Pregabalin Extended Release

5 WARNINGS AND PRECAUTIONS Angioedema: Angioedema [e.g., swelling of the face, mouth (tongue, lips, and gums) and neck (throat and larynx)] can occur and may be associated with life-threatening respiratory compromise requiring emergency treatment. Discontinue pregabalin extended-release tablets immediately in patients with these symptoms. ( 5.1 ) Hypersensitivity reactions: Hypersensitivity reactions (e.g., hives, dyspnea, and wheezing) can occur. Discontinue pregabalin extended-release tablets immediately in these patients. ( 5.2 ) Suicidal Behavior and Ideation: Antiepileptic drugs, including pregabalin, the active ingredient in pregabalin extended-release tablets, increase the risk of suicidal thoughts or behavior. ( 5.3 ) Respiratory Depression: May occur with LYRICA when used with concomitant CNS depressants or in the setting of underlying respiratory impairment. Monitor patients and adjust dosage as appropriate. ( 5.4 ) Dizziness and Somnolence: May cause dizziness and somnolence and impair patients ability to drive or operate machinery. ( 5.5 ) Increased seizure frequency may occur in patients with seizure disorders if pregabalin extended-release tablets is rapidly discontinued. Withdraw pregabalin extended-release tablets gradually over a minimum of 1 week. ( 5.6 ) Peripheral Edema : May cause peripheral edema. Monitor patients for the development of edema when co-administering pregabalin extended-release tablets and thiazolidinedione antidiabetic agents. ( 5.7 ) 5.1 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. Discontinue pregabalin extended-release tablets immediately in patients with these symptoms. Exercise caution when prescribing pregabalin extended-release tablets 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. 5.2 Hypersensitivity Reactions There have been postmarketing reports of hypersensitivity reactions in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue pregabalin extended-release tablets immediately in patients with these symptoms. 5.3 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including pregabalin, the active ingredient in pregabalin extended-release tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood 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 to 100 years) in the clinical trials analyzed. Table 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients With Events per 1000 Patients Drug Patients With Events per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients With Events per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 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 pregabalin extended-release tablets must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Inform patients, their caregivers, and families that pregabalin extended-release tablets can increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern immediately to healthcare providers. 5.4 Respiratory Depression There is evidence from case reports, human studies, and animal studies associating pregabalin with serious, life-threatening, or fatal respiratory depression when co-administered with central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe pregabalin extended-release tablets with another CNS depressant, particularly an opioid, or to prescribe pregabalin extended-release tablets to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating pregabalin extended-release tablets at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including pregabalin extended-release tablets). There is more limited evidence from case reports, animal studies, and human studies associating pregabalin with serious respiratory depression, without co-administered CNS depressants or without underlying respiratory impairment. 5.5 Dizziness and Somnolence Pregabalin extended-release tablets may cause dizziness and somnolence. Inform patients that pregabalin extended-release tablets-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery. Concomitant use of pregabalin extended-release tablets with other central nervous system (CNS) depressants may exacerbate these effects [see Drug Interactions (7) ] . In the pregabalin extended-release tablets controlled trials for pain indications, dizziness was experienced by 24% of pregabalin extended-release tablets-treated patients during the single-blind phase; somnolence was experienced by 15.8% of pregabalin extended-release tablets-treated patients. Dizziness and somnolence generally began shortly after the initiation of pregabalin extended-release tablets therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (2.4%, 1.2% each) during the single-blind phase of the controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients.. 5.6 Risks Associated with Abrupt or Rapid Discontinuation Following abrupt or rapid discontinuation of pregabalin extended-release tablets, some patients reported symptoms including, insomnia, nausea, headache, anxiety, and diarrhea. Increased seizure frequency may occur in patients with seizure disorders taking pregabalin extended-release tablets for pain if pregabalin extended-release tablets is rapidly discontinued. Taper pregabalin extended-release tablets gradually over a minimum of 1 week rather than discontinuing the drug abruptly. The efficacy of pregabalin extended-release tablets as adjunctive therapy for adult patients with partial onset seizures has not been established. 5.7 Peripheral Edema Pregabalin extended-release tablets treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials for pain indications, the incidence of peripheral edema for patients receiving pregabalin extended-release tablets in the single-blind phase was 5.3% of patients. In controlled clinical trials for pain indications, 0.8% of pregabalin extended-release tablets patients withdrew due to peripheral edema during the single-blind phase. Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, monitor patients for the development of edema when co-administering pregabalin extended-release tablets and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, monitor these patients for possible exacerbation of congestive heart failure symptoms when using pregabalin extended-release tablets. 5.8 Weight Gain Pregabalin extended-release tablets treatment may cause weight gain. In pregabalin extended-release tablets controlled trials for pain indications, weight gain was experienced by 4% of pregabalin extended-release tablets-treated patients during the single-blind phase. Adverse events of weight gain were observed in 3.7% of pregabalin extended-release tablets-treated patients and 1% of placebo-treated patients during the double-blind phase. In LYRICA controlled clinical trials of up to 14 weeks a gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. In studies with LYRICA, associated weight gain was related to pregabalin dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions (5.7) ] . Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies with LYRICA, the long-term cardiovascular effects of pregabalin-associated weight gain are 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 pregabalin-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open-label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA 1C ). 5.9 Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of pregabalin, an unexpectedly high incidence of hemangiosarcoma was identified in 2 different strains of mice [see Nonclinical Toxicology (13.1) ] . The clinical significance of this finding is unknown. Clinical experience during premarketing development of LYRICA provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients greater than 12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with pregabalin, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment. 5.10 Ophthalmological Effects In controlled studies for pain indications, 4.8% of patients treated with pregabalin extended-release tablets in the single-blind phase reported blurred vision, which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued pregabalin extended-release tablets treatment due to vision-related events (primarily blurred vision). Additionally, 0.7% of pregabalin extended-release tablets-treated patients as compared to no placebo-treated patients experienced blurred vision in the double-blind phase. Prospectively planned ophthalmologic testing during the premarketing development of pregabalin, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of LYRICA-treated patients and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICA-treated and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions. 5.11 Creatine Kinase Elevations LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least 3 times the upper limit of normal. Three LYRICA-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with pregabalin extended-release tablets if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. 5.12 Decreased Platelet Count Both pregabalin extended-release tablets and LYRICA treatment were associated with a decrease in platelet count. In the double-blind phase of controlled studies for pain indication, pregabalin extended-release tablets-treated patients experienced a median change from baseline in platelet count of 11 × 10 3 /mm 3 (for the PHN population) and 14 × 10 3 /mm 3 (for the FM population) as compared to 1 × 10 3 /mm 3 in placebo-treated patients (for both populations). LYRICA-treated patients experienced a mean maximal decrease in platelet count of 20 × 10 3 /mcL, compared to 11 × 10 3 /mcL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and less than 150 × 10 3 /mcL. A single LYRICA-treated subject developed severe thrombocytopenia with a platelet count less than 20 × 10 3 /mcL. In randomized controlled trials, LYRICA or pregabalin extended-release tablets were not associated with an increase in bleeding-related adverse reactions. 5.13 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 to 6 msec at pregabalin doses greater than or equal to 300 mg/day. This mean change difference was not associated with an increased risk of PR increase greater than or equal to 25% from baseline, an increased percentage of subjects with on-treatment PR greater than 200 msec, or an increased risk of adverse reactions of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories.