Antiepileptics

Pregabalin

Each hard capsule contains 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg or 300 mg of pregabalin. Lyrica capsules also contain lactose monohydrate

Hard capsule 25 mg capsule: White hard gelatine capsule, marked “Pfizer” on the cap and “PGN 25” on the body with black ink. 50 mg capsule: White hard gelatine capsule, marked “Pfizer” on the cap and “PGN 50” on the body with black ink. The body is also marked with a black band. 75 mg capsule: White and orange hard gelatine capsule, marked “Pfizer” on the cap and “PGN 75” on the body with black ink. 100 mg capsule: Orange hard gelatine capsules, marked “Pfizer” on the cap and “PGN 100” on the body with black ink. 150 mg capsule: White hard gelatine capsule, marked “Pfizer” on the cap and “PGN 150” on the body with black ink. 200 mg capsule: Light orange hard gelatine capsules, marked “Pfizer” on the cap and “PGN 200” on the body with black ink. 225 mg capsule: White and orange hard capsule, marked “Pfizer” on the cap and “PGN 225” on the body with black ink. 300 mg capsule: White and orange hard gelatine capsule, marked “Pfizer” on the cap and “PGN 300” on the body with black ink.

Neuropathic pain Lyrica is indicated for the treatment of peripheral and central neuropathic pain in adults. Epilepsy Lyrica is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation. Generalised Anxiety Disorder LYRICA is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.

The dose range is 150 to 600 mg per day given in either two or three divided doses.

Lyrica may be taken with or without food.

Neuropathic pain

Pregabalin treatment can be started at a dose of 150 mg per day. Based on individual patient response and tolerability, the dosage may be increased to 300 mg per day after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an additional 7-day interval.

Epilepsy

Pregabalin treatment can be started with a dose of 150 mg per day. Based on individual patient response and tolerability, the dosage may be increased to 300 mg per day after 1 week. The maximum dosage of 600 mg per day may be achieved after an additional week.

Generalised Anxiety Disorder

The dose range is 150 to 600 mg per day given as two or three divided doses. The need for treatment should be reassessed regularly.

Pregabalin treatment can be started with a dose of 150 mg per day. Based on individual patient response and tolerability, the dosage may be increased to 300 mg per day after 1 week. Following an additional week the dosage may be increased to 450 mg per day. The maximum dosage of 600 mg per day may be achieved after an additional week.

Discontinuation of pregabalin

In accordance with current clinical practice, if pregabalin has to be discontinued it is recommended this should be done gradually over a minimum of 1 week independent of the indication.

Patients with renal impairment

Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. As pregabalin clearance is directly proportional to creatinine clearance, dosage reduction in patients with compromised renal function must be individualised according to creatinine clearance (CLcr), as indicated in Table 1 determined using the following formula:

Pregabalin is removed effectively from plasma by haemodialysis (50% of drug in 4 hours). For patients receiving haemodialysis, the pregabalin daily dose should be adjusted based on renal function. In addition to the daily dose, a supplementary dose should be given immediately following every 4-hour haemodialysis treatment (see Table 1).

Table1. Pregabalin dosage adjustment based on renal function

Creatinine Clearance (CLcr ) (ml/min)	Total Pregabalin Daily dose *		Dose Regimen
	Starting dose (mg/day)	Maximum dose (mg/day)
span style="font-family: Times New Roman;"> 60	150	600	BID or TID
30 - <60	75	300	BID or TID
15 - <30	25 – 50	150	Once Daily or BID
< 15	25	75	Once Daily
Supplementary dosage following haemodialysis (mg)
	25	< 100	Single dose+

TID = Three divided doses

BID = Two divided doses

* Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose

⁺ Supplementary dose is a single additional dose

Use in patients with hepatic impairment

No dosage adjustment is required for patients with hepatic impairment.

Use in children and adolescents

Lyrica is not recommended for use in children below the age of 12 years and adolescents (12 - 17 years of age) due to insufficient data on safety and efficacy.

Use in the elderly (over 65 years of age)

Elderly patients may require a dose reduction of pregabalin due to a decreased renal function (see patients with renal impairment).

Use in children and adolescents (12 to 17 years of age) The safety and effectiveness of pregabalin in paediatric patients below the age of 12 years and adolescents has not been established. The use in children is not recommended

Elderly patients may require a dose reduction of pregabalin due to a decreased renal function (see patients with renal impairment in Adult Dosage).

Hypersensitivity to the active substance or to any of the excipients.

In accordance with current clinical practice, some diabetic patients who gain weight on pregabalin treatment may need to adjust hypoglycaemic medications.

There have been reports in the postmarketing experience of hypersensitivity reactions, including cases of angioedema. Pregabalin should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur.

Pregabalin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population. There have also been post marketing reports of loss of consciousness, confusion and mental impairment. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.

In controlled studies, a higher proportion of patients treated with pregabalin reported blurred vision than did patients treated with placebo which resolved in a majority of cases with continued dosing. In the clinical studies where ophthalmologic testing was conducted, the incidence of visual acuity reduction and visual field changes was greater in pregabalin-treated patients than in placebo-treated patients; the incidence of fundoscopic changes was greater in placebo-treated patients.

In the postmarketing experience, visual adverse reactions have also been reported, including vision loss, visual blurring or other changes of visual acuity, many of which were transient. Discontinuation of pregabalin may result in resolution or improvement of these visual symptoms.

Cases of renal failure have been reported and discontinuation of pregabalin did show reversibility of this adverse effect.

There are insufficient data for the withdrawal of concomitant antiepileptic medicinal products, once seizure control with pregabalin in the add-on situation has been reached, in order to reach monotherapy on pregabalin.

After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms have been observed in some patients. The following events have been mentioned: insomnia, headache, nausea, diarrhoea, flu syndrome, nervousness, depression, pain, sweating and dizziness. The patient should be informed about this at the start of the treatment.

Concerning discontinuation of long-term treatment of pregabalin there are no data of the incidence and severity of withdrawal symptoms in relation to duration of use and dosage of pregabalin.

There have been post-marketing reports of congestive heart failure in some patients receiving pregabalin. These reactions are mostly seen in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic indication. Pregabalin should be used with caution in these patients. Discontinuation of pregabalin may resolve the reaction.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse events in general, CNS adverse events and especially somnolence was increased. This may be attributed to an additive effect due to concomitant medication (e.g. anti-spasticity agents) needed for this condition. This should be considered when prescribing pregabalin in this condition.

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for pregabalin.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), does not inhibit drug metabolism in vitro, and is not bound to plasma proteins, it is unlikely to produce, or be subject to, pharmacokinetic interactions.

Accordingly, in in vivo studies no clinically relevant pharmacokinetic interactions were observed between pregabalin and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. Population pharmacokinetic analysis indicated that oral antidiabetics, diuretics, insulin, phenobarbital, tiagabine and topiramate had no clinically significant effect on pregabalin clearance.

Co-administration of pregabalin with the oral contraceptives norethisterone and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of either substance.

Pregabalin may potentiate the effects of ethanol and lorazepam. In controlled clinical trials, multiple oral doses of pregabalin co-administered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. In the postmarketing experience, there are reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.

No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction studies have only been performed in adults.

The pregabalin clinical programme involved over 9000 patients who were exposed to pregabalin, of whom over 5000 were in double-blind placebo controlled trials. The most commonly reported adverse reactions were dizziness and somnolence. Adverse reactions were usually mild to moderate in intensity. In all controlled studies, the discontinuation rate due to adverse reactions was 13% for patients receiving pregabalin and 7% for patients receiving placebo. The most common adverse reactions resulting in discontinuation from pregabalin treatment groups were dizziness and somnolence.

In the table below all adverse reactions, which occurred at an incidence greater than placebo and in more than one patient, are listed by class and frequency (very common (> 1/10), common (> 1/100, < 1/10), uncommon (>1/1000, <1/100) and rare (<1/1000)). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The adverse reactions listed may also be associated with the underlying disease and / or concomitant medications.

In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse events in general, CNS adverse events and especially somnolence was increased (see 4.4)

Additional reactions reported from post-marketing experience are included as Unknown frequency in italics in the list below.

After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms have been observed in some patients. The following events have been mentioned: insomnia, headache, nausea, diarrhoea, flu syndrome, nervousness, depression, pain, sweating and dizziness. The patient should be informed about this at the start of the treatment.

Concerning discontinuation of long-term treatment of pregabalin there are no data of the incidence and severity of withdrawal symptoms in relation to duration of use and dosage of pregabalin.

Pfizer Ltd

(POM)

01 July 2009