APMA News - September 2012 - (Page 18)

LYRICA® (pregabalin) CAPSULES BRIEF SUMMARY: For full prescribing information, see package insert. INDICATION AND USAGE LYRICA is indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy DOSAGE AND ADMINISTRATION LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week. Neuropathic Pain Associated with Diabetic Peripheral Neuropathy: • Administer in 3 divided doses per day • Begin dosing at 150 mg/day • May be increased to a maximum of 300 mg/day within 1 week • Dose should be adjusted for patients with reduced renal function Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA 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 creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, 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: CLCr = [140 - age (years)] x weight (kg) 72 x serum creatinine (mg/dL) (x 0.85 for female patients) 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 ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose. (For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.) For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1). Table 1. Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance Total Pregabalin Daily Dose (CLcr) (mL/min) (mg/day)* ≥60 30–60 15–30 <15 150 75 25–50 25 300 150 75 25–50 450 225 100–150 50–75 600 300 150 75 Dose Regimen BID or TID BID or TID QD or BID QD Supplementary dosage following hemodialysis (mg)† 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 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 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. *Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. † Supplementary dose is a single additional dose. CONTRAINDICATIONS LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy. WARNINGS AND PRECAUTIONS Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms. Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACEinhibitors]) may be at increased risk of developing angioedema. Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms. Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. 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 (monoand adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2. Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients Relative Risk: Risk Difference: with Events Per with Events Per Incidence of Events Additional Drug Patients 1000 Patients 1000 Patients in Drug Patients/Incidence with Events Per in Placebo Patients 1000 Patients Epilepsy Psychiatric Other Total 1.0 5.7 1.0 2.4 3.4 8.5 1.8 4.3 3.5 1.5 1.9 1.8 2.4 2.9 0.9 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 LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Inform patients, their caregivers, and families that LYRICA and other AEDs 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. Peripheral Edema LYRICA treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when co-administering LYRICA and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients. Dizziness and Somnolence LYRICA may cause dizziness and somnolence. Inform patients that LYRICArelated dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery. In the LYRICA controlled trials, dizziness was experienced by 30% of LYRICA-treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of LYRICA-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients. Weight Gain LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions, 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 LYRICA-associated weight gain are unknown. Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg. While the effects of LYRICA-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C). Abrupt or Rapid Discontinuation Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea. Taper LYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly. Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology, Carcinogenesis, Mutagenesis, Impairment of Fertility]. The clinical significance of this finding is unknown. Clinical experience during LYRICA’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment. Ophthalmological Effects In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision). Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICA-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions. Creatine Kinase Elevations LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three LYRICA-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. Decreased Platelet Count LYRICA treatment was associated with a decrease in platelet count. LYRICAtreated subjects experienced a mean maximal decrease in platelet count of 20 x 10 3/µL, compared to 11 x 10 3/µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <150 x 103/µL. A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 x 103/µL. In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions. PR Interval Prolongation LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with ontreatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years. Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each). Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and “thinking abnormal” (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo). Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Adverse Reactions Leading to Discontinuation In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients. Most Common Adverse Reactions Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”.

Table of Contents for the Digital Edition of APMA News - September 2012

APMA News - September 2012
President’s Message
Contents
US Surgeon General Addresses APMA at The National
2012 is a Milestone Year for APMA, and for Other Institutions as Well
APMA Member and Daughter Help Disabled Find their Freedom
Dr. Caporusso Promotes Podiatric Medicine on Capitol Hill
Use eAdvocacy to Reach Your Elected Leaders Today!
APMA by the Decade: 1982–1991
2012 Podiatric Practice Survey: Net Income Statistics
Reimbursement
Federal Advocacy Forum
List of Cosponsors to the Equity and Access for Podiatric Physicians Under Medicaid Act
APMAPAC Chair Report
IT Consultant
Website Wisdom
Technofile
Bylaws Propositions Due
Small Business 101
APMA All Stars
Resolutions Deadlines
In Short
Worthy of Note
CPME Invitation for Comments
Affiliates Corner
List of Affiliated Organizations
Insurance Advisor
New Members
Death Notices
APMAPAC Update
Annual Scientific Meeting Sponsors
Development Update
Classified Advertising
Dates to Remember
Advertising Index
10 Questions
Your APMA

APMA News - September 2012