Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: Unicorn Pharmaceuticals (Pty) Ltd, Cnr. Searle & Pontac Streets, Cape Town, South Africa, 8001
Known hypersensitivity to pregabalin or to any of the excipients of NEURALYN (see section 6.1).
Diabetic patients who gain weight on NEURALYN treatment may need to adjust hypoglycaemic medicines.
NEURALYN should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur.
NEURALYN treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population. There have 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 NEURALYN.
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 NEURALYN may result in resolution or improvement of these visual symptoms.
Renal failure has been reported and discontinuation of pregabalin, as in NEURALYN, did show reversibility of this adverse reaction.
After discontinuation of short-term and long-term treatment with pregabalin, as in NEURALYN, 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 NEURALYN use or shortly after discontinuing.
Discontinuation of long-term treatment of pregabalin, as in NEURALYN, data suggest that the incidence and severity of withdrawal symptoms may be dose related.
Congestive heart failure has been reported. These reactions are mostly seen in elderly cardiovascular compromised patients during pregabalin treatment for a neuropathic indication. NEURALYN should be used with caution in these patients. Discontinuation of NEURALYN may resolve the reaction.
Suicidal ideation and behaviour have been reported in patients treated with gabapentinoids such as pregabalin in NEURALYN 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 (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 NEURALYN and opioids will be used in combination, measures to prevent constipation may be considered (especially in female patients and the elderly).
Caution is advised when prescribing pregabalin concomitantly with opioids due to risk of respiratory depression and CNS depression (see section 4.5). 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. This increased risk was observed at low doses of pregabalin (≤300 mg) and there was a trend for a greater risk at high doses of pregabalin (>300 mg).
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 NEURALYN misuse, abuse or dependence (development of tolerance, dose escalation, intentional overdose, drug-seeking behaviour have been reported).
Encephalopathy has been reported, mostly in patients with underlying conditions that may precipitate encephalopathy.
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 opioids, and the elderly may be at higher risk of experiencing this severe adverse reaction. Dose adjustments may be necessary in these patients (see section 4.2).
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, NEURALYN is unlikely to produce, or be subject to, pharmacokinetic interactions.
Accordingly, in in vivo studies no clinically relevant pharmacokinetic interactions were observed between NEURALYN 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 NEURALYN had no clinically significant effect on the clearance of phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate and phenobarbitone.
Co-administration of NEURALYN with the oral contraceptives norethisterone and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of either medicine.
Multiple oral doses of NEURALYN co-administered with oxycodone, lorazepam, or ethanol did not result in clinically important effects on respiration. NEURALYN appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone. NEURALYN may potentiate the effects of ethanol and lorazepam.
In the post marketing experience, there are reports of respiratory failure and coma in patients taking NEURALYN and other CNS depressant medications.
No specific pharmacodynamic interaction studies were conducted in elderly volunteers. Interaction studies have only been performed in adults.
As potential risk for humans is unknown, effective contraception must be used in women of child-bearing potential
There are no adequate data on the use of NEURALYN in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk to humans is unknown. Therefore, NEURALYN should not be used during pregnancy.
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 NEURALYN.
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 development effects.
NEURALYN frequently causes dizziness and somnolence. Head and body injuries and road traffic incidents have also been reported with pregabalin, as contained in NEURALYN. 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.
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.
| MedDRA system organ class | Frequency | Adverse reactions |
|---|---|---|
| Infections and infestations | Frequent | Nasopharyngitis |
| Blood and the lymphatic system disorders | Less frequent | Neutropenia |
| Immune system disorders | Less frequent | Hypersensitivity, angioedema, allergic reaction |
| Metabolism and nutrition disorders | Frequent | Increased appetite |
| Less frequent | Anorexia, hypoglycaemia | |
| Psychiatric disorders | Frequent | Euphoric mood, confusion, irritability, disorientation, insomnia, decreased libido |
| Less frequent | Hallucination, panic attack, restlessness, agitation, depression, depressed mood, elevated mood, aggression, mood swings, depersonalisation, word finding difficulty, abnormal dreams, increased libido, anorgasmia, apathy, disinhibition | |
| Unknown frequency | Suicidal ideation and behaviour | |
| Nervous system disorders | Frequent | Dizziness, somnolence, headache, ataxia, coordination abnormal, tremor, dysarthria, amnesia, memory impairment, disturbance in attention, paraesthesia, hypoaesthesia, sedation, balance disorder, lethargy |
| Less frequent | 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 | Frequent | Blurred vision, diplopia |
| Less frequent | 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 | Frequent | Vertigo |
| Less frequent | Hyperacusis | |
| Cardiac disorders | Less frequent | Tachycardia, first degree atrioventricular block, sinus bradycardia, congestive heart failure, QT prolongation, sinus tachycardia, sinus dysrhythmia |
| Vascular disorders | Less frequent | Hypotension, hypertension, hot flushes, flushing, peripheral coldness |
| Respiratory, thoracic and mediastinal disorders | Less frequent | Dyspnoea, epistaxis, cough, nasal congestion, rhinitis, snoring, nasal dryness, pulmonary oedema, throat tightness |
| Frequency not known | Respiratory depression | |
| Gastrointestinal disorders | Frequent | Vomiting, nausea, constipation, diarrhoea, flatulence, abdominal distension, dry mouth |
| Less frequent | Gastro-oesophageal reflux disease, salivary hypersecretion, oral hypoaesthesia, ascites, pancreatitis, swollen tongue, dysphagia | |
| Hepatobiliary disorders | Less frequent | Elevated liver enzymes*, jaundice, hepatic failure, hepatitis |
| Skin and subcutaneous tissue disorders | Less frequent | Papular rash, urticaria, hyperhidrosis, pruritus, Stevens-Johnson syndrome, cold sweat |
| Musculoskeletal and connective tissue disorders | Frequent | Muscle cramp, arthralgia, back pain, pain in limb, cervical spasm |
| Less frequent | Joint swelling, myalgia, muscle twitching, neck pain, muscle stiffness, rhabdomyolysis | |
| Renal and urinary disorders | Less frequent | Urinary incontinence, dysuria, renal failure, oliguria, urinary retention |
| Reproductive system and breast disorders | Frequent | Erectile dysfunction |
| Less frequent | Sexual dysfunction, delayed ejaculation, dysmenorrhoea, breast pain, amenorrhoea, breast discharge, breast enlargement, gynaecomastia | |
| General disorders and administration site conditions | Frequent | Peripheral oedema, oedema, abnormal gait, fall, feeling drunk, feeling abnormal, fatigue |
| Less frequent | Generalised oedema, face oedema, chest tightness, pain, pyrexia, thirst, chills, asthenia | |
| Investigations | Frequent | Increased weight2 |
| Less frequent | 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).
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.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Side effects must also be reported to Unicorn Pharmaceuticals (Pty) Ltd to vigilance@unicornpharma.co.za.
Not applicable.
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