pregabalin 200 MG Oral Capsule [Lyrica]
DRUG INTERACTIONS
7 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 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 11 Pregabalin is described chemically as (S)-3-(aminomethyl)-5-methylhexanoic acid.
The molecular formula is C8H17NO2 and the molecular weight is 159.23.
The chemical structure of pregabalin is: Pregabalin is a white to off-white, crystalline solid with a pKa1 of 4.2 and a pKa2 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.
Lyrica 02
CLINICAL STUDIES
14.1 Neuropathic pain associated with diabetic peripheral neuropathy 14.2 Postherpetic Neuralgia 14.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures 14.4 Management of Fibromyalgia 1 2 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 degrees of improvement in pain from baseline to study endpoint, Figure 1 shows the fraction of patients achieving that degree 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 Pain Relief – Study DPN 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 degrees of improvement in pain from baseline to study endpoint, Figure 2 shows the fraction of patients achieving that degree 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 Pain Relief – Study DPN 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 ≥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 degrees of improvement in pain from baseline to study endpoint, Figure 3 shows the fraction of patients achieving that degree 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 Pain Relief – Study PHN 1 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 degrees of improvement in pain from baseline to study endpoint, Figure 4 shows the fraction of patients achieving that degree 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 Pain Relief – Study PHN 2 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 endpain 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 degrees of improvement in pain from baseline to study endpoint, Figure 5 shows the fraction of patients achieving that degree 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 Pain Relief – Study PHN 3 14.3 Adjunctive Therapy for Adult Patients with Partial Onset Seizures The efficacy of LYRICA as adjunctive therapy in partial onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter studies in adult patients.
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 7 shows median baseline seizure rates and median percent reduction in seizure frequency by dose.
Table 7: Seizure Response in Controlled, Add-On Epilepsy Studies 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 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.
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 8 and Table 8.
For various degrees of improvement in pain from baseline to study endpoint, Figure 8 shows the fraction of patients achieving that degree 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 8: Patients Achieving Various Levels of Pain Relief – Fibromyalgia Study F1 Table 8: Patient Global Response in Fibromyalgia Study F1 Patient Global Impression of Change Treatment Group (mg/day) % Any Improvement 95% CI 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) PGB = Pregabalin 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 1, and longer time to loss of overall assessment of patient status, as measured by the PGIC 2.
Figure 9: Time to Loss of Therapeutic Response, Fibromyalgia Study F2 (Kaplan-Meier Analysis) 1 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.
2 Time to PGIC lack of improvement was defined as time to PGIC assessments indicating less improvement than “much improvement.” Lyrica 03 Lyrica 04 Lyrica 05 Lyrica 06 Lyrica 07 Lyrica 08 Lyrica 09 Lyrica 10 Lyrica 11
HOW SUPPLIED
16 /STORAGE AND HANDLING 16 /STORAGE AND HANDLING 25 mg capsules: White, hard-gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 25” on the body; available in: Bottles of 90: NDC 0071-1012-68 50 mg capsules: White, hard-gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 50” and an ink band on the body, available in: Bottles of 90: NDC 0071-1013-68 Unit-Dose Blister Packages of 100: NDC 0071-1013-41 75 mg capsules: White/orange hard gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 75” on the body; available in: Bottles of 90: NDC 0071-1014-68 Unit-Dose Blister Packages of 100: NDC 0071-1014-41 100 mg capsules: Orange, hard-gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 100” on the body, available in: Bottles of 90: NDC 0071-1015-68 Unit-Dose Blister Packages of 100: NDC 0071-1015-41 150 mg capsules: White hard gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 150” on the body, available in: Bottles of 90: NDC 0071-1016-68 Unit-Dose Blister Packages of 100: NDC 0071-1016-41 200 mg capsules: Light orange hard gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 200” on the body, available in: Bottles of 90: NDC 0071-1017-68 225 mg capsules: White/light orange hard gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 225” on the body; available in: Bottles of 90: NDC 0071-1019-68 300 mg capsules: White/orange hard gelatin capsule printed with black ink “Pfizer” on the cap, “PGN 300” on the body, available in: Bottles of 90: NDC 0071-1018-68 20 mg/mL oral solution: 16 fluid ounce white high density polyethylene (HDPE) bottle with a polyethylene-lined closure: 16 fluid ounce bottle NDC 0071-1020-01
RECENT MAJOR CHANGES
Dosage and Administration, Oral Solution Concentration and Dispensing ( 2.6)
GERIATRIC USE
8.5 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 (2.5)].
DOSAGE FORMS AND STRENGTHS
– Capsules: 25mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg.
( 3) – Oral Solution: 20 mg/ mL.
( 3)
INDICATIONS AND USAGE
LYRICA is indicated for: – Neuropathic pain associated with diabetic peripheral neuropathy (DPN) ( 1.1) – Post herpetic neuralgia (PHN) ( 1.2) – Adjunctive therapy for adult patients with partial onset seizures ( 1.3) – Fibromyalgia ( 1.4)
PEDIATRIC USE
8.4 Pediatric Use 8.4 Pediatric Use The safety and efficacy of pregabalin in pediatric patients have not been established.
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 ≥50 mg/kg.
The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥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.
NUSRING MOTHERS
8.3 Nursing Mothers 8.3 Nursing Mothers It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats.
Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
WARNING AND CAUTIONS
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 may occur in patients with seizure disorders 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)
DOSAGE AND ADMINISTRATION
DPN Pain ( 2.1): – Administer in 3 divided doses per day – Begin dosing at 150 mg/day – May be increased to a maximum of 300 mg/day within 1 week.
PHN ( 2.2): – Administer in 2 or 3 divided doses per day – Begin dosing at 150 mg/day – May be increased to 300 mg/day within 1 week – Maximum dose of 600 mg/day.
Adjunctive Therapy for Adult Patients with Partial Onset Seizures ( 2.3): – Administer in 2 or 3 divided doses per day – Begin dosing at 150 mg/day – Maximum dose of 600 mg/day.
Fibromyalgia ( 2.4): – Administer in 2 divided doses per day – Begin dosing at 150 mg/day – May be increased to 300 mg/day within 1 week – Maximum dose of 450 mg/day.
Dose should be adjusted in patients with reduced renal function.
( 2.5) Oral Solution Concentration and Dispensing ( 2.6)