Summary Basis of Decision for Lyrica

3.3.1 Pharmacodynamics

Lyrica (pregabalin) is an analogue/derivative of the inhibitory neurotransmitter GABA, but does not bind to GABAa, GABAb or benzodiazepine receptors, nor is it an inhibitor of GABA uptake or degradation. Although the mechanism of action is not yet established, it appears that pregabalin interferes with GABA synthesis, and reduces the calcium-dependent release of several other neurotransmitters, including glutamate, noradrenaline, and substance P.

Pregabalin binds with high affinity to the alpha2-delta protein (a calcium channel subunit) of brain tissue. Reduction of the release of several neurotransmitters in vitro suggest a calcium channel blocking property for Lyrica. However, in contrast to vascular calcium channel blockers, pregabalin does not appear to alter systemic blood pressure or cardiac function.

3.3.2 Pharmacokinetics

Clinical studies were conducted to determine the absorption, distribution, metabolism, and excretion of pregabalin in humans, to assess the effects of drug dosing on pharmacokinetic (PK) parameters, and to explore the effects of intrinsic and extrinsic factors on PK parameters. Each study also collected data to assess the safety and tolerability of pregabalin. The clinical pharmacology program that defined the clinical pharmacokinetics of pregabalin consisted of 21 Phase 1 studies. All studies were conducted in accordance with Good Clinical Practices, and were consistent with US, EU, and Japanese guidelines on drug development.

Following oral dosing, the clinical pharmacology of pregabalin was characterized by nearly complete absorption and negligible metabolism. Since pregabalin underwent negligible metabolism, urinary excretion of unchanged drug was the primary route of elimination. Pregabalin exhibited linear pharmacokinetics; drug exposure increased as the dose increased. Following repeated dosing, plasma pregabalin concentrations achieved steady-state in 24-48 hours. The pregabalin accumulation ratio ranged from 1.62-1.76 for q8h and was 1.40 following q12h dosing. The volume of distribution of pregabalin was similar to total body water. Results showed that pregabalin penetrated into red blood cells and did not appreciably bind to plasma proteins. Since pregabalin was not appreciably metabolized, did not inhibit CYP450 isoenzymes, and did not bind to plasma proteins, drug-drug interactions based upon metabolism are highly unlikely.

When the same total daily dose (600 mg/day) was administered q8h and q12h, mean drug exposure (AUC) and steady-state maximum concentration values (Cmax) were similar. Furthermore, as the q8h regimen diverged from an even 8-hour dosing interval to an uneven TID regimen (e.g., shortertime intervals between doses taken during the day and a longer interval between theevening and morning doses), the difference in the steady state values for Cmax and Cmin for q8h and q12h administration were further reduced. Therefore, pregabalin exposure is considered comparable, whether the total daily dose is divided into 2 or 3 doses.

Special Populations

Renal Impairment - Dose adjustments are required for patients with renal impairment. Since almost all of the systemically absorbed pregabalin is cleared unchanged by the kidney, the clearance of pregabalin is directly proportional to the creatinine clearance. Based on studies conducted in subjects with renal impairment, it is recommended that dosage adjustments be made according to renal function.

Liver Impairment - No dose adjustments are required for patients with hepatic impairment. Since the liver does not metabolize pregabalin to any appreciable extent, there is no basis for decreased clearance due to hepatic impairment.

Race - The pharmacokinetics of pregabalin in Japanese subjects were similar to those seen in US subjects. Results also showed that the relationship between daily dose and pregabalin drug exposure was also similar among Caucasians, Blacks, and Hispanics.

Gender - The relationship between daily dose and pregabalin drug exposure was similar between genders.

Age - A reduction in pregabalin dose may be required in patients with age-related compromised renal function. Results from healthy, elderly (>65 years) subjects showed increased pregabalin half-life and exposure, consistent with age-related changes in renal function. Results from premenopausal and postmenopausal women showed similar daily dose and pregabalin drug exposure.

Drug Interactions

Pregabalin pharmacokinetic parameters were not significantly changed when administered with valproic acid, carbamazepine, lamotrigine, phenytoin, gabapentin, lorazepam, oxycodone, or ethanol. Additional population pharmacokinetic analyses also showed that carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, tiagabine, valproic acid, oral hypoglycemic therapies, insulin, or diuretics did not significantly alter pregabalin pharmacokinetics.

Clinical pharmacology drug interaction studies have shown that pregabalin does not significantly change the pharmacokinetics of valproic acid, carbamazepine, lamotrigine, phenytoin, gabapentin, lorazepam, oxycodone, ethanol, or oral contraceptives (norethindrone and ethinyl estradiol). Population pharmacokinetic analyses also showed that the pharmacokinetics of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproic acid are not significantly changed with concomitant pregabalin.

Overall, doses of pregabalin and oxycodone; pregabalin and ethanol; and, pregabalin and lorazepam, whether administered alone or in combination, produced no clinically important respiratory suppression. Pregabalin appears to potentiate or be additive in the impairment of cognitive and gross motor function caused by oxycodone, ethanol, and lorazepam.

Safety

In the Phase 1 studies, pregabalin doses from 75 to 900 mg/day were generally tolerated by healthy subjects. The results of these studies supported further study in patients at doses up to 600 mg/day. The most frequently reported adverse events in clinical pharmacology studies were dizziness, somnolence, headache, stupor, thinking abnormal, asthenia, nausea, euphoria, amblyopia, abnormal gait, constipation, dry mouth, incoordination, and infection. Clinical laboratory test abnormalities were generally sporadic, transient, and considered to be unrelated to pregabalin administration. Overall, no clinically significant electrocardiogram (ECG) abnormalities were observed. There were also no clinically important changes in blood pressure or heart rate.

3.3.3 Clinical Efficacy

Clinical data consisted of short-term, controlled, and long-term open-label trials to evaluate the safety and efficacy of pregabalin in patients with diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN).

• Five DPN, randomized, double-blind, placebo-controlled trials included titration periods of 0-2 weeks and had fixed-dose durations of 4-11 weeks.
• Four PHN, double-blind, placebo-controlled trials included titration periods of 0-1 week with fixed-dose durations of 5-12 weeks.

Key enrollment criteria, design, methodology, safety and efficacy parameters were the same for the DPN and PHN studies. One exception was that patients in PHN studies were allowed to use a variety of analgesics concomitantly with the study drug whereas patients in DPN trials were only allowed to use standard and simple (over-the-counter) analgesics.

A total of 979 and 852 patients received various doses of pregabalin in the DPN and PHN trials, respectively. In the controlled DPN studies, there were a total of 319 elderly (>65 years) patients of whom 73 patients were >75 years of age. Similarly, in PHN trials, 661 patients were elderly of whom 379 (57%) were >75 years of age.

The primary efficacy measure was the end-point mean pain score, defined as the mean pain score from the last 7 pain diary entries while the patient was on study medication. Patients used a daily pain diary with an 11-point, numeric pain rating scale: 0 (no pain) to 10 (worst possible pain). Other supplemental and secondary measures included by-week analysis of pain score data, responder rate (% of patients who achieved either >30% or >50% reduction in mean pain score at end-point vs baseline), Present Pain Intensity, sleep interference due to pain, Patient and Clinical Global Impression of Change (PGIC and CGIC), and Quality of Life Questionaire.

Pregabalin efficacy was established for DPN and PHN in the controlled clinical trials.

• In the DPN trials, primary efficacy measures in most pregabalin arms were statistically more significant (more effective) than placebo. Exceptions included the pregabalin 75 and 150 mg/day treatment arms. Efficacy data indicated a favourable trend towards dosing three times a day (TID) with a minimum effective dose or, at least, a starting dose of 150 mg/day. Doses from 150 to 600 mg/day (BID, twice a day; or TID), appeared to be similarly efficacious, with 75 mg/day being a non-therapeutic dose. Supplemental and secondary efficacy measures such as sleep interference due to pain, PGIC and CGIC were mostly positive and supportive of the primary end-point.
  
  
• In the PHN trials, study results showed a dose-dependent increase in efficacy in reducing pain. Whether administered as BID or TID regimen, pregabalin doses from 150 to 600 mg/day appeared to be similarly efficacious with 150 mg/day likely being the minimum effective dose or at least the starting dose. The pregabalin 75 mg/day was a non-therapeutic dose. With few exceptions, positive results of supplemental and secondary end-points such as responder rates, sleep disturbance due to pain, PGIC, CGIC and improvements in quality of life measures were supportive of the findings in primary efficacy outcome.

For both DPN and PHN studies, the minimum effective dose appears to be 150 mg/day in either a BID or TID regimen (pregabalin 75 mg/day is a sub-therapeutic dose). The therapeutic range is identified to be between 150 and 600 mg/day with the best combined safety and efficacy results obtained at 300 mg/day target dose. While the 300 mg/day dose appears to have the best efficacy/side effect profile, pregabalin 600 mg/day is associated with higher rates of adverse events and more frequent study discontinuations. Doses between 300 and 600 mg/day or >600 mg/day were not studied. Doses higher than 300 mg/day should be reserved for patients who can tolerate 300 mg/day well but do not experience satisfactory pain relief at this dose.

3.3.4 Clinical Safety

Clinical safety of pregabalin was studied in short-term controlled trials (5 in DPN and 4 in PHN), and long-term open-label trials. Information from the Periodic Safety Update Reports was also evaluated.

Controlled Trials

The controlled trials are described in Section 3.3.3 Clinical Efficacy. Safety was evaluated by the reporting of adverse events; physical, neurological and peripheral sensory exams; visual field and acuity screening; dilated ophthalmoscopy; and ECG and clinical laboratory tests.

Most Common Adverse Events - The overall profile and incidence of adverse events (AEs) in both DPN and PHN populations were similar with incidence rates being different from placebo starting at the low end of the therapeutic range (pregabalin 150 mg/day). While acknowledging that both populations, and especially PHN patients were mostly elderly, much higher reporting rates of dizziness (pregabalin 23% vs placebo 7%), somnolence (pregablin 14% vs placebo 4%), peripheral edema (pregabalin 10.4% vs placebo 2.9%), weight gain (pregabalin 4.2% vs placebo 0.4%) and amblyopia (pregabalin 4.4% vs placebo 2.0%) were noted in pregabalin-treated patients.

Serious Adverse Events - Overall, 2.5% of the patients in placebo arms experienced serious AEs compared to 3.6% in pregabalin groups. The most common serious AEs included chest pain, accidental injury, pneumonia, congestive heart failure and myocardial infarction. This pattern continued in the corresponding long-term trials. Despite some subtle differences, comparison of DPN and PHN trials did not reveal any particular trends in pattern or occurrence of various serious AEs that may be attributed to the specific patient population. There was a slightly higher reporting rate of peripheral edema in the pregabalin arms of PHN trials and this condition led to patient withdrawal more frequently in the PHN trials.

Discontinuations - Discontinuations were mostly dose-dependent and occurred in similar rates (25-30%) in pregabalin and placebo arms. However, 11% of the patients in pregabalin arms discontinued due to AEs (placebo, 5%). This was reversed for discontinuations due to lack of efficacy (pregabalin 4% vs placebo 8%). Dizziness was the most common AE leading to discontinuation in PHN trials (4.1% pregabalin, 0.8% placebo). Cases of peripheral edema that led to discontinuation were reported in 3.2% of the PHN patients that received 600 mg/day as compared to 0.3% for placebo. Also, regardless of pregabalin dose, renal-impaired patients experienced more AEs and discontinued trials more frequently. A warning statement for patients with renal impairment is documented in the Product Monograph.

Deaths - As of February, 2003, the integrated clinical safety database indicated 5 deaths in pregabalin arms (5/1556, 0.32%) vs one in placebo groups (1/764, 0.13%) of controlled clinical trials. Elderly PHN patients had the highest proportion of deaths at 1.7%.

Long-Term Trials

DPN Studies - The overall safety profile in long-term trials (1164 patients) was similar to the profile in the controlled clinical studies with the exception of weight gain that appeared to increase with long-term exposure and increased dosing. Overall, a 7% or greater increase in body weight was experienced by 21.5% of patients in the combined controlled and uncontrolled DPN studies. The most common AEs such as peripheral edema, accidental injury, somnolence and dizziness occurred at >8%. Weight gain was reported as an adverse event in 8.2% of patients in uncontrolled DPN studies. Approximately 13% of the patients in long-term studies discontinued due to AEs (e.g., nervous system-related events such as dizziness and somnolence) but peripheral edema was the most frequent individual AE leading to patient withdrawal at 1.3%.

PHN Studies - In the PHN studies (735 patients) an increased reporting of weight gain with long-term exposure to pregabalin was observed in the PHN population as compared to the control studies. The most common AEs were somnolence, dizziness, accidental injury, and peripheral edema (all >8%), mostly considered "related" to pregabalin treatment. Nearly 20% of the patients discontinued due to AEs that were mostly associated with the nervous system. Again, peripheral edema was the most common event leading to withdrawal (2.9%).

Compared to controlled studies, incidence of weight gain increased with long-term exposure to pregabalin and was observed across various pregabalin doses, with the weight gain increasing as the dose increased. Overall, a 7% or greater increase in body weight was experienced by 15.6% of patients in the combined controlled and uncontrolled PHN studies. In some trials, weight gain was one of the most common reported AEs at or above 13%. Weight gain was reported as an adverse event in 7.5% of patients in uncontrolled PHN studies. On average in the PHN trials, weight gain was experienced by 7.5% of the patients (placebo 0.3%). In many instances, weight gain was considered "related" to pregabalin treatment.

Periodic Safety Update Reports

The initial Periodic Safety Update Reports (PSURs) covered the reporting period July 07, 2004 to January 06, 2005 with an estimated clinical trial and postmarketing exposure of 464 and 15,000 patients, respectively. Patients ranged in age between 28 and 83 years.

Clinical Trials - Six cases of AEs were reported. Of interest was one case of "drug withdrawal syndrome" and one case of leg thrombosis. In both cases, based on the available information, the role of pregabalin could not be excluded.

Postmarketing Exposure - The most common AEs were dizziness, nausea, fatigue, and headache. The AE profile of pregabalin from the postmarketing dataset was similar to the profile from the clinical trials; edema (patients with or without history and ranging between 17-74 years), somnolence and vision-related AEs (diplopia and amblyopia, reduced acuity and accommodation disorders) were reported. AEs clearly associated with pregablin treatment such as peripheral edema, weight increase, vision-related AEs, dizziness and somnolence are listed in the WARNINGS AND PRECAUTIONS section of the Product Monograph.

3.3.5 Issues Outstanding

In recommending an NOC for pregabalin, the Central Nervous System Division has required a letter of commitment from the sponsor, committing to providing PSURs every 6 months for 3 years, with a special emphasis on monitoring tumorigenic potential, vision-related adverse events, peripheral edema, dizziness/somnolence, suicide-related events, and weight increase.