Lyrica (pregabalin)
The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
General Information
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.
Clinical Results
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.
Postherpetic Neuralgia
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.
Epilepsy
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).
Ongoing Study Commitments
- 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
Side Effects
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.
Mechanism of Action
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.
Literature References
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
Additional Information
For additional information regarding Lyrica, neuropathic pain
associated with diabetic peripheral neuropathy, postherpetic
neuralgia, or epilepsy, please visit the
Lyrica web
page.