Each hard capsule contains 25, mg, 75 mg or 150 mg pregabalin.
Excipients/Inactive Ingredients: Capsule contents: Pregelatinised starch, Talc (E553b).
Capsule shell: 25 mg hard capsules: titanium dioxide (E171), gelatin, black printing ink (shellac, black iron oxide (E172), propylene glycol) in capsule shell.
75 mg hard capsules: titanium dioxide (E171), gelatin, yellow iron oxide (E172), black printing ink (shellac, black iron oxide (E172), propylene glycol) in capsule shell.
150 mg hard capsules: titanium dioxide (E171), gelatin, red iron oxide (E172), yellow iron oxide (E172), black printing ink (shellac, black iron oxide (E172), propylene glycol) in capsule shell.
Pharmacotherapeutic Group: Antiepileptics, other antiepileptics. ATC Code: N03AX16.
Pharmacology: Pharmacodynamics: The active substance, pregabalin, is a gamma-aminobutyric acid analogue [(S)-3-(aminomethyl)-5-methylhexanoic acid].
Mechanism of action: Pregabalin binds to an auxiliary subunit (α2-δ protein) of voltage-gated calcium channels in the central nervous system.
Clinical efficacy and safety: Neuropathic pain: Efficacy has been shown in trials in diabetic neuropathy and post herpetic neuralgia. Efficacy has not been studied in other models of neuropathic pain.
Pregabalin has been studied in 9 controlled clinical trials of 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 to 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 placebo had a 50% improvement in pain score. For patients not experiencing somnolence, such an 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 placebo.
Epilepsy: Adjunctive Treatment: Pregabalin has been studied in 3 controlled clinical trials of 12 week duration with either BID or TID dosing. Overall, the safety and efficacy profiles for BID and TID dosing regimens were similar.
A reduction in seizure frequency was observed by Week 1.
Generalised Anxiety Disorder: Pregabalin has been studied in 6 controlled trials of 4-6 week duration, an elderly study of 8 week 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.
Fibromyalgia: Pregabalin as monotherapy has been studied in 5 placebo-controlled studies, three of 12 weeks fixeddose duration, one of 7 weeks fixed-dose duration, and a 6-month study demonstrating long-term efficacy. Pregabalin treatment in all fixed-dose studies produced a significant reduction in pain associated with fibromyalgia at doses from 300 to 600 mg per day (BID).
In the three 12-week fixed-dose studies, 40% of pregabalin-treated patients experienced a 30% or more improvement in pain score versus 28% of the patients on placebo; 23% of treated patients experienced a 50% or more improvement in pain score versus 15% of the patients on placebo.
Pregabalin produced significantly superior global assessment scores via the Patient Global Impression of Change (PGIC) in the three 12-week fixed-dose studies as compared to placebo treatment (41% patients feeling very much or much improved on pregabalin versus 29% on placebo). As measured by Fibromyalgia Impact Questionnaire (FIQ), pregabalin produced a statistically significant improvement in function versus placebo treatment in 2 out of the 3 fixed-dose studies in which it was evaluated.
Pregabalin treatment produced significant improvements in patient-reported sleep outcomes in the 4 fixed-dose studies as measured by Medical Outcomes Study Sleep Scale (MOS-SS) Sleep disturbance subscale, MOS-SS overall sleep problem index, and the daily sleep quality diary.
In the 6-month study, improvement in pain, global assessment (PGIC), function (FIQ total score) and sleep (MOS-SS Sleep disturbance subscale) were maintained for pregabalin-treated patients for a significantly longer period compared to placebo.
Pregabalin 600 mg per day showed an additional improvement in patient-reported sleep outcomes as compared to 300 and 450 mg per day; mean effects on pain, global assessment, and FIQ were similar at 450 and 600 mg per day, although the 600 mg per day dose was less well tolerated.
Pharmacokinetics: Pregabalin steady-state pharmacokinetics are similar in healthy volunteers, patients with epilepsy receiving anti-epileptic drugs and patients with chronic pain.
Absorption: 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, administration of pregabalin with food has no clinically significant effect on the extent of pregabalin absorption.
Distribution: 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.
Biotransformation: Pregabalin undergoes negligible metabolism in humans. Following a dose of 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.
Elimination: 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 Pharmacokinetics in special patient groups: Renal impairment as follows). Dose adjustment in patients with reduced renal function or undergoing haemodialysis is necessary (see Table 1 under Dosage & Administration).
Linearity/non-linearity: 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.
Pharmacokinetics in special patient groups: Gender: Clinical trials indicate that gender does 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, dose reduction in patients with renal impairment and dose supplementation following haemodialysis is necessary (see Table 1 under Dosage & Administration).
Hepatic impairment: No specific pharmacokinetic studies were carried out in patients with impaired liver function. 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.
Older people (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 associated with increasing age. Reduction of pregabalin dose may be required in patients who have age related compromised renal function (see Table 1 under Dosage & Administration).
Breast feeding mothers: The pharmacokinetics of 150 mg pregabalin given every 12 hours (300 mg daily dose) was evaluated in 10 lactating women who were at least 12 weeks postpartum. Lactation had little to no influence on pregabalin pharmacokinetics. Pregabalin was excreted into breast milk with average steady state concentrations approximately 76% of those in maternal plasma. The estimated average daily infant dose of pregabalin from breast milk (assuming mean milk consumption of 150 mL/kg/day) was 0.31 mg/kg/day, which on a mg/kg basis would be approximately 7% of the maternal dose.
Toxicology: Preclinical safety data: In conventional safety pharmacology studies in animals, pregabalin was well-tolerated at clinically relevant doses. In repeated dose toxicity studies in rats and monkeys CNS effects were observed, including hypoactivity, hyperactivity and ataxia. An increased 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 exposures >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 were conducted in rats and mice. No tumours 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 tumours 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 tumour formation in mice involves platelet changes and associated endothelial cell proliferation. These platelet changes were not present 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 hyperactivity 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. Neurobehavioral/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. Reduced acoustic startle response was observed in juvenile rats 1-2 weeks after exposure at >2 times the human therapeutic exposure. Nine weeks after exposure, this effect was no longer observable.
Neuropathic pain: Rewisca is indicated for the treatment of neuropathic pain which includes diabetic peripheral neuropathy and post-herpetic neuralgia in adults.
Epilepsy: Rewisca is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.
Generalised Anxiety Disorder: Rewisca is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.
Fibromyalgia: Rewisca is indicated for the management of fibromyalgia.
Posology: The dose range is 150 to 600 mg per day given in either two or three divided doses.
Pregabalin treatment can be started at a dose of 150 mg per day given as two or three divided doses. Based on individual patient response and tolerability, the dose 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 given as two or three divided doses. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after 1 week. The maximum dose 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 dose may be increased to 300 mg per day after 1 week. Following an additional week the dose may be increased to 450 mg per day. The maximum dose of 600 mg per day may be achieved after an additional week.
The recommended dose of pregabalin is 300 to 450 mg per day. Dosing should begin at 75 mg two times a day (150 mg per day) and may be increased to 150 mg two times a day (300 mg per day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg per day may be further increased to 225 mg two times a day (450 mg per day). Although pregabalin was also studied at 600 mg per day, there is no evidence that this dose confers additional benefit and that this dose was less tolerated.
In view of the dose-dependent adverse reactions, treatment with doses above 450 mg per day is not recommended.
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 (see Precautions & Adverse Reactions).
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 (see Pharmacology: Pharmacokinetics under Actions), dose 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: (See equation.)
Click on icon to see table/diagram/image
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).
Click on icon to see table/diagram/image
Patients with hepatic impairment:
No dose adjustment is required for patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
The safety and efficacy of Rewisca in children below the age of 12 years and in adolescents (12-17 years of age) have not been established. No data are available. The use in children and adolescents is not recommended.
Older people (over 65 years of age):
Older people may require a dose reduction of pregabalin due to a decreased renal function (see Patients with renal impairment as previously mentioned).
Method of administration: Rewisca may be taken with or without food.
Rewisca is for oral use only.
Symptoms: In overdoses up to 15 g, no unexpected adverse reactions were reported.
In the post-marketing experience, the most commonly reported adverse events observed when pregabalin was taken in overdose included affective disorder, somnolence, confusional state, depression, agitation, and restlessness. Seizures were also reported.
Management: Treatment of pregabalin overdose should include general supportive measures and may include haemodialysis if necessary (see Table 1 under Dosage & Administration).
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Diabetic patients: In accordance with current clinical practice, some diabetic patients who gain weight on pregabalin treatment may need to adjust hypoglycaemic medicinal products.
Hypersensitivity reactions: 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.
Dizziness, somnolence, loss of consciousness, confusion, and mental impairment: Pregabalin treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in older people. 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 medicinal product.
Vision-related effects: In the post-marketing experience, transient visual blurring and other changes in visual acuity have been reported in patients treated with pregabalin. Discontinuation of pregabalin may result in resolution or improvement of these visual symptoms.
Withdrawal of concomitant antiepileptic medicinal products: 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.
Withdrawal symptoms: 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, anxiety, hyperhidrosis, diarrhoea, flu syndrome, nervousness, depression, pain, sweating and dizziness. The patient should be informed about this at the start of the treatment.
Pregabalin is not known to be active at receptor sites associated with drugs of abuse. Cases of misuse and abuse have been reported in the post-marketing database. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of pregabalin misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).
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.
Renal failure: Although the effects of discontinuation on the reversibility of renal failure have not been systematically studied, improved renal function following discontinuation or dose reduction of pregabalin has been reported.
Congestive heart failure: There have been post-marketing reports of congestive heart failure in some patients receiving pregabalin. 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. Because there are limited data on severe congestive heart failure patients, pregabalin should be used with caution in these patients (see Adverse Reactions).
Creatine kinase levels: Treatment with pregabalin was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum values were 60 U/L for pregabalin-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 2% of patients on pregabalin and 1% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three pregabalin-treated patients had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and pregabalin is not completely understood because the cases had documented factors that may have caused or contributed to these events. Pregabalin should be discontinued if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur in the context of symptoms of myopathy.
Suicidal ideation and behaviour: 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.
Effects on ability to drive and use machines: Rewisca may have minor or moderate influence on the ability to drive and use machines. Rewisca may cause dizziness and somnolence and therefore may influence the ability to drive or use machines. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether this medicinal product affects their ability to perform these activities.
Pregnancy: There are no adequate data from the use of pregabalin in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown.
Rewisca should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. Effective contraception must be used in women of child bearing potential.
Breast-feeding: Pregabalin is excreted into breast milk (see Pharmacology: Pharmacokinetics under Actions). As the safety of pregabalin on newborns/infants is unknown, breast-feeding is not recommended during treatment with pregabalin. A decision must be made whether to discontinue breast feeding or to discontinue pregabalin therapy taking into account the benefit of breast- feeding for the child and the benefit of therapy for the woman.
Summary of the safety profile:
The pregabalin clinical programme involved over 12,000 patients who were exposed to pregabalin, of whom over 7000 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 14% for patients receiving pregabalin and 5% for patients receiving placebo. The most common adverse reactions resulting in discontinuation from pregabalin treatment groups were dizziness and somnolence.
Tabulated list of adverse reactions:
Selected adverse drug reactions that were treatment related in the pooled analysis of clinical trials, are listed in the table as follows by System Organ Class (SOC). The frequency of these terms has been based on all-causality adverse drug reactions in the clinical trial data set very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).
The adverse reactions listed may also be associated with the underlying disease and/or concomitant medicinal products. (See Table 2.)
Click on icon to see table/diagram/image
The following adverse drug reactions were reported during Post-Marketing Surveillance: Immune system disorders:
Uncommon: Hypersensitivity; Rare: Angioedema, allergic reaction.
Nervous system disorders:
Very Common: Headache; Uncommon: Loss of consciousness, mental impairment.
Rare: Congestive heart failure.
Respiratory, thoracic and mediastinal disorders:
Rare: Pulmonary oedema*.
Common: Nausea, diarrhea; Rare: Swollen tongue.
Skin and subcutaneous tissue disorders:
Uncommon: Face swelling, pruritus.
Renal and urinary disorders:
Rare: Urinary retention.
Reproductive system and breast disorders:
General disorders and administration site conditions:
* Adverse drug reaction frequency estimated using "The Rule of 3".
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.
In vivo studies and population pharmacokinetic analysis: 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.
Oral contraceptives, norethisterone and/or ethinyl oestradiol: Co-administration of pregabalin with the oral contraceptives norethisterone and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of either substance.
Central nervous system influencing medical products: 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. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.
In the post-marketing experience, there are reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications.
Reduced lower gastrointestinal tract function: There are post-marketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when pregabalin was co-administered with medications that have the potential to produce constipation, such as opioid analgesics.
Interactions and older people: No specific pharmacodynamic interaction studies were conducted in older volunteers.
Special precautions for disposal: No special requirements.
Incompatibilities: Not applicable.
Do not store above 30°C.
Shelf life: 2 years.
N03AX16 - pregabalin ; Belongs to the class of other antiepileptics.
Hard cap 25 mg (the body of the capsule is white colour, the cap of the capsule is white colour, capsule cap is imprinted with black mark P25, the content of the capsule is white to off white powder, capsule size no. 4) x 30's. 75 mg (the body of the capsule is brownish yellow colour, the cap of the capsule is brownish yellow colour, capsule cap is imprinted with black mark P75, the content of the capsule is white to off white powder, capsule size no. 4) x 30's. 150 mg (the body of the capsule is white colour, the cap of the capsule is yellowish brown colour, capsule cap is imprinted with black mark P150, the content of the capsule is white to off white powder, capsule size no. 2) x 30's.