ENR 2186544 ENR 2186545 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT <invented name> 100 mg capsules, hard 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each capsule, hard contains: 100 mg flupirtine maleate For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Capsule, hard Oblong, hard-shell gelatine capsules with a red body and a red cap of 18 mm. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications <invented name> 100 mg capsules is indicated for treatment of acute mild to moderate pain. 4.2 Posology and method of administration Posology The dosage should be adjusted to the intensity of pain and the patient’s individual response. The usual dose is 100 mg of flupirtine maleate 3 to 4 times daily, at as evenly spaced intervals as possible. A daily dose of 600 mg flupirtine maleate should not be exceeded. Duration of use Duration of use is individually determined, as prescribed by the doctor. The duration of acute treatment is generally up to 7 days. Elderly Patients Patients over 65 years of age should start the treatment taking 100 mg of flupirtine maleate each morning and evening. The dose can be increased depending on the intensity of pain and tolerability. Renal impairment In patients with considerably reduced renal function or hypoalbuminaemia, a daily dose of 300 mg flupirtine maleate should not be exceeded. If higher doses are required, these patients should be subject to careful medical surveillance. Page 1 ENR 2186544 ENR 2186545 Hepatic impairment Patients with pre-existing liver disease and alcohol abuse should not take <invented name> (see section 4.3). Paediatric population The safety and efficacy of flupirtine maleate in children and adolescents aged under 18 years have not been established. Method of administration The capsules should be taken with sufficient liquid (preferably water) without chewing. Where possible, the capsules should be taken with the upper body in a vertical position. In exceptional cases, the capsule can be opened and only its contents taken/administered (e.g. via a tube). Due to the very bitter taste, taste neutralisation with suitable food (e.g. a banana) is recommended when orally administering the capsule contents. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. In patients at risk of hepatic encephalopathy and patients with cholestasis, flupirtine maleate should not be administered, as onset or deterioration of encephalopathy or ataxia may occur in these patients. Due to the muscle tension-relieving effect of flupirtine maleate, patients with myasthenia gravis should not be treated with <invented name>. In view of the predominantly hepatic biotransformation of flupirtine maleate, patients with pre-existing liver disease and alcohol abuse should not take <invented name>. Patients with active or known history of tinnitus should not be treated with <invented name>. Studies in this patient group showed a possible increased risk of developing elevated liver enzyme levels. 4.4 Special warnings and precautions for use In patients with impaired hepatic and renal function, monitoring of liver enzymes or creatinine levels is indicated. A dose reduction is required for patients over 65 years or with significantly impaired renal function or hypoalbuminaemia (see section 4.2). During treatment with flupirtine maleate, false-positive findings for bilirubin, urobilinogen and urinary protein could occur. Reactions to assay methods for the quantitative determination of serum bilirubin may also yield false results. At higher doses, green discolouration of the urine is possible in individual cases, but has no clinical relevance. Page 2 ENR 2186544 ENR 2186545 4.5 Interaction with other medicinal products and other forms of interaction <invented name> can potentiate the effect of alcohol and medications with sedative or muscle relaxant properties. As flupirtine is highly protein bound, protein binding displacement of other co-administered highly protein-bound medications is likely. Corresponding in vitro studies have been performed with diazepam, warfarin, acetylsalicylic acid, benzylpenicillin, digitoxin, glibenclamide, propranolol and clonidine. Only in the case of warfarin and diazepam did displacement from albumin binding reach such a level that, if flupirtine maleate is co- administered, potentiation of the effect of these medications cannot be excluded. It is therefore recommended that the prothrombin time be more frequently monitored when co- treating with <invented name> and coumarin derivatives, in order to exclude a possible effect or to reduce the coumarin dose as appropriate. There is no evidence of interactions with other anticoagulants (acetylsalicylic acid or similar). Liver enzyme levels should be monitored in good time and at regular intervals when <invented name> is co-administered with other medicines which are likewise mainly degraded via the liver. Combination of flupirtine maleate with medicines containing paracetamol or carbamazepine should be avoided. 4.6 Fertility, pregnancy and lactation Pregnancy There are no adequate data from the use of flupirtine in pregnant women. Animal studies revealed no evidence of teratogenic effects. However, it was observed after administration of maternally toxic doses, embryotoxic effects (see section 5.3). The potential risk for humans is unknown. <invented name> should not be used during pregnancy unless clearly necessary. Lactation Based on studies to date, small fractions of flupirtine are excreted in human milk. <invented name> should therefore not be used during lactation unless clearly necessary. If treatment is absolutely necessary during lactation, breast-feeding must be discontinued. 4.7 Effects on ability to drive and use machines Even when used as directed, this medicinal product can alter the ability to react. Patients experiencing drowsiness or dizziness during treatment with <invented name> should not drive or use machines. This particularly applies in interaction with alcohol. 4.8 Undesirable effects The following categories are used when stating the frequency of undesirable effects: Page 3 ENR 2186544 ENR 2186545 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) As part of controlled clinical studies and during clinical use of flupirtine maleate in more than 1.5 million treated patients, the following undesirable effects have occurred. Very Common Uncommon Very rare Not common known Immune Allergic system reactions, disorders hyperthermia Psychiatric Sleep disorders, Confusion disorders anorexia, depression, agitation/nervousness Nervous Fatigue Dizziness, bouts of system (approx. sweating, tremor, disorders 15% of headache, dry mouth patients), particularly at the start of therapy Eye disorders Visual disturbances Gastrointestinal Heartburn, disorders nausea/vomiting, gastric complaints, constipation, abdominal pain, flatulence, diarrhoea Hepatobiliary Increase Liver disorders in liver failure enzymes, hepatitis. Skin and Rash, subcutaneous urticaria, tissue disorders pruritus The undesirable effects are mostly dose-dependent. In many cases, they resolve during the course of further treatment or are reversible upon cessation of therapy. 4.9 Overdose There have been isolated cases of overdose taken with suicidal intent, whereby ingestion of up to 5 g flupirtine maleate led to the following symptoms: nausea, exhaustion, tachycardia, tearfulness, stupor, impaired consciousness, dry mouth. Page 4 ENR 2186544 ENR 2186545 A recovery was made within 6 to 12 hours following emesis or therapy with forced diuresis, activated charcoal and electrolyte infusions. Life-threatening conditions have not been seen. In the event of an overdose or intoxication, central nervous manifestations are likely based on the findings available from animal experiments, as well as potential hepatotoxicity in the form of increased metabolic stress on the liver. Treatment must be symptomatic. There is no known antidote. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Analgesics; other analgesics and antipyretics ATC code: N02BG07 Flupirtine is the prototype of the SNEPCO substance class (Selective NEuronal Potassium Channel Opener). It is a centrally acting, non-opioid analgesic; Flupirtine activates G-protein-coupled inwardly rectifying K+ channels of the nerve cell. The outflow of K+ causes the resting membrane potential to stabilise; activation of the nerve cell membrane is reduced. As a result, activation of NMDA receptors is indirectly inhibited, as Mg2+ blockade of the NMDA receptor is not reversed until cell membrane depolarisation has taken place (indirect NMDA receptor antagonism). At therapeutically relevant concentrations, flupirtine does not bind to 1, 2, 5HT1, 5HT2, dopamine, benzodiazepine, opiate, central muscarinic or nicotinic receptors. This centrally acting substance results in three main effects: Analgesic effect Due to selective opening of neuronal voltage-independent K+ channels and the associated outflow of K+, the resting potential of the nerve cell is stabilised. The neuron is less excitable. The ensuing indirect NMDA antagonism of flupirtine protects the neurons against influx of Ca2+. Thus, the sensitising effect of the rise in intracellular Ca2+ is buffered. During neuronal excitation, transmission of ascending nociceptive impulses is thus inhibited.