Pregabalin Actavis

Pregabalin.

Each hard capsule contains either 25 mg, 50 mg, 75 mg or 150 mg of pregabalin.
Excipients/Inactive Ingredients: Capsule core: Mannitol, Corn starch, Pregelatinised corn starch, Talc.
Capsule printing ink (black): Shellac, Dehydrated alcohol, Isopropyl alcohol, Butyl alcohol, Propylene glycol, Strong ammonium solution, Black iron oxide (E172), Potassium hydroxide.
Hard capsule: 25 mg, 50 mg & 150 mg: Gelatine, Titanium dioxide (E171). 75 mg: Gelatine, Titanium dioxide (E171), Iron Oxide Red (E172).

Neuropathic pain: Pregabalin Actavis is indicated for the treatment of peripheral and central neuropathic pain in adults.
Epilepsy: Pregabalin Actavis is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.
Generalised anxiety disorder: Pregabalin Actavis is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.
Fibromyalgia: Pregabalin Actavis 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.
Neuropathic pain: 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.
Epilepsy: 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.
Fibromyalgia: The recommended dose of pregabalin for fibromyalgia 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 well tolerated. In view of the dose-dependent adverse reactions, treatment with doses above 450 mg/day is not recommended (see Adverse Reactions). Because pregabalin is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function.
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 and Adverse Reactions).
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, dose reduction in patients with compromised renal function must be individualised according to creatinine clearance (CL_cr), as indicated in Table 1 determined using the following formula: (See formula.)

Click on icon to see table/diagram/image

Pregabalin is removed effectively from plasma by hemodialysis (50% of drug in 4 hours). For patients receiving hemodialysis, 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 hemodialysis treatment (see Table 1).

Click on icon to see table/diagram/image

Hepatic impairment: No dose adjustment is required for patients with hepatic impairment.
Paediatric population: The safety and efficacy of Pregabalin Actavis in children below the age of 12 years and in adolescents (12-17 years of age) have not been established. Currently available data are described in Adverse Reactions but no recommendation on a posology can be made.
Elderly: Elderly patients may require a dose reduction of pregabalin due to a decreased renal function.
Method of administration: Pregabalin Actavis may be taken with or without food.
Pregabalin Actavis is for oral use only.

In the post-marketing experience, the most commonly reported adverse reactions observed when pregabalin was taken in overdose included, somnolence, confusional state, agitation, and restlessness. Seizures were also reported.
In rare occasions, cases of coma have been reported.
Treatment of pregabalin overdose should include general supportive measures and may include hemodialysis if necessary (see Table 1 under Dosage & Administration).

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

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 post-marketing 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 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 medicinal product.
Vision-related effects: In controlled trials, 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 post-marketing experience, visual adverse reactions have also been reported, including loss of vision, 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.
Renal failure: Cases of renal failure have been reported and in some cases discontinuation of pregabalin did show reversibility of this adverse reaction.
Withdrawal of concomitant anti-epileptic medicinal products: There are insufficient data for the withdrawal of concomitant anti-epileptic 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, diarrhea, flu syndrome, nervousness, depression, pain, convulsion, hyperhidrosis and dizziness, suggestive of physical dependence. The patient should be informed about this at the start of the treatment.
Convulsions, including status epilepticus and grand mal convulsions, may occur during pregabalin use or shortly after discontinuing pregabalin.
Concerning discontinuation of long-term treatment of pregabalin, data suggest that the incidence and severity of withdrawal symptoms may be dose related.
Congestive heart failure: 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.
Respiratory depression: There have been reports of severe respiratory depression in relation to pregabalin use. Patients with compromised respiratory function, respiratory or neurological disease, renal impairment, concomitant use of CNS depressants and the elderly may be at higher risk of experiencing this severe adverse reaction. Dose adjustments may be necessary in these patients (see Dosage & Administration).
Treatment of central neuropathic pain due to spinal cord injury: In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions in general, central nervous system (CNS) adverse reactions and especially somnolence was increased. This may be attributed to an additive effect due to concomitant medicinal products (e.g., anti-spasticity agents) needed for this condition. This should be considered when prescribing pregabalin in this condition.
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 studies 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.
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. When pregabalin and opioids will be used in combination, measures to prevent constipation may be considered (especially in female patients and elderly).
Concomitant use with opioids: Caution is advised when prescribing pregabalin concomitantly with opioids due to risk of CNS depression (see Interactions). In a case-control study of opioid users, those patients who took pregabalin concomitantly with an opioid had an increased risk for opioid-related death compared to opioid use alone (adjusted odds ratio [aOR], 1.68 [95% CI, 1.19 - 2.36]). This increased risk was observed at low doses of pregabalin (≤ 300 mg, aOR 1.52 [95% CI, 1.04 - 2.22]) and there was a trend for a greater risk at high doses of pregabalin (> 300 mg, aOR 2.51 [95% CI 1.24 - 5.06]).
Misuse, abuse potential or dependence: Cases of misuse, abuse and dependence have been reported. Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of pregabalin misuse, abuse or dependence (development of tolerance, dose escalation, drug-seeking behaviour have been reported).
Encephalopathy: Cases of encephalopathy have been reported, mostly in patients with underlying conditions that may precipitate encephalopathy.
Effects on ability to drive and use machines: Pregabalin Actavis may have minor or moderate influence on the ability to drive and use machines. Pregabalin Actavis 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.

Women of childbearing potential/Contraception in males and females: As the potential risk for humans is unknown, effective contraception must be used in women of childbearing potential.
Pregnancy: 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.
Pregabalin Actavis should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the fetus).
Breast-feeding: Pregabalin is excreted into human milk. The effect of pregabalin on newborns/infants is, unknown. 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.
Fertility: There are no clinical data on the effects of pregabalin on female fertility.
In a clinical trial to assess the effect of pregabalin on sperm motility, healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment, there were no effects on sperm motility.
A fertility study in female rats has shown adverse reproductive effects. Fertility studies in male rats have shown adverse reproductive and developmental effects. The clinical relevance of these findings is unknown.

The pregabalin clinical program involved over 8,900 patients exposed to pregabalin, of whom over 5,600 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 12% 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.
In Table 2 as follows 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 (≥1/1,000, <1/100), rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). 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 medicinal products.
In the treatment of central neuropathic pain due to spinal cord injury the incidence of adverse reactions in general, CNS adverse reactions and especially somnolence was increased (see Precautions).
Additional reactions reported from post-marketing experience are included in italics in Table 2. (See Table 2.)

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After discontinuation of short-term and long-term treatment with pregabalin withdrawal symptoms have been observed in some patients. The following reactions have been mentioned: insomnia, headache, nausea, anxiety, diarrhoea, flu syndrome, convulsions, nervousness, depression, pain, hyperhidrosis and dizziness, suggestive of physical dependence. The patient should be informed about this at the start of the treatment.
Concerning discontinuation of long-term treatment of pregabalin, data suggest that the incidence and severity of withdrawal symptoms may be dose-related.
Paediatric population: The pregabalin safety profile observed in five paediatric studies in patients with partial seizures with or without secondary generalisation (12 week efficacy and safety study in patients 4 to 16 years of age, n=295; 14 day efficacy and safety study in patients 1 month to younger than 4 years of age, n=175; pharmacokinetic and tolerability study, n=65; and two 1year open label follow on safety studies, n=54 and n=431) was similar to that observed in the adult studies of patients with epilepsy. The most common adverse events observed in the 12 week study with pregabalin treatment were somnolence, pyrexia, upper respiratory tract infection, increased appetite, weight increased, and nasopharyngitis. The most common adverse events observed in the 14 day study with pregabalin treatment were somnolence, upper respiratory tract infection, and pyrexia (see Dosage & Administration).
Controlled Studies with Fibromyalgia: Adverse Reactions Leading to Discontinuation: In clinical trials of patients with fibromyalgia, 19% of patients treated with pregabalin (150-600 mg/day) and 10% of patients treated with placebo discontinued prematurely due to adverse reactions. In the pregabalin treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (6%) and somnolence (3%). In comparison, <1% of placebo-treated patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the pregabalin treatment group than in the placebo treatment group, were fatigue, headache, balance disorder, and weight increased. Each of these adverse reactions led to withdrawal in approximately 1% of patients.
Most Common Adverse Reactions: Table 3 lists all adverse reactions, regardless of causality, occurring in ≥2% of patients with fibromyalgia in the 'all pregabalin' treatment group for which the incidence was greater than in the placebo treatment group. A majority of pregabalin-treated patients in clinical studies experienced adverse reactions with a maximum intensity of "mild" or "moderate". (See Table 3.)

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Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

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 estradiol 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 the post-marketing experience, there are reports of respiratory failure, coma and deaths in patients taking pregabalin and opioids and/or other CNS depressant medicinal products. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.
Interactions and the elderly: No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction studies have only been performed in adults.

Incompatibilities: Not applicable.

Anticonvulsants / Anxiolytics

N02BF02 - pregabalin ; Belongs to the class of gabapentinoids. Used to relieve pain and other conditions.

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