Pregabalin Extended Release

In view of the dose-dependent adverse reactions and the higher rate of treatment discontinuation due to adverse reactions, dosing above 330 mg/day should be reserved only for those patients who have on-going pain and are tolerating 330 mg daily.

The maximum recommended dose of pregabalin extended-release tablets is 660 mg once daily. 4 Conversion from LYRICA Capsules or Oral Solution to Pregabalin Extended-Release Tablets When switching from LYRICA to pregabalin extended-release tablets on the day of the switch, instruct patients to take their morning dose of LYRICA as prescribed and initiate pregabalin extended-release tablets therapy after an evening meal.

Table 1. 5 mg tablets taken once a day. 300 mg/daily 330 mg/day 450 mg/daily 495 mg/day 495 mg = 3 × 165 mg tablets taken once a day. 600 mg/daily 660 mg/day 660 mg = 2 × 330 mg tablets taken once a day. 5 Patients with Renal Impairment Use of pregabalin extended-release tablets is not recommended for patients with creatinine clearance (CLcr) less than 30 mL/min or who are undergoing hemodialysis.

Those patients should receive LYRICA. In view of dose-dependent adverse reactions and because pregabalin is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on CLcr, as indicated in Table 2.

To use the dosing tables, an estimate of the patient's 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: Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr greater than or equal to 60 mL/min).

Then refer to Table 2 to determine the corresponding renal adjusted dose. (For example: A patient initiating pregabalin extended-release tablets therapy for postherpetic neuralgia with normal renal function [CLcr greater than or equal to 60 mL/min], receives a single daily dose of 165 mg/day pregabalin.

) Table 2: Pregabalin Extended-Release Tablets Dosage Adjustment Based on Renal Function Creatinine Clearance (CLcr) (mL/min) Total Pregabalin Extended-Release Tablets Daily Dose (mg/day) Dose Regimen greater than or equal to 60 165 330 495 495 mg = 3 × 165 mg tablets taken once a day.

660 660 mg = 2 × 330 mg tablets taken once a day. 5 mg tablets taken once a day 330 Once a day less than 30/hemodialysis Dose with LYRICA PRINCIPAL DISPLAY PANEL - 50 mg/500 mg Tablet Bottle Label

0) 0 Other Adverse Reactions Observed During Clinical Studies with LYRICA and pregabalin extended-release tablets In addition to the adverse reactions reported during the controlled studies with pregabalin extended-release tablets in postherpetic neuralgia, the following adverse reactions have been reported in patients treated with LYRICA and pregabalin extended-release tablets during all clinical studies.

This listing does not include those adverse reactions already listed above. The adverse reactions are categorized by system organ class and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Adverse reactions of major clinical importance are described in the Warnings and Precautions section (5) . 2 Postmarketing Experience with LYRICA The following adverse reactions have been identified during post-approval use of LYRICA.

These adverse reactions have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: breast enlargement, bullous pemphigoid, gynecomastia. There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking pregabalin with opioids or other CNS depressants, or in the setting of underlying respiratory impairment.

, intestinal obstruction, paralytic ileus, constipation) when LYRICA was co-administered with medications that have the potential to produce constipation, such as opioid analgesics.

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. 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. 7) of suicidal thinking or behavior compared to patients randomized to placebo.

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. 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. 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 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) ] . 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.

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..

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. 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. 3% of patients. 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.

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.

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.

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.

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. 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. 3 kg (range: -10 to 9 kg) weight gain in placebo patients.

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 ).

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. 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). 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. 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. 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.

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.

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.