Lyrica (pregabalin) - 4 indications

Scroll down for information on each indication:

• the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia; approved December 2004
• the adjunctive treatment partial-onset seizures in patients 1 month of age and older; approved June 2005
• the treatment of fibromyalgia; approved June 2007
• the management of neuropathic pain associated with spinal cord injury; approved June 2012

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 the following conditions:

• the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN)
• as adjunctive therapy for the treatment of partial-onset seizures in patients 1 month of age and older
• the management of fibromyalgia in adults
• the management of neuropathic pain associated with spinal cord injury

Lyrica is supplied as capsules and solution, both for oral administration. Lyrica is given orally with or without food. When discontinuing treatment, taper gradually over a minimum of 1 week. Scroll down for the recommended dosing/administration for each condition.

Mechanism of Action

Lyrica (pregabalin) binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin has not been fully elucidated, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's anti-nociceptive and antiseizure effects in animals. In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha2-delta containing-calcium channel trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord.

While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), 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. However, in cultured neurons prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport. Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.

Side Effects

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

• dizziness
• somnolence
• dry mouth
• edema
• blurred vision
• weight gain
• thinking abnormal (primarily difficulty with concentration/attention)

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

• increased weight
• increased appetite

Indication 1 - the management of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia

approved December 2004

Dosing/Administration

• Neuropathic Pain Associated with Diabetic Peripheral Neuropathy in Adults
  • The maximum recommended dose of Lyrica is 100 mg three times a day (300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability.
• Postherpetic Neuralgia in Adults
  • The recommended dose of Lyrica is 75 to 150 mg two times a day, or 50 to 100 mg three times a day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Begin dosing at 75 mg two times a day, or 50 mg three times a day (150 mg/day). The dose may be increased to 300 mg/day within 1 week based on efficacy and tolerability.
  • Patients who do not experience sufficient pain relief following 2 to 4 weeks of treatment with 300 mg/day, and who are able to tolerate Lyrica, may be treated with up to 300 mg two times a day, or 200 mg three times a day (600 mg/day). In view of the dose-dependent adverse reactions and the higher rate of treatment discontinuation due to adverse reactions, reserve dosing above 300 mg/day for those patients who have on-going pain and are tolerating 300 mg daily.

Clinical Trial Results

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

The FDA 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.

Indication 2 - the adjunctive treatment partial-onset seizures in patients 1 month of age and older

approved June 2005

Dosing/Administration

The recommended dosages for adults and pediatric patients 1 month of age and older are shown below. Administer the total daily dosage orally in two or three divided doses as indicated in Table 1. In pediatric patients, the recommended dosing regimen is dependent upon body weight. Based on clinical response and tolerability, dosage may be increased, approximately weekly.

Age and Body Weight	Recommended Initial Dosage	Recommended Maximum Dosage	Frequency of Administration
Adults (17 years and older)	150 mg/day	600 mg/day	2 or 3 divided doses
Pediatric patients weighing 30 kg or more	2.5 mg/kg/day	10 mg/kg/day (not to exceed 600 mg/day)	2 or 3 divided doses
Pediatric patients weighing less than 30 kg	3.5 mg/kg/day	14 mg/kg/day	1 month to less than 4 years of age: 3 divided doses 4 years of age and older: 2 or 3 divided doses

Clinical Trial Results

The FDA 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).

Indication 3 - the treatment of fibromyalgia

approved June 2007

Dosing/Administration

The recommended dose of Lyyrica for fibromyalgia is 300 to 450 mg/day. Begin dosing at 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day).

Clinical Trial Results

The efficacy of LYRICA for management of fibromyalgia was established in one 14-week, double-blind, placebo-controlled, multicenter study (F1) and one six-month, randomized withdrawal study (F2). Studies F1 and F2 enrolled patients with a diagnosis of fibromyalgia using the American College of Rheumatology (ACR) criteria (history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites).  The studies showed a reduction in pain by visual analog scale. In addition, improvement was demonstrated based on a patient global assessment (PGIC), and on the Fibromyalgia Impact Questionnaire (FIQ).

Indication 4 - the management of neuropathic pain associated with spinal cord injury

approved June 2012

Dosing/Administration

The recommended dose range of Lyrica for the treatment of neuropathic pain associated with spinal cord injury is 150 to 600 mg/day. The recommended starting dose is 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient pain relief after 2 to 3 weeks of treatment with 150 mg two times a day and who tolerate Lyrica may be treated with up to 300 mg two times a day.

Clinical Trial Results

The efficacy of Lyrica for the management of neuropathic pain associated with spinal cord injury was established in two double-blind, placebo-controlled, multicenter studies. Patients were enrolled with neuropathic pain associated with spinal cord injury that persisted continuously for at least three months or with relapses and remissions for at least six months. A total of 63% of patients completed study 1 and 84% completed study 2. The patients had a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numerical pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). The baseline mean pain scores across the two studies ranged from 6.5 to 6.7.

Patients were allowed to take opioids, non-opioid analgesics, antiepileptic drugs, muscle relaxants, and antidepressant drugs if the dose was stable for 30 days prior to screening. Patients were allowed to take acetaminophen and nonsteroidal anti-inflammatory drugs during the studies.

Study SCI 1: This 12-week, randomized, double-blind, parallel-group, multicenter, flexible dose (150–600 mg/day) study compared pregabalin with placebo. The 12-week study consisted of a 3-week dose adjustment phase and a 9-week dose maintenance phase. Treatment with Lyrica 150–600 mg/day statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline. 

Study SCI 2: This 16-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter, flexible dose (150–600 mg/day, in increments of 150 mg) study compared the efficacy, safety and tolerability of pregabalin with placebo. The 16-week study consisted of a 4-week dose adjustment phase and a 12-week dose maintenance phase. Treatment with Lyrica statistically significantly improved the endpoint weekly mean pain score, and increased the proportion of patients with at least a 30% and 50% reduction in pain score from baseline.