Pregabalin: Package Insert and Label Information

PREGABALIN — pregabalin capsule
MARKSANS PHARMA LIMITED

1 INDICATIONS & USAGE

Pregabalin capsules are 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
Pediatric use information is approved for Pfizer’s LYRICA® (pregabalin) Capsules and Oral Solution products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2 DOSAGE & ADMINISTRATION

2.1 IMPORTANT ADMINISTRATION INSTRUCTIONS

Pregabalin capsules are given orally with or without food.

When discontinuing pregabalin capsules, taper gradually over a minimum of 1 week [see Warnings and Precautions (5.6)].

Because pregabalin capsules are 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 IN ADULTS

The maximum recommended dose of pregabalin capsules are 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 pregabalin capsules were 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 IN ADULTS

The recommended dose of pregabalin capsules 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 pregabalin capsules, 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 adult patients 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 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.

Table 1. Recommended Dosage for Adults and Pediatric Patients 4 Years and Older

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 4 years of age and older: 2 or 3 divided doses

Both the efficacy and adverse event profiles of pregabalin capsules have been shown to be dose-related. The effect of dose escalation rate on the tolerability of pregabalin capsules has not been formally studied.

The efficacy of adjunctive pregabalin capsules in patients taking gabapentin has not been evaluated in controlled trials. Consequently, dosing recommendations for the use of pregabalin capsules with gabapentin cannot be offered.

Pediatric use information is approved for Pfizer’s LYRICA® (pregabalin) Capsules and Oral Solution products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.5 MANAGEMENT OF FIBROMYALGIA IN ADULTS

The recommended dose of pregabalin capsules 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 pregabalin capsules were 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 IN ADULTS

The recommended dose range of pregabalin capsules 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 pregabalin capsules 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 pregabalin capsules are eliminated primarily by renal excretion, adjust the dose in adult patients with reduced renal function. The use of pregabalin capsules 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:

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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 pregabalin capsule 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)* Dose Regimen
Greater than or equal to 60 150 300 450 600 BID or TID
30 to 60 75 150 225 300 BID or TID
15 to 30 25 to 50 75 100 to 150 150 QD or BID
Less than 15 25 25 to 50 50 to 75 75 QD
Supplementary dosage following hemodialysis (mg)†
Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25 to 50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50 to 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

TID= Three divided doses; BID = Two divided doses; QD = Single daily dose.
* Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose.
† Supplementary dose is a single additional dose.

3 DOSAGE FORMS & STRENGTHS

Capsules: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg

[see Description (11)and How Supplied/Storage and Handling (16)]

4 CONTRAINDICATIONS

Pregabalin capsules are contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy [see Warnings and Precautions (5.2)].

5 WARNINGS AND PRECAUTIONS

5.1 ANGIOEDEMA

There have been postmarketing reports of angioedema in patients during initial and chronic treatment with pregabalin. 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 pregabalin immediately in patients with these symptoms.

Exercise caution when prescribing pregabalin 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 pregabalin. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue pregabalin immediately in patients with these symptoms.

5.3 SUICIDAL BEHAVIOR AND IDEATION

Antiepileptic drugs (AEDs), including pregabalin, 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 to 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 Psychiatric Other Total 1.0 5.7 1.0 2.4 3.4 8.5 1.8 4.3 3.5 1.5 1.9 1.8 2.4 2.9 0.9 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 pregabalin 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.

5.4 RESPIRATORY DEPRESSION

There is evidence from case reports, human studies, and animal studies associating pregabalin with serious, life-threatening, or fatal respiratory depression when co-administered with central nervous system (CNS) depressants, including opioids, or in the setting of underlying respiratory impairment. When the decision is made to co-prescribe pregabalin with another CNS depressant, particularly an opioid, or to prescribe pregabalin to patients with underlying respiratory impairment, monitor patients for symptoms of respiratory depression and sedation, and consider initiating pregabalin at a low dose. The management of respiratory depression may include close observation, supportive measures, and reduction or withdrawal of CNS depressants (including pregabalin).

There is more limited evidence from case reports, animal studies, and human studies associating pregabalin with serious respiratory depression, without co-administered CNS depressants or without underlying respiratory impairment.

5.5 DIZZINESS AND SOMNOLENCE

Pregabalin may cause dizziness and somnolence. Inform patients that pregabalin-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery [see Patient Counseling Information (17)].

In the pregabalin controlled trials in adult patients, dizziness was experienced by 30% of pregabalin-treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of pregabalin-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of pregabalin 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 pregabalin-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 pregabalin controlled trials in pediatric patients (4 to less than 17 years of age) for the treatment of partial-onset seizures, somnolence was reported in 21% of pregabalin-treated patients compared to 14% of placebo-treated patients, and occurred more frequently at higher doses.

Pediatric use information is approved for Pfizer’s LYRICA® (pregabalin) Capsules and Oral Solution products. However, due to Pfizer’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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