Pregabalin

There are postmarketing 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).

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 (CLcr), as indicated in the table below determined using the following formula:

CL_cr(ml/min) = [1,23 x [140 – age (years)] x weight (kg) / serum creatinine (μmol/l)] (x 0,85 for female patients)

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).

Pregabalin Dose Adjustment Based on Renal Function:

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

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 central nervous system (CNS) depressant medicinal products. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.

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.

There have been postmarketing 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.

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

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 should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the foetus).

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.

Pregabalin may have minor or moderate influence on the ability to drive and use machines. Pregabalin 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.

The pregabalin clinical programme 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 the list 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 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). 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.

Additional reactions reported from postmarketing experience are included in italics in the list below.

Infections and infestations

Common: Nasopharyngitis

Blood and lymphatic system disorders

Uncommon: Neutropaenia

Immune system disorders

Uncommon: Hypersensitivity

Rare: Angioedema, allergic reaction

Metabolism and nutrition disorders

Common: Appetite increased

Uncommon: Anorexia, hypoglycaemia

Psychiatric disorders

Common: Euphoric mood, confusion, irritability, disorientation, insomnia, libido decreased

Uncommon: Hallucination, panic attack, restlessness, agitation, depression, depressed mood, elevated mood, aggression, mood swings, depersonalisation, word finding difficulty, abnormal dreams, libido increased, anorgasmia, apathy

Rare: Disinhibition

Nervous system disorders

Very Common: Dizziness, somnolence, headache

Common: Ataxia, coordination abnormal, tremor, dysarthria, amnesia, memory impairment, disturbance in attention, paraesthesia, hypoaesthesia, sedation, balance disorder, lethargy

Uncommon: Syncope, stupor, myoclonus, loss of consciousness, psychomotor hyperactivity, dyskinesia, dizziness postural, intention tremor, nystagmus, cognitive disorder, mental impairment, speech disorder, hyporeflexia, hyperaesthesia, burning sensation, ageusia, malaise

Rare: Convulsions, parosmia, hypokinesia, dysgraphia

Eye disorders

Common: Vision blurred, diplopia

Uncommon: Peripheral vision loss, visual disturbance, eye swelling, visual field defect, visual acuity reduced, eye pain, asthenopia, photopsia, dry eye, lacrimation increased, eye irritation

Rare: Vision loss, keratitis, oscillopsia, altered visual depth perception, mydriasis, strabismus, visual brightness

Ear and labyrinth disorders

Common: Vertigo

Uncommon: Hyperacusis

Cardiac disorders

Uncommon: Tachycardia, atrioventricular block first degree, sinus bradycardia, congestive heart failure

Rare: QT prolongation, sinus tachycardia, sinus arrhythmia

Vascular disorders

Uncommon: Hypotension, hypertension, hot flushes, flushing, peripheral coldness

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea, epistaxis, cough, nasal congestion, rhinitis, snoring, nasal dryness

Rare: Pulmonary oedema, throat tightness

Gastrointestinal disorders

Common: Vomiting, nausea, constipation, diarrhoea, flatulence, abdominal distension, dry mouth

Uncommon: Gastrooesophageal reflux disease, salivary hypersecretion, hypoaesthesia oral

Rare: Ascites, pancreatitis, swollen tongue, dysphagia

Hepatobiliary disorders

Uncommon: Elevated liver enzymes*

Rare: Jaundice

Very rare: Hepatic failure, hepatitis

Skin and subcutaneous tissue disorders

Uncommon: Rash papular, urticaria, hyperhidrosis, pruritus

Rare: Stevens Johnson syndrome, cold sweat

Musculoskeletal and connective tissue disorders

Common: Muscle cramp, arthralgia, back pain, pain in limb, cervical spasm

Uncommon: Joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness

Rare: Rhabdomyolysis

Renal and urinary disorders

Uncommon: Urinary incontinence, dysuria

Rare: Renal failure, oliguria, urinary retention

Reproductive system and breast disorders

Common: Erectile dysfunction

Uncommon: Sexual dysfunction, ejaculation delayed, dysmenorrhoea, breast pain

Rare: Amenorrhoea, breast discharge, breast enlargement, gynaecomastia

General disorders and administration site conditions

Common: Oedema peripheral, oedema, gait abnormal, fall, feeling drunk, feeling abnormal, fatigue

Uncommon: Generalised oedema, face oedema, chest tightness, pain, pyrexia, thirst, chills, asthenia

Investigations

Common: Weight increased

Uncommon: Blood creatine phosphokinase increased, blood glucose increased, platelet count decreased, blood creatinine increased, blood potassium decreased, weight decreased

Rare: White blood cell count decreased

* Alanine aminotransferase increased (ALT) and aspartate aminotransferase increased (AST).

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 four 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 1 year open label follow on safety study, n=54) 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.