pregabalin 50 MG Oral Capsule [Lyrica]
DRUG INTERACTIONS
7 Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (less than 2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement.
In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions.
Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate.
Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs [see Clinical Pharmacology (12) ] .
Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol.
Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs.
No clinically important effects on respiration were seen.
OVERDOSAGE
10 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of LYRICA.
The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences.
Treatment or Management of Overdose There is no specific antidote for overdose with LYRICA.
If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway.
General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient.
Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA.
Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.
Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).
DESCRIPTION
11 Pregabalin is described chemically as ( S )-3-(aminomethyl)-5-methylhexanoic acid.
The molecular formula is C 8 H 17 NO 2 and the molecular weight is 159.23.
The chemical structure of pregabalin is: Pregabalin is a white to off-white, crystalline solid with a pK a1 of 4.2 and a pK a2 of 10.6.
It is freely soluble in water and both basic and acidic aqueous solutions.
The log of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 is – 1.35.
LYRICA (pregabalin) Capsules are administered orally and are supplied as imprinted hard-shell capsules containing 25, 50, 75, 100, 150, 200, 225, and 300 mg of pregabalin, along with lactose monohydrate, cornstarch, and talc as inactive ingredients.
The capsule shells contain gelatin and titanium dioxide.
In addition, the orange capsule shells contain red iron oxide and the white capsule shells contain sodium lauryl sulfate and colloidal silicon dioxide.
Colloidal silicon dioxide is a manufacturing aid that may or may not be present in the capsule shells.
The imprinting ink contains shellac, black iron oxide, propylene glycol, and potassium hydroxide.
LYRICA (pregabalin) oral solution, 20 mg/mL, is administered orally and is supplied as a clear, colorless solution contained in a 16 fluid ounce white HDPE bottle with a polyethylene-lined closure.
The oral solution contains 20 mg/mL of pregabalin, along with methylparaben, propylparaben, monobasic sodium phosphate anhydrous, dibasic sodium phosphate anhydrous, sucralose, artificial strawberry #11545 and purified water as inactive ingredients.
Chemical Structure
CLINICAL STUDIES
14 14.1 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The efficacy of the maximum recommended dose of LYRICA for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in three double-blind, placebo-controlled, multicenter studies with three times a day dosing, two of which studied the maximum recommended dose.
Patients were enrolled with either Type 1 or Type 2 diabetes mellitus and a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for 1 to 5 years.
A total of 89% of patients completed Studies DPN 1 and DPN 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 6.1 to 6.7.
Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin.
Patients recorded their pain daily in a diary.
Study DPN 1: This 5-week study compared LYRICA 25, 100, or 200 mg three times a day with placebo.
Treatment with LYRICA 100 and 200 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.
There was no evidence of a greater effect on pain scores of the 200 mg three times a day dose than the 100 mg three times a day dose, but there was evidence of dose dependent adverse reactions [see Adverse Reactions (6.1) ] .
For a range of levels of improvement in pain intensity from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that level of improvement.
The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.
Patients who did not complete the study were assigned 0% improvement.
Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
Figure 1: Patients Achieving Various Levels of Improvement in Pain Intensity – Study DPN 1 Figure 1 Study DPN 2: This 8-week study compared LYRICA 100 mg three times a day with placebo.
Treatment with LYRICA 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.
For various levels of improvement in pain intensity from baseline to study endpoint, Figure 2 shows the fraction of patients achieving that level of improvement.
The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.
Patients who did not complete the study were assigned 0% improvement.
Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
Figure 2: Patients Achieving Various Levels of Improvement in Pain Intensity– Study DPN 2 Figure 2 14.2 Postherpetic Neuralgia The efficacy of LYRICA for the management of postherpetic neuralgia was established in three double-blind, placebo-controlled, multicenter studies.
These studies enrolled patients with neuralgia persisting for at least 3 months following healing of herpes zoster rash and a minimum baseline 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).
Seventy-three percent of patients completed the studies.
The baseline mean pain scores across the 3 studies ranged from 6 to 7.
Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to pregabalin.
Patients recorded their pain daily in a diary.
Study PHN 1: This 13-week study compared LYRICA 75, 150, and 300 mg twice daily with placebo.
Patients with creatinine clearance (CLcr) between 30 to 60 mL/min were randomized to 75 mg, 150 mg, or placebo twice daily.
Patients with creatinine clearance greater than 60 mL/min were randomized to 75 mg, 150 mg, 300 mg or placebo twice daily.
In patients with creatinine clearance greater than 60 mL/min treatment with all doses of LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.
Despite differences in dosing based on renal function, patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by higher rates of discontinuation due to adverse reactions.
For various levels of improvement in pain intensity from baseline to study endpoint, Figure 3 shows the fraction of patients achieving that level of improvement.
The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.
Patients who did not complete the study were assigned 0% improvement.
Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
Figure 3: Patients Achieving Various Levels of Improvement in Pain Intensity– Study PHN 1 Figure 3 Study PHN 2: This 8-week study compared LYRICA 100 or 200 mg three times a day with placebo, with doses assigned based on creatinine clearance.
Patients with creatinine clearance between 30 to 60 mL/min were treated with 100 mg three times a day, and patients with creatinine clearance greater than 60 mL/min were treated with 200 mg three times daily.
Treatment with LYRICA statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.
For various levels of improvement in pain intensity from baseline to study endpoint, Figure 4 shows the fraction of patients achieving those levels of improvement.
The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.
Patients who did not complete the study were assigned 0% improvement.
Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
Figure 4: Patients Achieving Various Levels of Improvement in Pain Intensity – Study PHN 2 Figure 4 Study PHN 3: This 8-week study compared LYRICA 50 or 100 mg three times a day with placebo with doses assigned regardless of creatinine clearance.
Treatment with LYRICA 50 and 100 mg three times a day statistically significantly improved the endpoint mean pain score and increased the proportion of patients with at least a 50% reduction in pain score from baseline.
Patients with creatinine clearance between 30 to 60 mL/min tolerated LYRICA less well than patients with creatinine clearance greater than 60 mL/min as evidenced by markedly higher rates of discontinuation due to adverse reactions.
For various levels of improvement in pain intensity from baseline to study endpoint, Figure 5 shows the fraction of patients achieving that level of improvement.
The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%.
Patients who did not complete the study were assigned 0% improvement.
Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
Figure 5: Patients Achieving Various Levels of Improvement in Pain Intensity– Study PHN 3 Figure 5 14.3 Adjunctive Therapy for Partial Onset Seizures in Patients 4 Years of Age and Older Adjunctive Therapy for Partial Onset Seizures in Adult Patients The efficacy of LYRICA as adjunctive therapy for partial onset seizures in adult patients was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies.
Patients were enrolled who had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant antiepileptic drugs (AEDs).
Patients taking gabapentin were required to discontinue gabapentin treatment 1 week prior to entering baseline.
During an 8-week baseline period, patients had to experience at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks.
The mean duration of epilepsy was 25 years in these 3 studies and the mean and median baseline seizure frequencies were 22.5 and 10 seizures per month, respectively.
Approximately half of the patients were taking 2 concurrent AEDs at baseline.
Among the LYRICA-treated patients, 80% completed the double-blind phase of the studies.
Table 10 shows median baseline seizure rates and median percent reduction in seizure frequency by dose.
Table 10.
Seizure Response in Controlled, Add-On Epilepsy Studies in Adults Daily Dose of Pregabalin Dosing Regimen N Baseline Seizure Frequency/mo Median % Change from Baseline p-value, vs.
placebo Study E1 Placebo BID 100 9.5 0 50 mg/day BID 88 10.3 -9 0.4230 150 mg/day BID 86 8.8 -35 0.0001 300 mg/day BID 90 9.8 -37 0.0001 600 mg/day BID 89 9.0 -51 0.0001 Study E2 Placebo TID 96 9.3 1 150 mg/day TID 99 11.5 -17 0.0007 600 mg/day TID 92 12.3 -43 0.0001 Study E3 Placebo BID/TID 98 11 -1 600 mg/day BID 103 9.5 -36 0.0001 600 mg/day TID 111 10 -48 0.0001 In the first study (E1), there was evidence of a dose-response relationship for total daily doses of Lyrica between 150 and 600 mg/day; a dose of 50 mg/day was not effective.
In the first study (E1), each daily dose was divided into two equal doses (twice a day dosing).
In the second study (E2), each daily dose was divided into three equal doses (three times a day dosing).
In the third study (E3), the same total daily dose was divided into two equal doses for one group (twice a day dosing) and three equal doses for another group (three times a day dosing).
While the three times a day dosing group in Study E3 performed numerically better than the twice a day dosing group, this difference was small and not statistically significant.
A secondary outcome measure included the responder rate (proportion of patients with greater than or equal to 50% reduction from baseline in partial seizure frequency).
The following figure displays responder rate by dose for two of the studies.
Figure 6: Responder rate by add-on epilepsy study Figure 7: Seizure Reduction by Dose (All Partial Onset Seizures) for Studies E1, E2, and E3 Subset evaluations of the antiseizure efficacy of LYRICA showed no clinically important differences as a function of age, gender, or race.
Figure 6 Figure 7 Adjunctive Therapy for Partial Onset Seizures in Pediatric Patients 4 to Less Than 17 Years of Age The efficacy of LYRICA as adjunctive therapy in partial onset seizures was established in a 12-week, randomized, double-blind, placebo-controlled, multicenter study in pediatric patients 4 years to less than 17 years of age with partial onset seizures with or without secondary generalization.
During an 8-week baseline period, patients had to experience at least 6 partial onset seizures with no seizure-free period exceeding 4 weeks.
The mean duration of epilepsy was 6 years and the mean and median baseline seizure frequencies were 57 and 18 seizures per month, respectively.
Approximately 74% of the patients were taking 2 to 3 concurrent AEDs at baseline.
Among the LYRICA-treated patients, 87% completed the double-blind phase of the study.
In this study, LYRICA 2.5 mg/kg/day (maximum 150 mg/day) and 10 mg/kg/day (maximum 600 mg/day) were compared to placebo.
Administration of each daily dose was divided into two equal doses (twice a day dosing).
Because of higher weight-normalized clearance in patients with body weight less than 30 kg [see Clinical Pharmacology (12.3) ] , the LYRICA dose was increased by 40% to 3.5 mg/kg/day for patients weighing less than 30 kg randomized to the 2.5 mg/kg/day group or to 14 mg/kg/day for patients randomized to the 10 mg/kg/day group.
Table 11 shows median baseline seizure rates, median percent change from baseline in seizure rates, and percent difference relative to placebo (derived from the primary analysis model) by dose.
Table 11.
Seizure Response in Controlled Add-On Partial Onset Seizure Study in Pediatric Patients 4 to Less Than 17 Years of Age Daily Dose of LYRICA N Median Baseline Seizure Frequency/28 days Median % Change from Baseline % Difference Relative to Placebo p-value, versus placebo Abbreviations: BID=twice daily; N=number.
Placebo 93 16.5 -16.9 Not applicable 2.5 mg/kg/day (BID) 2.5 mg/kg/day: Maximum dose 150 mg/day.
Includes patients less than 30 kg for whom dose was adjusted to 3.5 mg/kg/day.
104 23.8 -27.3 -10.5 0.2577 10 mg/kg/day (BID) 10 mg/kg/day: Maximum dose 600 mg/day.
Includes patients less than 30 kg for whom dose was adjusted to 14 mg/kg/day.
97 17.5 -37.1 -21.0 0.0185 There was evidence of a dose-response relationship for total daily doses of LYRICA between 2.5 mg/kg/day and 10 mg/kg/day.
A significant improvement in seizure rate was observed for LYRICA 10 mg/kg/day group compared with placebo.
While the 2.5 mg/kg/day group performed numerically better than placebo, this difference was not statistically significant.
A key secondary efficacy measure, the responder rate (proportion of patients with greater than or equal to 50% reduction from baseline in partial seizure frequency) showed improvements for LYRICA groups compared with placebo.
The following figure displays responder rate by dose: Figure 8: Responder Rate (Greater than or Equal to 50% Reduction) Figure 8 14.4 Management of Fibromyalgia 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).
Study F1 : This 14-week study compared LYRICA total daily doses of 300 mg, 450 mg and 600 mg with placebo.
Patients were enrolled with a minimum mean baseline pain score of greater than or equal to 4 on an 11-point numeric pain rating scale and a score of greater than or equal to 40 mm on the 100 mm pain visual analog scale (VAS).
The baseline mean pain score in this trial was 6.7.
Responders to placebo in an initial one-week run-in phase were not randomized into subsequent phases of the study.
A total of 64% of patients randomized to LYRICA completed the study.
There was no evidence of a greater effect on pain scores of the 600 mg daily dose than the 450 mg daily dose, but there was evidence of dose-dependent adverse reactions [see Adverse Reactions (6.1) ] .
Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
The results are summarized in Figure 9 and Table 12.
For various levels of improvement in pain intensity from baseline to study endpoint, Figure 9 shows the fraction of patients achieving that level of improvement.
The figure is cumulative.
Patients who did not complete the study were assigned 0% improvement.
Some patients experienced a decrease in pain as early as Week 1, which persisted throughout the study.
Figure 9: Patients Achieving Various Levels of Improvement in Pain Intensity – Fibromyalgia Study F1 Table 12.
Patient Global Response in Fibromyalgia Study F1 Patient Global Impression of Change Treatment Group (mg/day) % Any Improvement 95% CI PGB = Pregabalin Placebo 47.6 (40.0,55.2) PGB 300 68.1 (60.9, 75.3) PGB 450 77.8 (71.5, 84.0) PGB 600 66.1 (59.1, 73.1) Figure 9 Study F2 : This randomized withdrawal study compared LYRICA with placebo.
Patients were titrated during a 6-week open-label dose optimization phase to a total daily dose of 300 mg, 450 mg, or 600 mg.
Patients were considered to be responders if they had both: 1) at least a 50% reduction in pain (VAS) and, 2) rated their overall improvement on the PGIC as “much improved” or “very much improved.” Those who responded to treatment were then randomized in the double-blind treatment phase to either the dose achieved in the open-label phase or to placebo.
Patients were treated for up to 6 months following randomization.
Efficacy was assessed by time to loss of therapeutic response, defined as 1) less than 30% reduction in pain (VAS) from open-label baseline during two consecutive visits of the double-blind phase, or 2) worsening of FM symptoms necessitating an alternative treatment.
Fifty-four percent of patients were able to titrate to an effective and tolerable dose of LYRICA during the 6-week open-label phase.
Of the patients entering the randomized treatment phase assigned to remain on LYRICA, 38% of patients completed 26 weeks of treatment versus 19% of placebo-treated patients.
When considering return of pain or withdrawal due to adverse events as loss of response (LTR), treatment with LYRICA resulted in a longer time to loss of therapeutic response than treatment with placebo.
Fifty-three percent of the pregabalin-treated subjects compared to 33% of placebo patients remained on study drug and maintained a therapeutic response to Week 26 of the study.
Treatment with LYRICA also resulted in a longer time to loss of response based on the FIQ Time to worsening of the FIQ was defined as the time to a 1-point increase from double-blind baseline in each of the subscales, and a 5-point increase from double-blind baseline evaluation for the FIQ total score.
, and longer time to loss of overall assessment of patient status, as measured by the PGIC Time to PGIC lack of improvement was defined as time to PGIC assessments indicating less improvement than “much improvement.” .
Figure 10: Time to Loss of Therapeutic Response, Fibromyalgia Study F2 (Kaplan-Meier Analysis) Figure 10 14.5 Management of Neuropathic Pain Associated with Spinal Cord Injury 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.
The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 12 is presented in Figure 11.
Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.
Figure 11 : Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 1 Figure 11 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.
The fraction of patients achieving various levels of improvement in pain intensity from baseline to Week 16 is presented in Figure 12.
Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.
Figure 12 : Patients Achieving Various Levels of Improvement in Pain Intensity – Study SCI 2 Figure 12
HOW SUPPLIED
16 /STORAGE AND HANDLING Product: 50090-0993 Product: 50090-1229 Product: 50090-1231 Product: 50090-1304
RECENT MAJOR CHANGES
Indications and Usage ( 1 ) 5/2018 Dosage and Administration, Adjunctive Therapy for Partial Onset Seizures in Patients 4 Years of Age and Older ( 2.4 ) 5/2018 Dosage and Administration, Dosing for Adult Patients with Renal Impairment ( 2.7 ) 5/2018
GERIATRIC USE
8.5 Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older.
In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older.
In controlled clinical studies of LYRICA in epilepsy, there were only 10 patients 65 to 74 years of age, and 2 patients who were 75 years of age or older.
No overall differences in safety and efficacy were observed between these patients and younger patients.
In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older.
Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy.
LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function.
Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment [see Dosage and Administration (2.7) ] .
DOSAGE FORMS AND STRENGTHS
3 Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg Oral Solution: 20 mg/mL [see Description (11) and How Supplied/Storage and Handling (16) ] Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg.
( 3 ) Oral Solution: 20 mg/mL.
( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action LYRICA (pregabalin) binds with high affinity to the alpha 2 -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 alpha 2 -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 alpha 2 -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 GABA A , GABA B , or benzodiazepine receptors, does not augment GABA A 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.
INDICATIONS AND USAGE
1 LYRICA is indicated for: Management of neuropathic pain associated with diabetic peripheral neuropathy Management of postherpetic neuralgia Adjunctive therapy for the treatment of partial onset seizures in patients 4 years of age and older Management of fibromyalgia Management of neuropathic pain associated with spinal cord injury LYRICA is indicated for: Neuropathic pain associated with diabetic peripheral neuropathy (DPN) ( 1 ) Postherpetic neuralgia (PHN) ( 1 ) Adjunctive therapy for the treatment of partial onset seizures in patients 4 years of age and older ( 1 ) Fibromyalgia ( 1 ) Neuropathic pain associated with spinal cord injury ( 1 )
PEDIATRIC USE
8.4 Pediatric Use Neuropathic Pain Associated with Diabetic Peripheral Neuropathy, Postherpetic Neuralgia, and Neuropathic Pain Associated with Spinal Cord Injury Safety and effectiveness in pediatric patients have not been established.
Fibromyalgia Safety and effectiveness in pediatric patients have not been established.
A 15-week, placebo-controlled trial was conducted with 107 pediatric patients with fibromyalgia, ages 12 through 17 years, at LYRICA total daily doses of 75–450 mg per day.
The primary efficacy endpoint of change from baseline to Week 15 in mean pain intensity (derived from an 11-point numeric rating scale) showed numerically greater improvement for the pregabalin-treated patients compared to placebo-treated patients, but did not reach statistical significance.
The most frequently observed adverse reactions in the clinical trial included dizziness, nausea, headache, weight increased, and fatigue.
The overall safety profile in adolescents was similar to that observed in adults with fibromyalgia.
Adjunctive Therapy for Partial Onset Seizures The safety and effectiveness of LYRICA as adjunctive treatment for partial onset seizures in pediatric patients 4 to less than 17 years of age have been established in a 12-week, double-blind, placebo-controlled study (n = 295) [see Clinical Studies (14.3) ] .
Patients treated with LYRICA 10 mg/kg/day had, on average, a 21.0% greater reduction in partial onset seizures than patients treated with placebo (p = 0.0185).
Patients treated with LYRICA 2.5 mg/kg/day had, on average, a 10.5% greater reduction in partial onset seizures than patients treated with placebo, but the difference was not statistically significant (p = 0.2577).
Responder rates (50% or greater reduction in partial onset seizure frequency) were a key secondary efficacy parameter and showed numerical improvement with LYRICA compared with placebo: the responder rates were 40.6%, 29.1%, and 22.6%, for LYRICA 10 mg/kg/day, LYRICA 2.5 mg/kg/day, and placebo, respectively.
The most common adverse reactions (≥5%) with LYRICA in this study were somnolence, weight increased, and increased appetite [see Adverse Reactions (6.1) ].
The use of LYRICA 2.5 mg/kg/day in pediatric patients is further supported by evidence from adequate and well-controlled studies in adults with partial-onset seizures and pharmacokinetic data from adult and pediatric patients [see Clinical Pharmacology (12.3) ].
Safety and effectiveness in patients less than 4 years of age have not been established.
Juvenile Animal Data In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses greater than or equal to 50 mg/kg.
The neurobehavioral changes of acoustic startle persisted at greater than or equal to 250 mg/kg and locomotor activity and water maze performance at greater than or equal to 500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects.
The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day.
A no-effect dose was not established.
PREGNANCY
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYRICA during pregnancy.
To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.
This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves.
Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ .
Risk Summary There are no adequate and well-controlled studies with LYRICA in pregnant women.
However, in animal reproduction studies, increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including skeletal malformations, retarded ossification, and decreased fetal body weight were observed in the offspring of rats and rabbits given pregabalin orally during organogenesis, at doses that produced plasma pregabalin exposures (AUC) greater than or equal to 16 times human exposure at the maximum recommended dose (MRD) of 600 mg/day [see Data ] .
In an animal development study, lethality, growth retardation, and nervous and reproductive system functional impairment were observed in the offspring of rats given pregabalin during gestation and lactation.
The no-effect dose for developmental toxicity was approximately twice the human exposure at MRD.
The background risk of major birth defects and miscarriage for the indicated populations are unknown.
However, the background risk in the U.S.
general population of major birth defects is 2–4% and of miscarriage is 15–20% of clinically recognized pregnancies.
Advise pregnant women of the potential risk to a fetus.
Data Animal Data When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at greater than or equal to 1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses.
Fetal body weights were decreased at the highest dose.
The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day.
A no-effect dose for rat embryo-fetal developmental toxicity was not established.
When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose.
The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD.
In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at greater than or equal to 100 mg/kg and offspring survival was decreased at greater than or equal to 250 mg/kg.
The effect on offspring survival was pronounced at doses greater than or equal to 1250 mg/kg, with 100% mortality in high-dose litters.
When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at greater than or equal to 250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg.
The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD.
In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures greater than or equal to 50 times the mean human exposure (AUC (0–24) of 123 µg∙hr/mL) at the MRD.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Angioedema (e.g., swelling of the throat, head and neck) can occur, and may be associated with life-threatening respiratory compromise requiring emergency treatment.
Discontinue LYRICA immediately in these cases.
( 5.1 ) Hypersensitivity reactions (e.g., hives, dyspnea, and wheezing) can occur.
Discontinue LYRICA immediately in these patients.
( 5.2 ) Increased seizure frequency or other adverse reactions may occur if LYRICA is rapidly discontinued.
Withdraw LYRICA gradually over a minimum of 1 week.
( 5.3 ) Antiepileptic drugs, including LYRICA, increase the risk of suicidal thoughts or behavior.
( 5.4 ) LYRICA may cause peripheral edema.
Exercise caution when co-administering LYRICA and thiazolidinedione antidiabetic agents.
( 5.5 ) LYRICA may cause dizziness and somnolence and impair patients’ ability to drive or operate machinery.
( 5.6 ) 5.1 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 [ACE-inhibitors]) may be at increased risk of developing angioedema.
5.2 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.
5.3 Increased Risk of Adverse Reactions with Abrupt or Rapid Discontinuation As with all antiepileptic drugs (AEDs), withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders.
Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea.
If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week rather than discontinue the drug abruptly.
5.4 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 (mono- and 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 3 shows absolute and relative risk by indication for all evaluated AEDs.
Table 3.
Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 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.
5.5 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 in adult patients, 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.
5.6 Dizziness and Somnolence LYRICA may cause dizziness and somnolence.
Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery [see Patient Counseling Information (17) ] .
In the LYRICA controlled trials in adult patients, 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 [see Drug Interactions (7) ] .
In the LYRICA controlled trial in pediatric patients for the treatment of partial onset seizures, somnolence was experienced by 21% of LYRICA-treated patients compared to 14% of placebo-treated patients, and occurred more frequently at higher doses.
5.7 Weight Gain LYRICA treatment may cause weight gain.
In LYRICA controlled clinical trials in adult patients 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 (5.5) ] .
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 HbA 1C ).
5.8 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 (13.1) ] .
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 greater than 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.
5.9 Ophthalmological Effects In controlled studies in adult patients, 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 [see Patient Counseling Information (17) ] .
5.10 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 in adult patients 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.
5.11 Decreased Platelet Count LYRICA treatment was associated with a decrease in platelet count.
LYRICA-treated subjects experienced a mean maximal decrease in platelet count of 20 × 10 3 /µL, compared to 11 × 10 3 /µL in placebo patients.
In the overall database of controlled trials in adult patients, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and less than 150 × 10 3 /µL.
A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 × 10 3 / µL.
In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions.
5.12 PR Interval Prolongation LYRICA treatment was associated with PR interval prolongation.
In analyses of clinical trial ECG data in adult patients, the mean PR interval increase was 3–6 msec at LYRICA doses greater than or equal to 300 mg/day.
This mean change difference was not associated with an increased risk of PR increase greater than or equal to 25% from baseline, an increased percentage of subjects with on-treatment PR greater than 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Angioedema Advise patients that LYRICA may cause angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise.
Instruct patients to discontinue LYRICA and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.1) ] .
Hypersensitivity Advise patients that LYRICA has been associated with hypersensitivity reactions such as wheezing, dyspnea, rash, hives, and blisters.
Instruct patients to discontinue LYRICA and immediately seek medical care if they experience these symptoms [see Warnings and Precautions (5.2) ] .
Adverse Reactions with Abrupt or Rapid Discontinuation Advise patients to take LYRICA as prescribed.
Abrupt or rapid discontinuation may result in increased seizure frequency in patients with seizure disorders, and insomnia, nausea, headache, anxiety, hyperhidrosis, or diarrhea [see Warnings and Precautions (5.3) ] .
Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including LYRICA, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of 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 [see Warnings and Precautions (5.4) ] .
Dizziness and Somnolence Counsel patients that LYRICA may cause dizziness, somnolence, blurred vision and other CNS signs and symptoms.
Accordingly, advise patients not to drive, operate complex machinery, or engage in other hazardous activities until they have gained sufficient experience on LYRICA to gauge whether or not it affects their mental, visual, and/or motor performance adversely [see Warnings and Precautions (5.6) ] .
Weight Gain and Edema Counsel patients that LYRICA may cause edema and weight gain.
Advise patients that concomitant treatment with LYRICA and a thiazolidinedione antidiabetic agent may lead to an additive effect on edema and weight gain.
For patients with preexisting cardiac conditions, this may increase the risk of heart failure [see Warnings and Precautions (5.5 and 5.7) ] .
Ophthalmological Effects Counsel patients that LYRICA may cause visual disturbances.
Inform patients that if changes in vision occur, they should notify their physician [see Warnings and Precautions (5.9) ] .
Creatine Kinase Elevations Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever [see Warnings and Precautions (5.10) ] .
CNS Depressants Inform patients who require concomitant treatment with central nervous system depressants such as opiates or benzodiazepines that they may experience additive CNS side effects, such as somnolence [see Warnings and Precautions (5.6) and Drug Interactions (7) ] .
Alcohol Tell patients to avoid consuming alcohol while taking LYRICA, as LYRICA may potentiate the impairment of motor skills and sedating effects of alcohol.
Missed Dose Counsel patients if they miss a dose, they should take it as soon as they remember.
If it is almost time for the next dose, they should skip the missed dose and take the next dose at their regularly scheduled time.
Instruct patients not to take two doses at the same time.
Pregnancy There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LYRICA during pregnancy [see Use in Specific Populations (8.1) ] .
Lactation Advise nursing mothers that breastfeeding is not recommended during treatment with LYRICA [ see Use in Specific Populations (8.2) ] .
Male Fertility Inform men being treated with LYRICA who plan to father a child of the potential risk of male-mediated teratogenicity.
In preclinical studies in rats, pregabalin was associated with an increased risk of male-mediated teratogenicity.
The clinical significance of this finding is uncertain [see Nonclinical Toxicology (13.1) and Use in Specific populations (8.3) ] .
Dermatopathy Instruct diabetic patients to pay particular attention to skin integrity while being treated with LYRICA and to inform their healthcare provider about any sores or skin problems.
Some animals treated with pregabalin developed skin ulcerations, although no increased incidence of skin lesions associated with LYRICA was observed in clinical trials [see Nonclinical Toxicology (13.2) ] .
DOSAGE AND ADMINISTRATION
2 For adult indications, begin dosing at 150 mg/day.
For partial onset seizure dosing in pediatric patients 4 years of age and older, refer to section 2.4.
( 2.2 , 2.3 , 2.4 , 2.5 , 2.6 ) Dosing recommendations: INDICATION Dosing Regimen Maximum Dose DPN Pain ( 2.2 ) 3 divided doses per day 300 mg/day within 1 week PHN ( 2.3 ) 2 or 3 divided doses per day 300 mg/day within 1 week.
Maximum dose of 600 mg/day.
Adjunctive Therapy for Partial Onset Seizures in Patients 4 Years of Age and Older ( 2.4 ) 2 or 3 divided doses per day Maximum dose of 600 mg/day.
Fibromyalgia ( 2.5 ) 2 divided doses per day 300 mg/day within 1 week.
Maximum dose of 450 mg/day.
Neuropathic Pain Associated with Spinal Cord Injury ( 2.6 ) 2 divided doses per day 300 mg/day within 1 week.
Maximum dose of 600 mg/day.
Dose should be adjusted in adult patients with reduced renal function.
( 2.7 ) 2.1 Important Administration Instructions LYRICA is given orally with or without food.
When discontinuing LYRICA, taper gradually over a minimum of 1 week [see Warnings and Precautions (5.3) ] .
Because LYRICA is eliminated primarily by renal excretion, adjust the dose in adult patients with reduced renal function [see Dosage and Administration (2.7) ].
2.2 Neuropathic Pain Associated with Diabetic Peripheral Neuropathy 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.
Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional significant benefit and this dose was less well tolerated.
In view of the dose-dependent adverse reactions, treatment with doses above 300 mg/day is not recommended [see Adverse Reactions (6.1) ] .
2.3 Postherpetic Neuralgia 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 [see Adverse Reactions (6.1) ] .
2.4 Adjunctive Therapy for Partial Onset Seizures in Patients 4 Years of Age and Older The recommended dosage for adults and pediatric patients 4 years of age and older is included in Table 1.
Administer the total daily dosage orally in two or three divided doses.
In pediatric patients 4 years of age and older, the recommended dosing regimen is dependent upon body weight.
Based on clinical response and tolerability, dosage may be increased, approximately weekly.
Table 1: Recommended Dosage for Adults and Pediatric Patients 4 Years and Older Age and Body Weight Recommended Initial Dosage (administer in two or three divided doses) Recommended Maximum Dosage (administer in two or three divided doses) Adults (17 years and older) 150 mg/day 600 mg/day Pediatric patients weighing 30 kg or more 2.5 mg/kg/day 10 mg/kg/day (not to exceed 600 mg/day) Pediatric patients weighing 11 kg to less than 30 kg 3.5 mg/kg/day 14 mg/kg/day Both the efficacy and adverse event profiles of LYRICA have been shown to be dose-related.
The effect of dose escalation rate on the tolerability of LYRICA has not been formally studied.
The efficacy of add-on LYRICA in patients taking gabapentin has not been evaluated in controlled trials.
Consequently, dosing recommendations for the use of LYRICA with gabapentin cannot be offered.
2.5 Management of Fibromyalgia The recommended dose of LYRICA 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).
Although LYRICA was also studied at 600 mg/day, there is no evidence that this dose confers additional benefit and this dose was less well tolerated.
In view of the dose-dependent adverse reactions, treatment with doses above 450 mg/day is not recommended [see Adverse Reactions (6.1) ] .
2.6 Neuropathic Pain Associated with Spinal Cord Injury 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 [see Clinical Studies (14.5) ] .
2.7 Dosing for Adult Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in adult patients with reduced renal function.
The use of LYRICA in pediatric patients with compromised renal function has not been studied.
Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 2.
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: 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 greater than or equal to 60 mL/min).
Then refer to Table 2 to determine the corresponding renal adjusted dose.
(For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr greater than or equal to 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 2 ).
Table 2.
Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance (CLcr) (mL/min) Total Pregabalin Daily Dose (mg/day) Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose.
Dose Regimen TID= Three divided doses; BID = Two divided doses; QD = Single daily dose.
Greater than or equal to 60 150 300 450 600 BID or TID 30–60 75 150 225 300 BID or TID 15–30 25–50 75 100–150 150 QD or BID Less than 15 25 25–50 50–75 75 QD Supplementary dosage following hemodialysis (mg) Supplementary dose is a single additional dose.
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 Cockcroft and Gault equation