyst, chills, malaise, overdose, moniliasis, hernia, viral infection, photosensitivity reaction, pelvic pain, abdomen enlarged, abscess, neck rigidity, lab test abnormal, drug level increased, carcinoma, sepsis, suicide attempt, reaction unevaluable |
| Rare | Infection fungal, unexpected benefit, chills and fever, body odor, drug level decreased, halitosis, hangover effect, injection site reaction, hormone level altered, hypothermia, infection bacterial, injection site hemorrhage, intentional overdose, mucous membrane disorder, accidental overdose, adenoma, anaphylactoid reaction, ascites, chest pain substernal, death, sarcoidosis, sudden death, immune system disorder, increased drug effect, injection site pain, Lupus Erythematosus syndrome, medication error, sarcoma, shock, tolerance decreased |
| Cardiovascular | |
| Frequent | Hypertension, vasodilatation |
| Infrequent | Palpitation, migraine, tachycardia, peripheral vascular disorder, electrocardiogram abnormal, cardiovascular disorder, angina pectoris, congestive heart failure, hemorrhage, myocardial infarct, hypotension, postural hypotension, ventricular extrasystoles, atrial fibrillation, coronary artery disorder, bradycardia, cerebrovascular accident, arrhythmia, cerebral ischemia, vascular disorder, sinus bradycardia, myocardial ischemia, bundle branch block, AV block first degree, arteriosclerosis, deep thrombophlebitis, phlebitis, arterial anomaly, heart failure, pulmonary embolus, retinal vascular disorder, varicose vein |
| Rare | Heart arrest, vascular anomaly, occlusion, supraventricular tachycardia, atrial arrhythmia, atrial flutter, cerebral infarct, coronary occlusion, thrombophlebitis, thrombosis, cardiomegaly, extrasystoles, pallor, AV block, AV block second degree, cardiomyopathy, peripheral gangrene, QT interval prolonged, retinal artery occlusion, supraventricular extrasystoles, cerebral hemorrhage, digitalis intoxication, ventricular arrhythmia, aortic stenosis, bigeminy, cerebrovascular disorder, left heart failure, ventricular tachycardia, AV block complete, carotid occlusion, carotid thrombosis, cor pulmonale, embolus lower extremity, endocarditis, heart block, increased capillary fragility, intracranial aneurysm, nodal tachycardia, QT interval shortened, retinal vein thrombosis, ST elevated, T inverted, vascular headache, vasculitis |
| Digestive system | |
| Frequent | Nausea, diarrhea, anorexia, gastrointestinal disorder |
| Infrequent | Gastroenteritis, tooth disorder, periodontal abscess, colitis, gastritis, liver function tests abnormal, increased salivation, thirst, nausea and vomiting, rectal disorder, gingivitis, dysphagia, stomatitis, mouth ulceration, cholelithiasis, rectal hemorrhage, gastrointestinal hemorrhage, glossitis, tooth caries, abnormal stools, cholecystitis, melena, oral moniliasis, esophagitis, tongue disorder, cheilitis, tongue edema |
| Rare | Eructation, pancreatitis, stomach ulcer, ulcerative stomatitis, esophageal stenosis, fecal incontinence, gum hemorrhage, intestinal obstruction, enteritis, peptic ulcer, enterocolitis, gum hyperplasia, hepatomegaly, liver fatty deposit, tenesmus, biliary pain, fecal impaction, jaundice, periodontitis, ulcerative colitis, aphthous stomatitis, cholestatic jaundice, gastrointestinal carcinoma, hemorrhagic gastritis, hepatitis, liver tenderness, nausea, vomiting and diarrhea, salivary gland enlargement, stomach atony, bloody diarrhea, cardiospasm, duodenal ulcer, gamma glutamyl transpeptidase increased, hematemesis, hepatoma, intestinal perforation, intestinal stenosis, intestinal ulcer, leukoplakia of mouth, necrotizing pancreatitis, pancreas disorder, pseudomembranous colitis, sialadenitis, stomach ulcer hemorrhage, tongue discoloration |
| Endocrine system | |
| Infrequent | Diabetes mellitus, hypothyroidism |
| Body System | Adverse Events |
| Rare | Goiter, prolactin increased, thyroid disorder, gonadotropic follicle stim hormone increase, hyperthyroidism, thyroiditis, adrenal insufficiency, parathyroid disorder, thyroid carcinoma, thyroid neoplasia, virilism |
| Hemic and lymphatic | |
| Infrequent | Anemia, leukopenia, thrombocytopenia, lymphadenopathy, hypochromic anemia, leukocytosis, eosinophilia |
| Rare | Lymphocytosis, petechia, iron deficiency anemia, cyanosis, lymphedema, polycythemia, lymphoma like reaction, megaloblastic anemia, splenomegaly, purpura, thrombocythemia, thrombocytopenic purpura, chronic leukemia, coagulation disorder, erythrocytes abnormal, leukemoid reaction, lymphangitis, macrocytic anemia, pancytopenia, prothrombin decreased, rupture of spleen, sedimentation rate increased |
| Metabolic and nutritional | |
| Infrequent | Hyperglycemia, SGPT increased, hypoglycemia, hypokalemia, hypercholesteremia, SGOT increased, weight loss, hyperlipemia, amylase increased, hyperuricemia, alkaline phosphatase increased, creatinine increased, hyponatremia, gout, dehydration, BUN increased, healing abnormal |
| Rare | Hypercalcemia, hyperkalemia, hypocalcemia, bilirubinemia, alcohol intolerance, hypoglycemic reaction, ketosis, calcium disorder, hypochloremia, hypomagnesemia, hypoproteinemia, NPN increased, uremia, acidosis, avitaminosis, enzymatic abnormality, gamma globulins increased, hypernatremia, hypophosphatemia, lactic acidosis, obesity |
| Musculoskeletal system | |
| Frequent | Arthralgia, myalgia, arthritis, leg cramps, myasthenia |
| Infrequent | Tendon disorder, arthrosis, joint disorder, bone disorder, tenosynovitis, bursitis, tendinous contracture, osteoporosis, tendon rupture, bone pain |
| Rare | Rheumatoid arthritis, osteomyelitis, rhabdomyolysis, myopathy, muscle atrophy, myositis, pyogenic arthritis, bone neoplasm, musculoskeletal congenital anomaly, pathological fracture |
| Nervous system | |
| Frequent | Insomnia, anxiety, libido decreased, depersonalization, hypertonia, neuropathy |
| Infrequent | Reflexes decreased, sleep disorder, abnormal dreams, hostility, hallucinations, hyperkinesia, personality disorder, dysarthria, hyperesthesia, hypokinesia, circumoral paresthesia, libido increased, neuralgia, vestibular disorder, aphasia, movement disorder, hyperalgesia, apathy, hypotonia, convulsion, facial paralysis, psychosis |
| Rare | Drug dependence, neuritis, paranoid reaction, CNS depression, CNS neoplasia, manic reaction, neurosis, extrapyramidal syndrome, meningitis, hemiplegia, reflexes increased, akathisia, delirium, paralysis, withdrawal syndrome, brain edema, CNS stimulation, dyskinesia, encephalopathy, foot drop, grand mal convulsion, hypalgesia, peripheral neuritis, psychotic depression, addiction, arachnoiditis, cerebellar syndrome, cogwheel rigidity, dementia, dystonia, Guillain-Barre syndrome, intracranial hemorrhage, multiple sclerosis, myelitis, schizophrenic reaction, subarachnoid hemorrhage, torticollis |
| Respiratory system | |
| Frequent | Sinusitis, rhinitis, dyspnea, cough increased, pneumonia, lung disorder |
| Infrequent | Asthma, epistaxis, laryngitis, voice alteration, respiratory disorder, sputum increased |
| Rare | Apnea, emphysema, aspiration pneumonia, hyperventilation, lung edema, pleural disorder, |
| Body System | Adverse Events |
| atelectasis, hemoptysis, hiccup, hypoxia, laryngismus, lung fibrosis, pleural effusion, lung function decreased, pulmonary hypertension, yawn, bronchiectasis, bronchiolitis, carcinoma of lung, hypoventilation, laryngeal neoplasia, nasal septum disorder, pneumothorax | |
| Skin and appendages | |
| Infrequent | Pruritus, sweating, skin disorder, acne, dry skin, alopecia, skin ulcer, herpes simplex, urticaria, nail disorder, eczema, herpes zoster, skin benign neoplasm, fungal dermatitis, maculopapular rash, vesiculobullous rash, skin carcinoma, furunculosis, skin discoloration, skin hypertrophy, psoriasis, seborrhea, hirsutism |
| Rare | Skin nodule, angioedema, cutaneous moniliasis, skin atrophy, exfoliative dermatitis, pustular rash, ichthyosis, skin melanoma, subcutaneous nodule, sweating decreased, hair disorder, lichenoid dermatitis, melanosis, miliaria, purpuric rash, skin necrosis, Stevens Johnson Syndrome |
| Special sense | |
| Frequent | Eye disorder, conjunctivitis, otitis media |
| Infrequent | Retinal disorder, tinnitus, eye pain, cataract specified, dry eyes, taste perversion, ear pain, lacrimation disorder, ear disorder, deafness, eye hemorrhage, photophobia, glaucoma, vitreous disorder, corneal lesion, otitis externa, refraction disorder, blepharitis, retinal edema, taste loss, abnormality of accommodation |
| Rare | Hyperacusis, keratitis, mydriasis, parosmia, ptosis, retinal hemorrhage, color blindness, retinal depigmentation, retinal detachment, corneal opacity, corneal ulcer, iritis, night blindness, optic atrophy, retinal degeneration, cataract NOS, scleritis, strabismus, anisocoria, blindness, exophthalmos, keratoconjunctivitis, ophthalmoplegia, papilledema |
| Urogenital system | |
| Frequent | Anorgasmia |
| Infrequent | Urinary frequency, urinary incontinence, cystitis, abnormal ejaculation, urination impaired, dysuria, metrorrhagia, hematuria, vaginal moniliasis, prostatic disorder, vaginitis, dysmenorrhea, urinary urgency, kidney calculus, breast pain, menstrual disorder, amenorrhea, menorrhagia, kidney function abnormal, nephritis, urine abnormality, vaginal hemorrhage, urinary retention, urinary tract disorder, leukorrhea, breast neoplasm, menopause, oliguria, polyuria, albuminuria, pyuria, |
| Rare | Breast carcinoma, penis disorder, papanicolau smear suspicious, fibrocystic breast, prostatic carcinoma, uterine fibroids enlarged, acute kidney failure, creatinine clearance decreased, nephrosis, nocturia, polycystic kidney, bladder carcinoma, breast enlargement, cervicitis, cervix disorder, female lactation, glycosuria, gynecomastia, hypomenorrhea, kidney pain, mastitis, pyelonephritis, kidney failure, breast abscess, epididymitis, orchitis, prostate neoplasia, prostatic specific antigen increase, salpingitis, urogenital disorder, urolithiasis, uterine disorder, vulvovaginal disorder, balanitis, bladder calculus, calcium crystalluria, cervix neoplasm, dyspareunia, endometrial carcinoma, endometrial disorder, glomerulitis, hydronephrosis, ovarian cancer, unintended pregnancy, urethral pain, urethritis, urogenital anomaly, urogenital neoplasia, uterine hemorrhage |
Comparison of Gender and Race
The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race.
Peripheral Edema
Incidence of peripheral edema in pre-marketing controlled peripheral neuropathic pain studies was 10.4% in the pregabalin group compared with 2.9% in the placebo group. In clinical trials, these events of peripheral edema were dose-related, mostly mild to moderate in intensity and rarely led to withdrawal. Peripheral edema was not associated with cardiovascular complications such as hypertension or congestive heart failure and there was no evidence of hemodilution or changes in any laboratory parameters indicative of underlying organ dysfunction (See WARNINGS AND PRECAUTIONS - Peripheral Edema).
Weight Gain
In the pre-marketing controlled peripheral neuropathic pain studies, patients on pregabalin had a higher incidence (5.9%) of weight gain as defined by a >= 7% increase from baseline weight as compared with the placebo group (1.6%). The mean change in the pregabalin group was an increase of 1.5 kg compared with 0.2 kg in the placebo group; few patients (0.1%) withdrew due to weight gain. This weight gain was dose-related, and not associated with clinically important changes in blood pressure or cardiovascular adverse events. There was no relationship between baseline body mass index and the incidence of >= 7% weight gain in the controlled trials. Based on the results of a controlled study of reproductive function in healthy male volunteers, the >= 7% weight gain on pregabalin appeared to be reversible. In this study, there were no reports of peripheral edema (See WARNINGS AND PRECAUTIONS - Weight Gain).
Abnormal Hematologic And Clinical Chemistry Findings
In all pre-marketing controlled trials, 1.0% of patients on pregabalin and 0.5% of placebo patients had an increase in creatine kinase of >3X upper limit of normal. Renal dysfunction was generally not associated with the elevated creatine kinase in these patients. Mean changes in creatine kinase ranged from 9.6 to 26.3 U/L for pregabalin-treated patients and 4.8 U/L for the placebo patients (see DOSAGE AND ADMINISTRATION, Patients With Renal Impairment). Routine therapeutic drug monitoring or clinical laboratory testing is not required for patients treated with LYRICA (see WARNINGS AND PRECAUTIONS, Creatinine Kinase Elevations).
Post-Marketing Adverse Drug Reactions
The worldwide post-marketing experience to date with LYRICA is consistent with the clinical program. The following adverse events have also been reported during post-marketing experience with LYRICA are shown below. There are insufficient data to support an estimate of their incidence or to establish causation. Cardiovascular: congestive heart failure. These reactions are mostly seen in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic pain indication (see WARNINGS AND PRECAUTIONS, Congestive Heart Failure).
Eye disordersWARNINGS AND PRECAUTIONS, Opthalmological Effects
: diplopia, vision blurred, visual disturbance. There have also been rare reports of accommodation disorder, eyelid edema and eye redness (see
)
Gastrointestinal disorders
: diarrhea, dry mouth, nausea, vomiting
General disorders and administration site conditions
: fatigue, feeling abnormal, pain
Nervous system disordersWARNINGS AND PRECAUTIONS, Dizziness and Somnolence
: ataxia, coordination abnormal, dizziness, dysarthria, headache, memory impairment, paresthesia, somnolence, speech disorder, tremor (see
)
Psychiatric disorders:
confusional state, depression, insomnia, psychotic disorder. There have been rare reports of psychotic disorders in patients receiving pregabalin.
Renal and urinary disorders: Respiratory, thoracic and mediastinal disorders: Skin and subcutaneous tissue disorders:
urinary retention
dyspnea
pruritus
Drug Abuse and Dependence/Liability
In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, a single dose of LYRICA (pregabalin) 450 mg received subjective ratings of "good drug effect", "high", and "liking" to a degree that was similar to a single dose of diazepam 30 mg. In controlled clinical studies in over 5500 patients, 4% of LYRICA-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse event. However, in clinical trials of diabetic peripheral neuropathy, euphoria was reported as an adverse event by 1.8% of LYRICA-treated patients and 0 % of placebo-treated patients, and in clinical trials of postherpetic neuralgia, euphoria was reported as an adverse event by 0.9% of LYRICA-treated patients and 0% of placebo-treated patients. In clinical studies, following abrupt or rapid discontinuation of pregabalin, some patients reported symptoms including insomnia, nausea, headache or diarrhea suggestive of physical dependence [see WARNINGS AND
].
Pregabalin is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, physicians should carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behaviour).
Overview
Since pregabalin is predominately excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), does not inhibit drug metabolism in vitro, and is not bound to plasma proteins, LYRICA (pregabalin) is unlikely to produce, or be subject to, pharmacokinetic interactions.
Pharmacokinetic
: In vitro drug metabolism studies revealed that pregabalin at concentrations which were, in general, 10-fold greater than observed in Phase 2/3 clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4
enzyme systems.
: The drug interaction data described in this section were obtained from studies involving healthy adults, patients with epilepsy, and patients with chronic pain disorders.
In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no clinically significant 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.
: The results of a population pharmacokinetic analysis indicated that in patients with partial seizures tiagabine had no clinically significant effect on pregabalin clearance.
: The pharmacokinetics of pregabalin and gabapentin were investigated in
12 healthy subjects following concomitant single dose administration of 100 mg pregabalin and 300 mg gabapentin, and in 18 healthy subjects following concomitant multiple dose administration of 200 mg pregabalin q8h and 400 mg gabapentin q8h. Gabapentin pharmacokinetics following single and multiple dose administration were unaltered by pregabalin coadministration. The rate of pregabalin absorption was reduced by approximately 26% (single dose administration) and 18% (multiple dose administration) based on lower Cmax values; however, the extent of pregabalin absorption was unaffected by gabapentin coadministration.
: Pregabalin coadministration (200 mg TID) had no effect on the steady state pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 ug, respectively) in healthy subjects.
: Multiple dose administration of pregabalin (300 mg BID) in healthy subjects had no effect on the rate and extent of lorazepam single dose pharmacokinetics and single dose administration of lorazepam (1 mg) had no clinically significant effect on the steady state pharmacokinetics of pregabalin.
: Multiple dose administration of pregabalin (300 mg BID) in healthy subjects had no effect on the rate and extent of oxycodone single dose pharmacokinetics. Single dose administration of oxycodone (10 mg) had no clinically significant effect on the steady state pharmacokinetics of pregabalin.
: Multiple dose administration of pregabalin (300 mg BID) in healthy subjects had no effect on the rate and extent of ethanol single dose pharmacokinetics and single dose administration of ethanol (0.7 g/kg) had no clinically significant effect on the steady state pharmacokinetics of pregabalin.
: A population pharmacokinetic analysis in patients with chronic pain showed no clinically significant effect on pregabalin clearance with the concomitant use of diuretics, oral hypoglycemics, and insulin.
Pharmacodynamic
Multiple oral doses of pregabalin co-administered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone. Pregabalin may potentiate the effects of ethanol and lorazepam.
Drug-Food Interactions
The rate of pregabalin absorption is decreased when given with food resulting in a decrease in Cmax by approximately 25% to 30% and an increase in Tmax to approximately 3 hours. However, administration of pregabalin with food has no clinically relevant effect on the total amount of pregabalin absorbed. Therefore, pregabalin can be taken with or without food.
Drug-Herb Interactions
LYRICA (pregabalin) has no known drug/herb interactions.
Drug-Laboratory Interactions
LYRICA has no known drug/laboratory test interactions.
Dosing Considerations
Patients with Impaired Renal Function
In accordance with current clinical practice, if LYRICA (pregabalin) has to be discontinued, it is recommended this should be done gradually over a minimum of 1 week. (see WARNINGS AND PRECAUTIONS, Abrupt or Rapid Discontinuation).
Adults:
The recommended starting dose for LYRICA is 150 mg/day, given in two or three divided doses (75 mg BID or 50 mg TID), with or without food in patients with a creatinine clearance rate of at least 60 mL/min. Efficacy of LYRICA has been demonstrated within the first week. Based on individual patient response and tolerability, the dose may be increased to 150 mg BID (300 mg/day) after one week. For patients who experience significant and ongoing pain and can tolerate pregabalin 300 mg/day well, maximum daily dose of 600 mg (300 mg twice a day, BID) can be used. However, in clinical trials, LYRICA 600 mg/day did not provide additional significant efficacy and patients treated with this dose experienced markedly higher rates of adverse events and discontinued the trial more frequently.
The recommended starting dose for LYRICA is 150 mg/day, given in two or three divided doses (75 mg BID or 50 mg TID), with or without food in patients with a creatinine clearance rate of at least 60 mL/min. Efficacy of LYRICA has been demonstrated within the first week. Based on individual patient response and tolerability, the dose may be increased to 150 mg BID (300 mg/day) after one week. For patients who experience significant and ongoing pain and can tolerate pregabalin 300 mg/day well, maximum daily dose of 600 mg (300 mg twice a day, BID) can be used. However, in clinical trials, LYRICA 600 mg/day did not provide additional significant efficacy and patients treated with this dose experienced markedly higher rates of adverse events and discontinued the trial more frequently.
The recommended starting dose for LYRICA is 150 mg/day, given in two divided doses (75 mg BID), with or without food in patients with a creatinine clearance rate of at least 60 mL/min. Efficacy of LYRICA has been demonstrated within the first week. Based on individual patient response and tolerability, the dose may be increased to 150 mg BID (300 mg/day) after one week. For patients who experience significant and ongoing pain and can tolerate pregabalin 300 mg/day well, a maximum daily dose of 600 mg (300 mg twice a day, BID) may be considered.
Dosage Adjustment Based on Renal Function
LYRICA is primarily eliminated by renal excretion. Therefore, the dose should be adjusted for patients with reduced renal function. Pregabalin clearance is directly proportional to creatinine clearance. Therefore, dosing adjustment should be based on creatinine clearance (CLCr), as indicated in Table 7. To use this dosing table, an estimate of the patient's creatinine clearance (CLCr) in mL/min is needed. CLCr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation:
[140 - age (years)] x weight(kg)
( x 0.85 for female patients)
creatinine (mg/dL)
Pregabalin is effectively removed from plasma by hemodialysis. Over a 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients receiving hemodialysis, pregabalin daily dose should be adjusted based on renal function. In addition to the daily dose adjustment, a supplemental dose should be given immediately following every 4-hour hemodialysis treatment (see Table 9).
Table 9. Pregabalin Dosage Adjustment Based on Renal Function | ||||
|---|---|---|---|---|
| Creatinine Clearance (CLcr) (mL/min) | Total Pregabalin Daily Dose (mg/day) a Recommended Dose Escalation * | Dose Regimen | ||
| Starting dose | Maximum daily dose | |||
| >= 60 | 150 | 300 | 600 | BID or TID |
| 30-60 | 75 | 150 | 300 | BID or TID |
| 15-30 | 25-50 | 75 | 150 | QD or BID |
| <15 | 25 | 25-50 | 75 | QD |
| Supplementary dosage following hemodialysis (mg) b | ||||
| Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25-50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg | ||||
TID = Three divided doses; BID = Two divided doses; QD = Single daily dose.
* Based on individual patient response and tolerability.
Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose.
Supplementary dose is a single additional dose.
Geriatrics (> 65 years):
Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in creatinine clearance. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function.
Pediatrics (<18 years of age):
The safety and efficacy of pregabalin in pediatric patients (<18 years of age) have not been established and its use in this patient population is not recommended.
Administration
LYRICA (pregabalin) is given orally with or without food (see DRUG INTERACTIONS, Drug Food Interactions).
The highest known dose of pregabalin received in the clinical development program was 15,000 mg in 1 patient. The types of adverse events experienced by patients who received an overdose were not clinically different from other patients receiving recommended doses of pregabalin.
There is no specific antidote for overdose with pregabalin. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. A Certified Poison Control Center should be contacted for up-to-date information on the management of overdose with pregabalin.
Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient's clinical state or in patients with significant renal impairment.
Mechanism of Action
Pharmacodynamics
LYRICA (pregabalin) binds with high affinity to the alpha2-delta protein (a calcium channel subunit) of brain tissues and has analgesic, antiepileptic, and anxiolytic activity. Pregabalin is known chemically as (S)-3-(aminomethyl)-5-methylhexanoic acid. Although the mechanism of action of pregabalin is unknown, results with genetically modified mice and with compounds structurally-related to pregabalin indicate that selective binding to the alpha2-delta protein is required for analgesic, antiepileptic and anxiolytic action in animal models. In vitro, pregabalin reduces the release of several neurotransmitters, suggesting a modulatory action on calcium channel function. Pregabalin does not mimic GABA at GABAA or GABAB receptors, nor does it augment GABAA responses like benzodiazepines or barbiturates. In contrast to vascular calcium channel blockers, pregabalin does not alter systemic blood pressure or cardiac function. Various in vitro and in vivo results differentiate pregabalin from GABA uptake inhibitors or GABA transaminase inhibitors. In addition, pregabalin does not block sodium channels, it is not active at opiate receptors, it does not alter cyclooxygenase enzyme activity, it is not a serotonin agonist, it is not a dopamine antagonist, and it is not an inhibitor of dopamine, serotonin or noradrenaline reuptake. Pregabalin treatment reduces pain-related behavior in neuropathic animal models of diabetes, peripheral nerve damage or chemotherapeutic insult and in a model of musculoskeletal-associated pain. Pregabalin given intrathecally prevents pain-related behaviors and reduces pain-related behavior caused by spinally administered agents, suggesting that it acts directly on tissues of the spinal cord or brain.
Pharmacokinetics
All pharmacological actions following pregabalin administration are due to the activity of the parent compound; pregabalin is not appreciably metabolized in humans. Mean steady-state plasma pregabalin concentration-time profiles following 75, 300, and 600 mg/day given in equally divided doses every 8 hours (TID) and 600 mg/day given in equally divided doses every 12 hours (BID) are shown in Table 10. Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject pharmacokinetic variability for pregabalin is low (<20%).
Table 10. Pregabalin Mean (CV%a) Steady-State Pharmacokinetic Parameter Values in Healthy Volunteers
| Dose (mg) | Regimen | Daily Dose (mg/day) | N | C maxss (mg/mL) | t m ax (hr) | C minss (mg/mL) | A UC (0-t) (mg @ hr/mL) | t 2 (hr) | C L/F (mL/min) |
| 25 | TID b | 75 | 8 | 1.39 | 0.9 | 0.45 | 6.7 | 5.9 | 64.1 |
| -19.5 | -34.2 | -25 | -18.3 | -17.3 | -16.1 | ||||
| 100 | TID | 300 | 6 | 5.03 | 0.8 | 1.94 | 25.2 | 6.3 | 68.9 |
| -21.3 | -31 | -33.6 | -23 | -19.6 | -20.9 | ||||
| 200 | TID | 600 | 11 | 8.52 | 0.9 | 3.28 | 41.7 | 6.3 | 81 |
| -14.8 | -22.2 | -29.2 | -12.8 | -13.6 | -11.7 | ||||
| 300 | BID c | 600 | 8 | 9.07 | 1.4 | 2.6 | 59 | 6.7 | 85.1 |
| -10.5 | -57.1 | -15.5 | -6.4 | -16.2 | -6.4 |
Cmaxss: Steady-state peak plasma concentration.
tmax: Time of peak plasma concentration at steady state.
Cminss: Steady-state trough plasma concentration
AUC(0-t): Area under the plasma concentration-time curve during one dosing interval at steady state
t2: Elimination half-life
CL/F: Oral clearance
a
: Percent coefficient of variation
b
: Total daily dose given in equally divided doses every 8 hours
c
: Total daily dose given in equally divided doses every 12 hours
Absorption: Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations occurring within 1.5 hours following both single- and multiple-dose administration. Pregabalin oral bioavailability is >= 90% and is independent of dose. Cmax (Figure 1) and AUC values increase proportionally following single- and multiple-dose administration. Following repeated administration, steady state is achieved within 24 to 48 hours. Multiple dose pharmacokinetics are predictable from single-dose data.
Figure 1. Individual and Mean Steady-State Pregabalin Cmax Values Following 75, 300 and 600 mg/day Given in Equally Divided Doses TID (q8h) to Healthy Volunteersa
a: Solid line is the regression line going through the origin; individual (# ) and mean () values.
Distribution: In preclinical studies, pregabalin has been shown to readily cross the blood brain barrier in mice, rats, and monkeys. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood-brain barrier. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. In humans, the apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is not bound to plasma proteins. At clinically efficacious doses of 150 and 600 mg/day, the average steady-state plasma pregabalin concentrations were approximately 1.5 and 6.0 mg/mL, respectively.
Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabeled pregabalin, approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, pregabalin (S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys.
Excretion: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. Pregabalin mean t1/2 is 6.3 hours. Pregabalin elimination is proportional to creatinine clearance. Pregabalin clearance is reduced in patients with impaired renal function (see DOSAGE AND ADMINISTRATION).
Special Populations and Conditions
Pregabalin undergoes negligible metabolism, is not bound to plasma proteins, and is eliminated predominately as unchanged drug by renal excretion. Clinically important differences in pregabalin pharmacokinetics due to race and gender have not been observed and are not anticipated.
Pharmacokinetics of pregabalin have not been studied in paediatric patients.
Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in creatinine clearance. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function (see
and
).
A population pharmacokinetic analysis of the Phase 2/3 clinical program showed that the relationship between daily dose and pregabalin drug exposure is similar between genders when adjusted for gender-related differences in creatinine clearance.
A population pharmacokinetic analysis of the Phase 2/3 clinical program showed that the relationship between daily dose and pregabalin drug exposure is similar among Caucasians, Blacks, and Hispanics.
Renal Insufficiency: Because renal elimination is the major elimination pathway, dosage reduction in patients with renal dysfunction is necessary. Pregabalin is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on hemodialysis, dosing must be modified (see DOSAGE AND ADMINISTRATION).
Store at 15degC-30degC.
Dosage Forms
LYRICA (pregabalin) is supplied as a hard gelatin capsule for daily oral administration. 25 mg capsules: White hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 25" on the body. 50 mg capsules: White hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 50" and an ink band on the body. 75 mg capsules: White/orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 75" on the body. 100 mg capsules: Orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 100" on the body. 150 mg capsules: White hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 150" on the body. 200 mg capsules: Light orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 200" on the body. 225 mg capsules: White/light orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 225" on the body. 300 mg capsules: White/orange hard gelatin capsule printed with black ink "Pfizer" on the cap, "PGN 300" on the body.
Composition
Each capsule of LYRICA (pregabalin) contains 25, 50, 75, 100, 150, 200, 225, or 300 mg pregabalin, lactose monohydrate, maize starch, and talc. The capsule shells contain gelatin and titanium dioxide. In addition, the orange capsule shells contain red iron oxide and the white capsule shells contain sodium lauryl sulfate and colloidal silicon dioxide. Colloidal silicon dioxide is a manufacturing aid, which may not be present. The markings on the capsules are in black ink, which contains shellac, black iron oxide, propylene glycol, potassium hydroxide and water.
Packaging
Capsules are packaged in HDPE bottles containing 60 capsules, and PVC/ aluminum blisters.