Lyrica (pregabalin)

Lyrica (pregabalin) is a modulator of voltage-gated calcium channels, designed to affect neurological transmission in multiple systems.

Lyrica is specifically indicated for the treatment of neuropathic pain associated with diabetic peripheral neuropathy, and postherpetic neuralgia. It is also indicated as an adjunctive therapy for the treatment of adult patients with partial onset seizures.

Lyrica is supplied as a hard-gelatin capsule for oral administration. Recommended initial dosing for the treatment of neuropathic pain associated with diabetic peripheral neuropathy is 50 mg thrice daily, with escalation permissible to 100 mg thrice daily within 1 week in patients with creatinine clearance of at least 60 ml/min, based on tolerability and efficacy. For the treatment of postherpetic neuralgia, recommended initial dosing is 75 mg twice daily or 50 mg thrice daily (in patients with creatinine clearance >60 ml/min), with escalation to 150 mg twice daily or 100 mg thrice daily (in patients with creatinine clearance >60 ml/min) permissible. For the adjunctive treatment of epilepsy, recommended initial dosing is 150 mg daily (as 50 mg thrice daily or 75 mg twice daily), with escalation to a maximum total daily dose of 600 mg (200 mg thrice daily or 300 mg twice daily) based on efficacy and tolerability. On conclusion of Lyrica therapy, dosing should be tapered over at least 1 week.

FDA Approval
Neuropathic Pain associated with Diabetic Peripheral Neuropathy
Approval of Lyrica for the treatment of neuropathic pain associated with diabetic peripheral neuropathy was based on results of 3 double-blind, placebo-controlled multicenter trials. Two of these studies investigated the maximum recommended dose of the drug:

• Study DPN 1: This study enrolled 337 patients, who were randomized to receive one of 3 doses of the drug (25 mg, 100 mg or 200 mg; n=240) or placebo (n=97) thrice daily for 5 weeks. Trial data indicated that the two higher doses of the drug produced significant improvements in mean pain score and increases in the portion of patients achieving a reduction in mean pain score of 50% or greater, compared to placebo. There was no significant difference in efficacy between the two higher doses, though incidence of adverse events was seen to be dose dependent.
• Study DPN2: This study enrolled 146 patients, who received either 100 mg Lyrica thrice daily (n=76) or placebo (n=70) for 8 weeks. Trial data indicated that the drug produced significant improvements in mean pain score and increases in the portion of patients achieving a reduction in mean pain score of 50% or greater, compared to placebo. Reductions in pain for some subjects were observed as early as week 1.

Approval of Lyrica for the treatment of postherpetic neuralgia was based on three double-blind, placebo-controlled, multicenter studies:

• Study PHN1: This trial enrolled 368 patients, who received one of three doses of Lyrica (75 mg, 150 mg or 300 mg; n=275) or placebo (n=93) twice daily for 13 weeks. Randomization was based on creatinine clearance rate: subjects with clearance between 30 ml/min and 60 ml/min received 75 mg, 150 mg, or placebo twice daily; while subjects with clearance >60 ml/min were randomized to 75 mg, 150 mg, 300 mg or placebo twice daily. Subjects with high creatinine clearance achieved significant improvements in mean pain score, and a significantly greater portion of these patients achieved reductions of >50% from baseline. Subjects with lower creatinine clearance experienced a higher rate of adverse events, including events leading to treatment discontinuation.
• Study PHN2: This trial enrolled 173 patients, who received one of two doses of Lyrica (100 mg or 200 mg; n=89) or placebo (n=84) thrice daily for 8 weeks. As with Study PHN1, patients were stratified by creatinine clearance rate (30 ml/min to 60 ml/min: 100 mg or placebo; 60+ ml/min: 200 mg or placebo). At both doses, the drug significantly improved mean pain score and increased the portion of patients experiencing a decrease in score of at least 50%. Some patients experienced persistent improvements as early as week 1.
• Study PHN3: This trial enrolled 238 patients, who received one of two doses of Lyrica (50 mg or 100 mg) or placebo thrice daily for 8 weeks. Both doses produced significant improvements in mean main score and increased the portion of patients who achieved a 50% or greater reduction in score from baseline, vs. placebo. Patients with lower creatinine clearance rates (30 mg/ml to 60 mg/ml) experienced significantly more treatment-related adverse events than higher clearance patients, including more adverse events warranting discontinuation of treatment.

Approval of Lyrica for the adjunctive treatment of epilepsy was based on results of three 12-week, randomized, double-blind, placebo-controlled, multicenter trials, which enrolled patients whose disease was not adequately controlled with 1-3 concomitant anti-epileptic drugs:

• Study E1: This trial enrolled 453 patients, who received one of four doses of the drug (25 mg, n=88; 75 mg, n=86; 150 mg, n=90; or 300 mg, n=89) or placebo (n=100) twice daily. All doses of the drug produced reductions in seizure frequency from baseline, and the magnitude of improvement was seen to be dose related. This reduction was non-significant for the lowest dose (-9%, p=0.4230), but was significant for the three other doses (-35%, p=0.0001; -37%, p=0.0001; -51%, p=0.0001, respectively) vs. placebo. The three higher doses also produced significant improvement in one of the trial’s key secondary endpoints, significantly and dose-dependently increasing the portion of patients experiencing a reduction in seizure frequency of at least 50% (31%, 40% and 51%, respectively).
• Study E2: This trial enrolled 287 subjects who received one of two doses of the drug (50 mg, n=99; or 200 mg, n=92) or placebo (n=96) thrice daily. Both doses produced significant reductions in median seizure frequency from baseline, relative to placebo (-17%, p=0.0007; -43%, p=0.0001, respectively).
• Study E3: This trial enrolled 312 patients, who received one of two doses of the drug (300 mg twice daily, n=103; or 200 mg thrice daily, n=111) or placebo (n=98). Both drugs significantly reduced median seizure frequency from baseline, vs. placebo (-36%, p=0.0001; -48%, p=0.0001, respectively). The difference in improvement between the two Lyrica doses was non-significant. Both doses also produced significant improvement in one of the trial’s key secondary endpoints, significantly increasing the portion of patients experiencing a reduction in seizure frequency of at least 50% (43% and 49%, respectively).

• Complete an adequate and well-controlled clinical study or studies to better assess the ophthalmologic effects of pregabalin.
  Protocol Submission: by 08/05
  Study Start: by 07/06
  Final Report Submission: by 01/09
• Complete an in vitro study of the propensity of pregabalin to induce CYP-enzyme metabolism
  Protocol Submission: by 02/05
  Study Start: by 03/05
  Final Report Submission: by 12/05
• Complete adequate and well-controlled clinical studies to assess the effect of pregabalin on nerve conduction velocity (NCV)
  Protocol Submission: by 04/04
  Study Start: by 09/04
  Final Report Submission: by 03/06
• Conduct an adequate and well-controlled clinical study of male reproductive function to confirm lack of effects on sperm motility and provide additional data on sperm concentration, FSH, and testosterone.
  Protocol Submission: by 04/06
  Study Start: by 03/07
  Final Report Submission: by 08/10
• Conduct a study or studies to further characterize and, if possible, to determine the mechanism(s) underlying the ocular lesions (retinal atrophy and corneal inflammation/mineralization) observed in the lifetime carcinogenicity studies in Wistar rats.
  Protocol Submission: by 07/06
  Study Start: by 06/07
  Final Report Submission: by 08/09
• Deferred pediatric study under PREA for the treatment of partial onset seizures in pediatric patients ages 1 month [44 weeks gestational age] to 16 years
  Final Report Submission: May 31, 2010

Adverse events associated with the use of Lyrica may include, but are not limited to, the following:

• Dizziness
• Somnolence
• Peripheral Edema
• Diplopia
• Dry Mouth
• Tremor
• Abnormal Thinking
• Infection
• Headache
• Pain
• Asthenia
• Ataxia
• Blurry Vision
• Constipation
• Edema

In addition, Lyrica is a Schedule V controlled substance. Studies of the drug in recreational users of sedative/hypnotic drugs indicated subjective psychoactive effects of a magnitude similar to the benzodiazepine diazepam. Roughly 4% of subjects reported eurphoria as an adverse event in trials, compared to 1% for placebo; some sub-populations reported euphoria rates as high as 12%. In addition, abrupt termination of treatment was associated with insomnia, nausea, headache and/or diarrhea. Patients receiving Lyrica should be monitored closely for evidence of dependence, misuse or abuse.

Use of Lyrica has been associated with creatine kinase elevations, including mean maximum elevations of 60 U/l. 2% of subjects experienced creatine kinase levels greater that 3x the upper limit of normal, and 3 patients reported rhabdomyolysis during clinical trials. Patients should be advised to promptly consult a healthcare professional if they experience unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Treatment should be discontinued if significant creatine kinase elevations are noted.

Use of Lyrica has also been associated with weight gain. This weight gain was not limited to patients experiencing drug-related edema, and it did not appear to be influenced by age, gender, or baseline BMI. The drug did not appear to cause loss of glycemic control in diabetic patients. The long term effects of Lyrica-mediated weight gain (if any) have not been characterized.

Dizziness and somnolence occur regularly with Lyrica administration. Patients are advised to avoid driving or operating heavy machinery while taking the drug.

The exact mechanism of Lyrica's action has not been fully characterized. Lyrica binds to the alpha2-delta auxiliary subunit of voltage-gated calcium channels. Blockade of these channels has been shown to inhibit the calcium-dependent release of a number of neurotransmitters. The drug is a structural derivative of the inhibitory neurotransmitter GABA, though it does not bind directly to GABAa, GABAb, or benzodiazepine receptors, does not augment GABAa responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. In cultured neurons prolonged application of pregabalin increased the density of GABA transporter protein and increased the rate of functional GABA transport. The drug does not achieve its antinociceptive or antiseizure activity through blockade of sodium channels, activation of opioid receptors, alteration of cyclooxygenase enzyme activity, through activity at serotonin and dopamine receptors, or through effect on dopamine, serotonin, or noradrenaline reuptake.

Beghi E Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines. Lancet Neurology 2004 Oct;3(10):618-21

Cunningham MO, Woodhall GL, Thompson SE, Dooley DJ, Jones RS. Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro. The European Journal of Neuroscience 2004 Sep;20(6):1566-76

Stahl SM. Mechanism of action of alpha2delta ligands: voltage sensitive calcium channel (VSCC) modulators. Journal of Clinical Psychiatry 2004 Aug;65(8):1033-4

Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 2004 Aug;110(3):628-38

For additional information regarding Lyrica, neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, or epilepsy, please visit the Lyrica web page.