Prerica 25 mg, 50 mg, 75 mg ,100 mg or 150 mg Capsules, hard

Neuropathic pain

PRERICA is indicated for the treatment of adult patients with neuropathic pain due to Herpes zoster infections and diabetes.

Posology

The recommended starting dose for PRERICA is 75 mg twice daily (150 mg/day), with or without food.

Based on individual patient response and tolerability, the dose may be increased to 150 mg twice daily after an interval of 3 to 7 days. In accordance with current clinical practice, if PRERICA must be discontinued, it is recommended this should be done gradually over a minimum of 1 week.

Special populations

Use in patients with renal impairment

PRERICA is eliminated from the systemic circulation primarily by renal excretion as unchanged pregabalin. As PRERICA clearance is directly proportional to creatinine clearance (see section 5.2 u2013 Renal impairment), 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:

CLCR(mL/min) = 1,23 x [140 u2013 age (years)] x weight (kg) (x 0,85 for female patients) / serum creatinine (u03bcmol/L)

Table 1. PRERICA dosage adjustment based on renal function

Supplementary dosage following haemodialysis (mg)

*Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose + Supplementary dose is a single additional dose

PRERICA is removed effectively from plasma by haemodialysis (50 % of the active ingredient in 4 hours). For patients receiving haemodialysis, the PRERICA 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).

Use in patients with hepatic impairment

No dosage adjustment is required for patients with hepatic impairment (see section 5.2).

Paediatric patients

The safety and effectiveness of PRERICA in patients below the age of 18 years with neuropathic pain has not been established.

Use in the elderly population (over 65 years of age)

No dosage adjustment is necessary for elderly patients unless their renal function is compromised, see Table 1.

Method of administration

PRERICA is given orally with or without food.

Hypersensitivity to pregabalin or to any of the excipients of PRERICA (see section 6.1).

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which can be life-threatening or fatal, have been reported rarely in association with pregabalin treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, pregabalin should be withdrawn immediately and an alternative treatment considered (as appropriate).

Diabetic patients

Diabetic patients who gain weight on PRERICA treatment may need to adjust hypoglycaemic medicines.

Hypersensitivity reactions

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

PRERICA 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 reports of loss of consciousness, confusion and mental impairment. Patients should be advised to exercise caution until they are familiar with the potential effects of PRERICA.

Vision-related effects

Visual adverse reactions have been reported, including loss of vision, visual blurring, or other changes of visual acuity, many of which were transient. Discontinuation of PRERICA may result in resolution or improvement of these visual symptoms.

Renal failure

Renal failure has been reported and discontinuation of pregabalin, as in PRERICA, did show reversibility of this adverse reaction.

Withdrawal symptoms

After discontinuation of short-term and long-term treatment with pregabalin, as in PRERICA, withdrawal symptoms have been observed. The following events have been mentioned: insomnia, headache, nausea, anxiety, diarrhoea, 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 PRERICA use or shortly after discontinuing. Discontinuation of long-term treatment of pregabalin, as in PRERICA, data suggest that the incidence and severity of withdrawal symptoms may be dose-related.

Congestive heart failure

Congestive heart failure has been reported. These reactions are mostly seen in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic indication. PRERICA should be used with caution in these patients. Discontinuation of PRERICA may resolve the reaction.

Suicidal ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with gabapentinoids such as pregabalin in PRERICA in several indications. Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients and caregivers should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Reduced lower gastrointestinal tract function

Reduced lower gastrointestinal tract function (e.g. intestinal obstruction, paralytic ileus, constipation) has been reported when pregabalin was co-administered with medicines that have the potential to produce constipation, such as opioid analgesics. When PRERICA 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 section 4.5). In reported case-control studies of opioid users, patients who took pregabalin concomitantly with an opioid had an increased risk for opioid-related death compared to opioid use alone. This increased risk was observed at low doses of pregabalin (u2264 300 mg) and there was a trend for a greater risk at high doses of pregabalin (> 300 mg).

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 PRERICA misuse, abuse, or dependence (development of tolerance, dose escalation, intentional overdose, drug-seeking behaviour have been reported).

Encephalopathy

Encephalopathy has been reported, mostly in patients with underlying conditions that may precipitate encephalopathy.

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 medicine metabolism in vitro, and is not bound to plasma proteins, PRERICA 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 PRERICA and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. In addition, population pharmacokinetic analysis indicated that the 3 commonly used medicine classes, oral antidiabetics, diuretics, and insulin, and the commonly used anti-epileptic medicines, phenytoin, carbamazepine, valproic acid, lamotrigine, phenobarbitone, tiagabine and topiramate had no clinically significant effect on pregabalin clearance.

Similarly, these analyses indicated that PRERICA had no clinically significant effect on the clearance of phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate and phenobarbitone.

Oral contraceptives, norethisterone and/or ethinyl oestradiol

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

Central nervous system influencing medicines

Multiple oral doses of PRERICA co-administered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. PRERICA appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone. PRERICA may potentiate the effects of ethanol and lorazepam.

In the post marketing experience, there are reports of respiratory failure and coma in patients taking PRERICA and other CNS depressant medications.

Interactions and the elderly

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

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 PRERICA in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Therefore, PRERICA should not be used during pregnancy.

Breastfeeding

Pregabalin is excreted into human milk (see section 5.2). The effect of pregabalin on new-borns/infants is unknown. Therefore, breastfeeding is not recommended during treatment with PRERICA.

Fertility

There are no clinical data on the effects of pregabalin on female fertility. A fertility study in female rats has shown adverse reproductive effects. Fertility studies in male rats have shown adverse reproductive and developmental effects.

PRERICA frequently causes dizziness and somnolence. Head and body injuries and road traffic incidents have also been reported with pregabalin, as contained in PRERICA. Therefore, patients are advised not to drive, operate complex machinery, or engage in other potentially hazardous activities until it is known whether this medicine affects their ability to perform these activities.

a) Summary of adverse effects

The most frequently reported adverse reactions were dizziness and somnolence. The most frequent adverse reactions resulting in discontinuation from pregabalin treatment are dizziness and somnolence.

In the table below the adverse reactions are listed by system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Additional reactions reported from post marketing experience are also included and listed according to frequency.

b) Tabulated summary of adverse reactions

MedDRA System Organ Class

Infections and infestations

Nasopharyngitis

Blood and lymphatic system disorders

Neutropoenia

Immune system disorders

Hypersensitivity, angioedema, allergic reaction

Metabolism and nutrition disorders

Increased appetite

Anorexia, hypoglycaemia

Psychiatric disorders

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

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

Suicidal ideation and behaviour

Nervous system disorders

Dizziness, somnolence,

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, convulsions, parosmia, hypokinesia, dysgraphia

Eye disorders

Blurred vision, diplopia

Peripheral vision loss, visual disturbance, eye swelling, visual field defect, reduced visual acuity, eye pain, asthenopia, photopsia, dry eye, increased lacrimation, eye irritation, vision loss, keratitis, oscillopsia, altered visual depth perception, mydriasis, strabismus, visual brightness

Ear and labyrinth disorders

Vertigo

Hyperacusis

Cardiac disorders

Tachycardia, first degree atrioventricular block, sinus bradycardia, congestive heart failure, QT prolongation, sinus tachycardia, sinus dysrhythmia

Vascular disorders

Hypotension, hypertension, hot flushes, flushing, peripheral coldness

Respiratory, thoracic and mediastinal disorders

Dyspnoea, epistaxis, cough, nasal congestion, rhinitis, snoring, nasal dryness, pulmonary oedema, throat tightness

Gastrointestinal disorders

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

Gastroesophageal reflux disease, salivary hypersecretion, oral hypoaesthesia, ascites, pancreatitis, swollen tongue, dysphagia

Hepatobiliary disorders

Elevated liver enzymes*, jaundice, hepatic failure, hepatitis

Skin and subcutaneous tissue disorders

Papular rash, urticaria, hyperhidrosis, pruritus, Stevens Johnson syndrome, cold sweat

Toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

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

Joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness, rhabdomyolysis

Renal and urinary disorders

Urinary incontinence, dysuria, renal failure, oliguria, urinary retention

Reproductive system and breast disorders

Erectile dysfunction

Sexual dysfunction, delayed ejaculation, dysmenorrhoea, breast pain, amenorrhoea, breast discharge, breast enlargement, gynaecomastia

General disorders and administration site conditions

Peripheral oedema, oedema, abnormal gait, fall, feeling drunk, feeling abnormal, fatigue

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

Investigations

Increased weight

Increased blood creatine phosphokinase, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood glucose, decreased platelet count, increased blood creatinine, decreased blood potassium, decreased weight, decreased white blood cell count

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

c) Description of selected adverse reactions

After discontinuation of short-term and long-term treatment with pregabalin reported 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, reported data suggest that the incidence and severity of withdrawal symptoms may be dose related.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

In documented post marketing experiences, 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 haemodialysis if necessary (see section 4.2 Table 1).