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SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
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
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.
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Hepatic impairment Patients with pre-existing liver disease and alcohol abuse should not take
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
In view of the predominantly hepatic biotransformation of flupirtine maleate, patients with pre-existing liver disease and alcohol abuse should not take
Patients with active or known history of tinnitus should not be treated with
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.
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4.5 Interaction with other medicinal products and other forms of interaction
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
Liver enzyme levels should be monitored in good time and at regular intervals when
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.
Lactation Based on studies to date, small fractions of flupirtine are excreted in human milk.
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
4.8 Undesirable effects
The following categories are used when stating the frequency of undesirable effects:
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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.
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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.
Muscle relaxing effect The pharmaceutical effects described for the analgesic effect are functionally supported by the promotion of mitochondrial Ca2+ uptake that is demonstrated at therapeutically relevant concentrations. Muscle relaxant effects occur as a result of associated inhibition of impulse transmission to motor neurons and corresponding effects on interneurons. This is primarily a tension-relieving effect and not a general muscle-relaxant effect.
Effect of chronification processes Chronification processes are to be regarded as neuronal conduction processes caused by the plasticity of neuronal functions. Via the induction of intracellular processes, the plasticity of neuronal functions induces a mechanism known as “wind up”, which leads to amplification of the response for subsequent incoming impulses. NMDA receptors are particularly important in triggering such changes (gene expression). Their indirect blockade by flupirtine causes suppression. Clinically relevant pain chronification is thereby counteracted or, in cases of existing chronification,
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“deletion” of pain memory is promoted by stabilisation of the membrane potential, thereby causing a reduction in pain sensitivity.
5.2 Pharmacokinetic properties
Approximately 90% of flupirtine is absorbed from the gastrointestinal tract after oral administration and 70% after rectal application. Around ¾ of the administered flupirtine dose is metabolised in the liver. During biotransformation, the metabolite M1 [2-amino-3-acetamino-6- (4-fluoro) - benzylaminopyridine] is produced by hydrolysis (phase I reaction) of the urethane structure and acetylation (phase II reaction) of the formed amine. This metabolite has approximate ly one-quarter of the analgesic potency of flupirtine and is hence involved in the effect of flupirtine. A further metabolite is produced by oxidative cleavage (phase I reaction) of the remaining p- fluorobenzyl and subsequent conjugation (phase II reaction) of the resultant p-fluorobenzoic acid with glycine. This metabolite (M2) is biologically inactive. Which isoenzyme is primarily involved in the (less significant) oxidative route of degradation has yet to be studied. Flupirtine is expected to have only minor interaction potential. The major fraction of the dose (69%) is renally eliminated. This fraction is comprised as follows: 27% unchanged parent substance, 28% metabolite M1 (acetyl metabolite), 12% metabolite M2 (p-fluorohippuric acid); the remaining one-third consists of several minor metabolites, the structure of which has yet to be elucidated. A small fraction of the dose is also excreted with the bile and faeces.
At approximately 7 hours (or 10 hours for the sum of the parent substance and metabolite M1), the plasma half-life is within a favourable range for analgesics. Following administration of flupirtine, the plasma levels behave in a dose-proportional manner within the range of 50-300 mg.
In elderly patients, a prolonged half-life was observed after repeated administration (see also section 4.2).
5.3 Preclinical safety data
In animal toxicology studies, flupirtine maleate, within the range of pharmacodynamically optimal effective doses, had no toxicologically relevant effect on organs or organ systems, either from a functional or morphological point of view.
Central nervous suppression was detectable at very high doses, particularly with acute administration of the substance, as well as potential hepatotoxicity in the form of increased metabolic stress on the liver.
In acute and subchronic interaction studies on animals with other medicinal products, particularly non-steroidal analgesics, there was no evidence of potentiation or modification of the toxic effect of the individual components; in particular, there were no signs of the metabolic stress on the liver that occurred in acute and chronic studies with flupirtine maleate in two animal species (mouse and rat). Adaptation to this metabolic stress was characterised by a slight increase - within the physiological range - in liver enzyme activities, hepatic
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weight gain with weak enzyme induction and, compared with the control group, a slightly increased rate of individual cell necrosis of hepatocytes, which were regenerated even after continued administration of the substance. Depending on the experimental design, the non-toxic doses determined in the chronic toxicity tests and in reproduction studies were approximately 3 times higher than the maximum therapeutic daily dose intended for humans. In vitro and in vivo studies produced no evidence of a mutagenic effect.
In carcinogenicity studies on mice and rats, there was no evidence of a carcinogenic potential. Nodular hyperplasia of liver cells occurred in the study on mice, which can be attributed - with a sufficient degree of certainty - to adaptive cellular responses to metabolic stress after long-term, high-dose administration of flupirtine maleate.
In reproductive toxicology studies, neither fertility nor offspring development was influenced at maximum doses tolerated by the parent animals. Except at highly toxic doses, no teratogenic effects were present.
6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients
Capsule Content: Calcium hydrogen phosphate dihydrate, Copovidone Magnesium stearate Colloidal anhydrous silica.
Capsule Shell: Gelatine Titanium dioxide (E171) Red iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
For DE/H/3503/001:
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Blister of PVC/aluminium foil 10, 20, 30, 50 and 60 capsules, hard.
For DE/H/3504/001/DC: Blister of PVC/aluminium foil 10, 30 and 50 capsules, hard.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused products or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
8. MARKETING AUTHORISATION NUMBER
9. DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
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