Katadolon^® Forte (Tablets) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Teva Operations Poland, Sp. z o.o. (Poland)

ATC Code

N02BG07 (Flupirtine)

Active Substance

Flupirtine (Rec.INN registered by WHO)

Dosage Form

Katadolon® Forte

Extended-release tablets 400 mg: 7, 14, 20, 42, or 84 pcs.

Dosage Form, Packaging, and Composition

Extended-release tablets oblong, biconvex, smooth on one side and with a score on the other side, light yellow or yellow in color with light and dark specks.

Excipients: methyl methacrylate and ethyl acrylate copolymer [2:1] – 22.5 mg, talc – 22.5 mg, calcium hydrogen phosphate dihydrate – 38 mg, microcrystalline cellulose – 59.74 mg, croscarmellose sodium – 34.95 mg, hypromellose – 8 mg, yellow iron oxide dye (E172) – 6.25 mg, colloidal anhydrous silicon dioxide – 2.06 mg, magnesium stearate – 6 mg.

7 pcs. – PVC/aluminum foil blisters (1) – cardboard packs.
10 pcs. – PVC/aluminum foil blisters (2) – cardboard packs.
14 pcs. – PVC/aluminum foil blisters (1) – cardboard packs.
14 pcs. – PVC/aluminum foil blisters (3) – cardboard packs.
14 pcs. – PVC/aluminum foil blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Non-opioid centrally acting analgesic

Pharmacotherapeutic Group

Non-narcotic analgesic agent

Pharmacological Action

Selective activator of neuronal potassium channels, a non-addictive and non-habit-forming centrally acting non-narcotic analgesic.

Flupirtine activates G-protein-coupled inwardly rectifying neuronal potassium channels. The efflux of K⁺ ions stabilizes the resting potential and reduces neuronal membrane excitability. This results in indirect inhibition of NMDA receptors, since the blockade of NMDA receptors by Mg²⁺ ions persists until cell membrane depolarization occurs (indirect antagonistic action on NMDA receptors).

At therapeutically relevant concentrations, Flupirtine does not bind to α₁– and α₂-adrenergic receptors, 5HT₁(5-hydroxytryptophan)-, 5HT₂-serotonin receptors, dopamine, benzodiazepine, opioid, central m- and n-cholinergic receptors. This central action of flupirtine leads to the realization of three main effects.

Analgesic effect

Due to the selective opening of voltage-gated potassium channels of neurons with concomitant efflux of K⁺ ions, the neuronal resting potential is stabilized. The neuron becomes less excitable. The indirect antagonism of flupirtine towards NMDA receptors protects neurons from the influx of Ca²⁺ ions. Thus, the sensitizing effect of increased intracellular Ca²⁺ ion concentration is mitigated.

Consequently, upon neuronal excitation, the transmission of ascending nociceptive impulses is inhibited.

Muscle relaxant effect

The pharmaceutical effects described for the analgesic action are functionally reinforced by the enhanced uptake of Ca²⁺ ions by mitochondria, which occurs at therapeutically relevant concentrations. The inhibition of impulse transmission to motor neurons and the corresponding influence on interneurons lead to a reduction in muscle tension. Thus, this effect is manifested mainly in relation to local muscle spasms, and not in relation to the entire musculature as a whole.

Influence on chronicification processes

Chronicification processes should be considered as processes of neuronal conduction due to the plasticity of neuronal functions.

Through the induction of intracellular processes, the elasticity of neuronal functions creates conditions for the implementation of mechanisms such as “wind-up”, in which the response to each subsequent impulse is enhanced. NMDA receptors (gene expression) are largely responsible for triggering such changes. The indirect blockade of these receptors by flupirtine counteracts the sensation of increased pain. Stabilization of the membrane potential alters the process and thus reduces pain sensitivity, creating unfavorable conditions for clinically significant pain chronicification. If the pain is already chronic, stabilization of the membrane potential facilitates the “erasure” of pain memory and thus reduces pain sensitivity.

Pharmacokinetics

Absorption

After oral administration, approximately 90% of flupirtine is absorbed from the gastrointestinal tract, and after rectal administration, about 70% of the dose is absorbed.

After administration of flupirtine in doses from 50 to 300 mg, its plasma concentration is dose-dependent.

The pharmacokinetics of the drug Katadolon^® Forte are determined by the features of its dosage form: a rapidly releasing fraction of flupirtine (100 mg) and a slowly releasing fraction of flupirtine (300 mg). With a single application of the drug, the C_max of flupirtine 0.8 µg/ml (0.4-1.5 µg/ml) was reached after 2.4 h, and with multiple administration (400 mg daily for 7 days) – after 1.9 h, with C_max being 1 µg/ml (0.6-2.4 µg/ml). Under the influence of food, a slight increase in absorption occurs (AUC_0-∞ 14.1 µg/ml×h compared to 10.7 µg/ml×h), as well as an increase in C_max (1 µg/ml compared to 0.8 µg/ml), with T_max increased (3.2 h compared to 2.4 h).

Metabolism

About 3/4 of the administered dose of flupirtine is metabolized in the liver. During metabolism, as a result of hydrolysis of the urethane structure (phase I reaction) and acetylation of the resulting amine (phase II reaction), metabolite M1 (2-amino-3-acetamido-6-(4-fluoro)-benzylaminopyridine) is formed. The analgesic effect of this metabolite is approximately one-quarter that of flupirtine, so it is also involved in the therapeutic effect of flupirtine.

Another metabolite is formed during oxidative cleavage (phase I reaction) of the residual fluorobenzyl group followed by conjugation (phase II reaction) of the resulting fluorobenzoic acid with glycine. This metabolite (M2) has no biological activity.

To date, no studies have been conducted to identify the isoenzyme responsible for the oxidative (less significant) metabolic pathway.

Flupirtine is presumed to have a low potential for drug interactions.

Excretion

The majority of the administered dose of flupirtine (69%) is excreted by the kidneys. This portion is characterized as follows: 27% – unchanged, 28% – metabolite M1 (acetyl metabolite), 12% – metabolite M2 (para-fluorohippuric acid);
The remaining third consists of several minor metabolites whose structure has not yet been studied. A small portion of the flupirtine dose is excreted in urine and feces.

T_1/2 is about 15 h; when taken with food, T_1/2 decreases. The main metabolite is excreted somewhat more slowly (T_1/2 about 20 h and 16 h, respectively).

Pharmacokinetics in special clinical cases

In elderly patients (over 65 years of age) after multiple administration of Katadolon^® Forte, 1 extended-release tablet per day for 7 days, against the background of increased distribution values, an increase in AUC_0-24 was observed: 22.9 µg/ml×h compared to 16.8 µg/ml×h for the control group consisting of younger patients; in addition, elderly patients showed an increase in T_1/2 (23.72 h compared to 15.94 h).

In patients with impaired renal function (CrCl<30 ml/min), compared with patients in the control group, an increase in AUC_0-24 was observed: 23.11 µg/ml×h compared to 16.8 µg/ml×h, as well as an increase in T_1/2(20.01 h compared to 15.94 h).

Indications

• Treatment of acute pain in adults.

The drug Katadolon^® Forte should be used if treatment with other analgesics (for example, NSAIDs or weak opioid drugs) is contraindicated.

ICD codes

Dosage Regimen

Flupirtine should be prescribed for the shortest possible time necessary to achieve adequate analgesia. The duration of treatment should not exceed 2 weeks.

The drug is taken orally, without chewing the tablet and with a sufficient amount of liquid (preferably water).

The dose is 400 mg once a day. If this dose is not sufficiently effective, then Katadolon^® in capsule form (100 mg) can be used at a higher daily dose.

Elderly patients (over 65 years) and patients with severe renal impairment: initial dose – 200 mg (1/2 tab.) once a day. Depending on the pain intensity and tolerance, the dose can be increased to 400 mg (1 tab.) once a day. In patients with severe renal impairment, the maximum daily dose should not exceed 400 mg. If it is necessary to use the drug at a higher dose, patients should be under medical supervision.

Katadolon^® Forte is not recommended for use in patients with hypoalbuminemia, as clinical studies of the drug in this patient group have not been conducted.

The safety and efficacy of flupirtine in children and adolescents have not been established. Katadolon^® Forte should not be used in children and adolescents under 18 years of age.

Adverse Reactions

Definition of frequency categories of adverse reactions: very common (≥1/10); common (≥1/100, but <1/10); uncommon (≥1/1000, but <1/100); rare (≥1/10,000, but <1/1000); very rare (<1/10,000); frequency unknown (cannot be estimated from the available data).

Hepatobiliary system: very common – increased activity of liver transaminases; frequency unknown – hepatitis, liver failure.

Immune system: uncommon – allergic reactions (in some cases accompanied by increased body temperature, skin rash, urticaria, skin itching).

Metabolism: common – lack of appetite.

Nervous system: common – sleep disturbance, depression, agitation and/or nervousness, dizziness, tremor, headache; uncommon – confusion.

Organ of vision: uncommon – visual impairment.

Digestive system: common – heartburn, dyspepsia, nausea, vomiting, stomach pain, constipation, abdominal pain, dry oral mucosa, flatulence, diarrhea.

Skin and subcutaneous tissues: common – increased sweating.

Other: very common – fatigue/weakness (in 15% of patients), especially at the beginning of treatment.

Adverse reactions mainly depend on the dose of the drug (except for allergic reactions). In many cases, they disappear on their own during or after the end of treatment.

In order to obtain new information on the safety of the drug, Katadolon^® Forte is subject to additional monitoring by healthcare professionals. It is recommended to report every case of adverse reaction that occurred during the use of the drug Katadolon^® Forte. This allows continuous monitoring of the benefit/risk ratio of the drug.

Contraindications

• Hypersensitivity to the components of the drug;
• Patients at risk of developing hepatic encephalopathy and patients with cholestasis, because encephalopathy may develop or the course of existing encephalopathy or ataxia may worsen;
• Patients with myasthenia gravis due to the muscle relaxant effect of flupirtine;
• Patients with concomitant liver disease or alcoholism;
• Concomitant use of flupirtine with other drugs that may have hepatotoxic effects;
• Patients with recently cured or existing tinnitus, because these patients have a high risk of increased liver enzyme activity;
• Childhood and adolescence under 18 years.

Use in Pregnancy and Lactation

Data on the use of flupirtine during pregnancy are insufficient. The potential risk to humans is unknown.

Katadolon^® Forte should not be used during pregnancy, except in cases where the benefit to the mother outweighs the potential risk to the fetus.

Experimental studies in animals have shown reproductive toxicity of flupirtine, but not teratogenicity.

According to studies, Flupirtine is excreted in breast milk in small amounts. In this regard, Katadolon^® Forte should not be used during breastfeeding except in cases of absolute necessity. If it is necessary to use the drug Katadolon^® Forte during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in liver diseases, including those accompanied by cholestasis and a high risk of developing hepatic encephalopathy.

Use in Renal Impairment

Contraindicated in renal impairment.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

In elderly patients over 65 years of age or with symptoms of severe renal failure, dose adjustment is required.

Special Precautions

In patients with impaired renal function, plasma creatinine concentration should be monitored.

In elderly patients over 65 years of age or with symptoms of severe renal failure, dose adjustment is required.

During treatment with Katadolon^® Forte, liver function should be monitored once a week, because therapy with flupirtine may lead to increased activity of liver transaminases, development of hepatitis and liver failure. If liver test results are abnormal or clinical symptoms appear that indicate liver damage, then the use of Katadolon^® Forte should be discontinued.

Patients should be warned that during treatment with Katadolon^® Forte, they should pay attention to any symptoms of liver damage (for example, lack of appetite, nausea, vomiting, stomach pain, fatigue, dark urine, jaundice, itching). If such symptoms occur, you should stop taking Katadolon^® Forte and consult a doctor immediately.

Katadolon^® Forte is not recommended for use in patients with hypoalbuminemia.

When treating with flupirtine, false-positive reactions of the diagnostic strip test for bilirubin, urobilinogen and protein in urine are possible. A similar reaction is possible with the quantitative determination of bilirubin concentration in blood plasma.

When using the drug, in some cases, urine may turn green, which is not a clinical sign of any pathology.

Effect on ability to drive vehicles and operate machinery

Katadolon^® Forte may affect concentration and the speed of human psychomotor reactions, even if used in accordance with the instructions for medical use. Patients experiencing drowsiness or dizziness during therapy with Katadolon^® Forte should refrain from driving vehicles and operating machinery.

When used concomitantly with alcohol, the negative impact on the speed of psychomotor reactions may be enhanced.

Overdose

There are reports of isolated cases of overdose with suicidal intent.

Symptoms when taking flupirtine at a dose of 5 g included nausea, tachycardia, pathological fatigue, tearfulness, dizziness, lightheadedness, loss of consciousness, dry oral mucosa.

Animal studies have shown that overdose can lead to CNS disorders, as well as manifestations of hepatotoxicity of the type of enhanced metabolic disorders in the liver.

Treatment after vomiting or the use of forced diuresis, intake of activated charcoal and administration of electrolytes, the condition recovered within 6-12 hours. No life-threatening conditions were reported. Symptomatic treatment should be carried out. A specific antidote is unknown.

Drug Interactions

Katadolon^® Forte can enhance the effect of ethanol, sedatives and muscle relaxants.

Since Flupirtine binds to plasma proteins to a significant extent, it is likely that other drugs used simultaneously with flupirtine may be displaced from plasma protein binding. Corresponding in vitro studies were conducted with the drugs warfarin, diazepam, acetylsalicylic acid, benzylpenicillin, digitoxin, glibenclamide, propranolol, clonidine.

However, only with the simultaneous use of flupirtine with warfarin and diazepam can the displacement of the latter from plasma protein binding reach such a degree that an enhancement of the effect of these drugs cannot be excluded. With the simultaneous use of flupirtine and indirect anticoagulants – coumarin derivatives (for example, warfarin) – it is recommended to monitor the prothrombin index more frequently in order to timely adjust the dose of indirect anticoagulants.

There are no data on interaction with other anticoagulants (acetylsalicylic acid and others). The simultaneous use of flupirtine with drugs that may affect liver function should be avoided.

The combined use of flupirtine and drugs containing paracetamol and carbamazepine should be avoided.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.