Class: Musculoskeletal System
Dosage Form: Tablets
Pregabalin………25, 50, 75, 150, 300 mg
a) Pharmacotherapeutic Group: Antiepleptics.
The active substance, pregabalin, is a gamma-aminoutyric analogue ((S)-3-(aminomethyl)-5-methylhexanoic acid).
b) Mechanism of Action:
Pregabalin binds to an auxillary subunit (alpha2-delta protein) of voltage-gated calcium channels in the central nervous system, potentially displacing [3H]-gabapentin.
c) Clinical Experience:
1) Neuropathic pain:
Efficacy has been shown in studies in diabetic neuropathy and post herpetic neuralgia. Efficacy has not been studied in other models of neuropathic pain.
Pregbalin has been studied in 9 controlled studies up to 13 weeks with twice a day dosing (BID) and up to 8 weeks with three times a day (TID) dosing. Overall, the safety and efficacy profiles for BID and TID dosing regimens were similar.
In clinical trials up o 13 weeks, a reduction in pain was seen by week 1 and was maintained throughout the treatment period.
In controlled clinical trials, 35% of the pregabalin treated patients and 18% of the patients on palcebo had a 50% improvement in pain score. For patients not experiencing somnolence, such as improvement was observed in 33% of patients treated with pregabalin and 18% of patients on placebo. For patients who experienced somnolence the responder rates were 48% on pregabalin and 16% on palcebo.
Pregabalin has been studied in 3 controlled clinical studies of 12 weeks duration with either twice a day dosing (BID) or three times a day (TID) dosing. Overall, the safety and efficacy profiles for BID and TID dosing regimens were similar.
A reduction in seizure frequency was observed in by week 1.
3) Generalised Anxiety Disorder:
Pregabalin has been studied in 6 controlled studies of 4-6 weeks duration, an elderly study of 8 weeks duration and a long-term relapse prevention study with a double blind relapse prevention phase of 6 months duration.
Relief of the symptoms of GAD as reflected by the Hamilton Anxiety Rating Scale (HAM-A) was observed by week 1.
In controlled clinical trials (4-8 week duration), 52% of the pregabalin treated patients and 38% of the patients on placebo had at least a 50% improvement in HAM-A total score from baseline to endpoint.
Pregabalin steady-state pharmacokinetics are similar in healthy volunteers, patients with epilepsy receiving antiepileptic drugs and patients with chronic pain.
Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations occurring within 1 hour following both single and multiple dose administration. Pregabalin oral bioavailability is estimated to be >= 90% and is independent of dose. Following repeated administration, steady state is achieved within 24 to 48 hours. The rate of pregabalin absorption is decreased when given with food resulting in a decrease in Cmax by approximately 25-30% and a delay in tmax to approximately 2.5 hours. However, an administration of pregabalin with food has no clinically significant effect on the extent of pregabalin absorption.
In preclinical studies, pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. In humans, the apparent volume of distribution of pregabalin following oral administration is approximately 0.56 L/kg. Pregabalin is not bound to plasma proteins.
Pregabalin undergoes negligible metabolism in humans. Following a dose or radiolabelled pregabalin, approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. In preclinical studies, there was no indication of racemisation of pregabalin S-enantiomer to the R-enantiomer.
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.
Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance (see Renal Impairment).
Dosage adjustment adjustment in patients with reduced renal function or undergoing haemodialysis is necessary.
Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject pharmacokinetic variability for pregabalin is low (<20%). Multiple dose pharmacokinetics are predictable from single-dose data. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.
f) Special Patients Groups:
Gender: Clinical trials indicate that gender dose not have a clinically significant influence on the plasma concentrations of pregabalin.
Renal impairment: Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by haemodialysis (following a 4 hour haemodialysis treatment plasma pregabalin concentrations are reduced by approximately 50%). Because renal elimination is the major elimination pathway, dosage reduction in patients with renal impairment and dosage supplementation following haemodialysis is necessary.
g) Hepatic impairment:
No specific pharmacokinetic studies were carried out in patients with impaired liver functions. Since pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma concentrations.
Elderly (over 65 years of age):
Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with decreases in creatinine clearance assocaited with increasing age. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function.
Pre-clinical Safety Data
In conventional safety pharmcology studies in amimals, pregabalin was well-tolerated at clinically relevant doses. In repeated dose toxicity studies in rants and monkeys CNS effects were observed, including hypoacidity, hyperactivity and ataxia. An increase incidence of retinal atrophy commonly observed in aged albino rats was seen after long term exposure to pregabalin at exposures >= 5 times the mean human exposure at the maximum recommended clinical dose.
Pregabalin was not teratogenic in mice, rats or rabbits. Foetal toxicity in rats and rabbits occurred only at exposures sufficiently above human exposure. In prenatal/postnatal toxicity studies, pregabalin induced offspring developmental toxicity in rats at expsoures > 2 times the maximum recommended human exposure.
Pregabalin is not genotoxic based on results of a battery of in vitro and in vivo tests.
Two-year carcinogenicity studies with pregabalin ere conducted in rats and mice. No tumors were observed in rats at exposures up to 24 times the mean human exposure at the maximum recommended clinical dose of 600 mg/day. In mice, no increased incidence of tumors was found at exposures similar to the mean human exposure, but an increased incidence of haemangiosarcoma was observed at higher exposures. The non-genotoxic mechanism of pregabalin-induced tumor formation in mice involves platelet changes and associated endothelial cell proliferation. These platelet changes were not presented in rats or in humans based on short term and limited long term clinical data. There is no evidence to suggest an associated risk to humans.
In juvenile rats the types of toxicity do not differ qualitatively from those observed in adult rats. However, juvenile rats are more sensitive. At therapeutic exposures, there was evidence of CNS clinical signs of hyperacivity and bruxism and some changes in growth (transient body weight gain suppression). Effects on the oestrus cycle were observed at 5-fold the human therapeutic exposure. Neurobenhavioral/cognitive effects were observed in juvenile rats 1-2 weeks after exposure > 2 times (acoustic startle response) or > 5 times (learning/memory) the human therapeutic exposure.
Lyrica is indicated in:
- Neuropathic pain: Lyrica is indicated for treatment of peripheral neuropathic pain in adults
- Epilepsy: Lyrica is indicated for treatment of Generalized Anxiety Disorder (GAD) in adults
Hypersensitivity to the active substance or to any of the excipients.
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 to be subject to, pharmacokintic 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 northisterone and/or ethinyl estradiol does not influence the steady-state pharmacokineitcs of either substance.
Multiple oral doses of pregabalin co-administered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone. Pregabalin may potentiate the effects of ethanol and lorazepam.
No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction studies have only been performed in adults.
The pregabalin clinical program 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, undesriable effects are presented in oder of decreasing seriousness.
The adverse reactions listed may also be associated with the underlying disease and/or concomitant medications.
Dosage and Administration:
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.
1. 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.
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 weeks. The maximum dosage of 600 mg per day may be achieved after an additional week.
3. Generalized 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 my per day. The maximum dosage of 600 mg per day may be achieved after an additional week.
4. 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.
5. 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 individualized according to creatinine clearance (CLcr).
Pregabalin is removed effectively from plasma by hemodialysis (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.
6. Patients with Hepatic Impairment:
No dosage adjustment is required for patients with hepatic impairment.
a) 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.
b) Use in the Elderly:
Elderly patients may require a dose reduction of pregabalin due to a decreased renal function (see patients with renal impairment).
In overdoses up to 15 g, no unexpected adverse reactions were reported. Treatment of pregabalin overdose should include general supportive measures and may include haemodialysis if necessary.
Pregnancy and Lactation:
There are no adequate data from the use of pregabalin in pregnant women.
Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.
Lyrica should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the fetus). Effective contraception must be used in women of child bearing potential.
It is not known if pregabalin is excreted in the breast milk of humans; however, it is present in the milk of rats. Therefore, breast-feeding is not recommended during treatment with pregabalin.
In accordance with current clinical practice, some diabetic patients who gain weight on pregabalin treatment need to adjust hypoglycemic medications. Pregabalin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population. Therefore, patients should be advised to exercise caution until they are familiar with the potential effects of the medication.
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 onserved 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 and use and dosage of pregabalin.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
PVC/Aluminum blisters each containing 10 hard gelatin capsules.
Store at room temperature, below 25°C.