Source: Health Products Regulatory Authority (ZA) Publisher: Strides Pharma SA (Pty) Ltd, 106 16<sup>th</sup> Road, Building 2, Midrand, 1685, South Africa
TIMIRIL is contraindicated in patients with hypersensitivity to pregabalin or to any of the excipients (see section 6.1).
There have been reports in the post-marketing reports of hypersensitivity reactions in patients shortly after initiation of treatment with pregabalin as in TIMIRIL, including cases of angioedema and urticaria. TIMIRIL should be discontinued immediately if symptoms of angioedema, such as facial, perioral or upper airway swelling occur.
TIMIRIL treatment has been associated with dizziness and somnolence, which could increase the occurrence of accidental injury (fall) in the elderly population. There have been postmarketing 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 medication.
After discontinuation of short-term and long-term treatment with TIMIRIL, withdrawal symptoms have been observed in some patients. The following events have been reported: insomnia, headache, nausea and diarrhoea.
Cases of renal failure have been reported and in some cases discontinuation or the dose reduction of pregabalin did show reversibility of this adverse reaction.
There have been post-marketing reports of congestive heart failure or deterioration of heart failure in some patients receiving TIMIRIL. TIMIRIL should be used with caution in patients with congestive heart failure.
Diabetic patients who gain weight on TIMIRIL treatment may need to adjust hypoglycaemic medicinal products.
Patients treated with anti-epileptic medicines have reported suicidal ideation and behaviour. Studies of anti-epileptic medicines has shown a slight increased risk of suicidal ideation and behaviour.
Reduced lower gastrointestinal tract function (e.g. intestinal obstruction, paralytic ileus, constipation) has been reported when pregabalin, as contained in TIMIRIL was given with medications such as opioid analgesics. If pregabalin and opioids are to be used in combination, measures to prevent constipation may be considered (especially in female patients and the elderly).
Patients on TIMIRIL should be monitored for symptoms of misuse, abuse or dependence as cases of the dose escalation, drug-seeking behaviour and development of tolerance have been reported. Caution should be used in patients with a history of substance abuse.
Cases of encephalopathy have been reported, mostly in patients with underlying conditions that may cause encephalopathy.
Since TIMIRIL 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, TIMIRIL is unlikely to produce, or be subject to, pharmacokinetic interactions.
No clinically relevant pharmacokinetic interactions were observed in studies, between TIMIRIL and phenytoin, carbamazepine, valproic acid, lamotrigine, gabapentin, lorazepam, oxycodone or ethanol. Population pharmacokinetic analysis indicated that oral anti-diabetics, diuretics insulin, phenytoin, carbamazepine, valproic acid, lamotrigine, phenobarbitone, tiagabine and topiramate, had no clinically significant effect on pregabalin clearance.
TIMIRIL appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone. TIMIRIL may potentiate the effects of ethanol and lorazepam. In postmarketing experience, there are reports of respiratory failure and coma in patients taking TIMIRIL and other central nervous system (CNS) depressant medications.
Co-administration of TIMIRIL with the oral contraceptives norethisterone and/or ethinyl oestradiol does not influence the steady-state pharmacokinetics of either substance.
As the potential risk of TIMIRIL to humans is unknown, effective contraception must be used in women of child-bearing potential.
There isn’t adequate data on the use of TIMIRIL in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk to humans is unknown. Therefore, TIMIRIL should not be used during pregnancy.
Pregabalin is excreted in the breast milk of humans, however, it was found to be present in the milk of rats. Therefore, breastfeeding is not recommended.
There is no clinical data on the effects of pregabalin on female fertility.
TIMIRIL frequently causes dizziness, somnolence, blurred vision and other CNS signs and symptoms. Patients are advised not to drive, operate complex machinery or engage in other potentially hazardous activities until it is known whether TIMIRIL affects their ability to perform activities (see section 4.4).
| MedDRA system organ class | Frequency | Adverse reactions |
|---|---|---|
| Blood and lymphatic system disorders | Less frequent | Neutropenia |
| Metabolism and nutrition disorders | Frequent | Increased appetite |
| Less frequent | Hypoglycaemia, anorexia | |
| Psychiatric disorders | Frequent | Euphoric mood, confusion, decreased libido, irritability |
| Less frequent | Depersonalisation, anorgasmia, restlessness, depression, agitation, mood swings, insomnia, depressed mood, word finding difficulty, hallucination, abnormal dreams, increased libido, panic attack, apathy, disinhibition, elevated mood | |
| Nervous system disorders | Frequent | Dizziness, somnolence, ataxia, disturbance in attention, abnormal coordination, memory impairment, tremor, dysarthria, paraesthesia |
| Less frequent | Cognitive disorder, hypoaesthesia, visual field defect, nystagmus, speech disorder, myoclonus, hyporeflexia, dyskinesia, psychomotor hyperactivity, dizziness postural, hyperaesthesia, ageusia, burning sensation, intention tremor, stupor, syncope | |
| Frequency unknown | Headache, loss of consciousness, mental impairment, reversible paralysis | |
| Eye disorders | Frequent | Vision blurred, diplopia |
| Less frequent | Visual disturbance, dry eye, eye swelling, visual acuity reduced, eye pain, asthenopia, increased lacrimation, photopsia, eye irritation, mydriasis, oscillopsia, altered visual depth perception, peripheral vision loss, strabismus, visual brightness | |
| Ear and labyrinth disorders | Frequent | Vertigo |
| Less frequent | Hyperacusis | |
| Cardiac disorders | Less frequent | Tachycardia, atrioventricular block first degree, sinus tachycardia, sinus bradycardia |
| Frequency unknown | Congestive heart failure | |
| Vascular disorders | Less frequent | Flushing, hot flushes, hypotension, peripheral coldness, hypertension |
| Respiratory, thoracic and mediastinal disorders | Less frequent | Dyspnoea, nasal dryness, nasopharyngitis, cough, nasal congestion, epistaxis, rhinitis, snoring, throat tightness |
| Gastrointestinal disorders | Frequent | Dry mouth, constipation, vomiting, flatulence |
| Less frequent | Abdominal distension, salivary hypersecretion, gastroesophageal reflux disease, hypoaesthesia oral, ascites, dysphagia, pancreatitis | |
| Frequency unknown | Rare cases of swollen tongue have been reported, diarrhoea, nausea | |
| Hepatobiliary disorders | Less frequent | Alanine aminotransferase increased (ALT) and aspartate aminotransferase increased (AST), jaundice, hepatic failure, hepatitis |
| Skin and subcutaneous tissue disorders | Less frequent | Sweating, rash papular, cold sweat, urticaria |
| Frequency unknown | Rare cases of face swelling have been reported, pruritus | |
| Musculoskeletal and connective tissue disorders | Less frequent | Muscle twitching, joint swelling, muscle cramp, myalgia, arthralgia, back pain, pain in limb, muscle stiffness, cervical spasm, neck pain, rhabdomyolysis |
| Renal and urinary disorders | Less frequent | Dysuria, urinary incontinence, oliguria, renal failure |
| Frequency unknown | Urinary retention | |
| Reproductive system and breast disorders | Frequent | Erectile dysfunction |
| Less frequent | Ejaculation delayed, sexual dysfunction, amenorrhoea, breast pain, breast discharge, dysmenorrhoea, breast hypertrophy | |
| Immune system disorders | Frequency unknown | Angioedema, allergic reaction, hypersensitivity |
| General disorders and administration site conditions | Frequent | Fatigue, peripheral oedema, feeling drunk, oedema, gait abnormal |
| Less frequent | Asthenia, fall, thirst, chest tightness, pain exacerbated, anasarca, pyrexia, rigors | |
| Investigations | Frequent | Weight increase |
| Less frequent | Blood creatine phosphokinase increased, platelet count decreased, blood glucose increased, blood creatinine increased, blood potassium decreased, weight decreased, white blood cell count decreased. |
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 the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
Not applicable.
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