Nolodatac (Flupirtine) capsules

Dosage form 

hard gelatin capsules No. 1 brown

Composition

1 capsule contains:

flupirtine maleate 100 mg

Excipients: calcium hydrogen phosphate dihydrate – 186 mg, copovidone – 6 mg of magnesium stearate to 2.0 mg silica colloidal anhydrous – 1.5 mg, carboximetilkrahmal sodium 4,5 mg.

Pharmacological action

Non-opioid analgesic Central action. Flupirtine is representative of a selective activator of neuronal potassium channels.

Flupirtine activates the associated G protein is neuronal potassium channels internal rectification. The exit of potassium ions causes a stabilization of the resting potential and decreased excitability of neuronal membranes. The result is indirect inhibition of NMDA receptors (N-methyl-D-aspartate), because blockade of NMDA receptors by magnesium ions is maintained until, until depolarization of the cell membrane (indirect antagonistic effect on NMDA receptors).

At therapeutically relevant concentrations is not associated with flupirtine ?1-, ?2-adrenergic receptors, 5НТ1(5-hydroxytryptophan)-, 5HT2-serotonin, dofaminovmi, benzodiazepine, opioid, Central m – and n-cholinergic receptors.

This Central action flupirtine leads to the implementation of the 3 main effects.

Analgesic effect

Due to selective opening of potential-dependent neuronal potassium channels with the concomitant release of potassium ions the resting potential of a neuron stabiliziruemost. The neuron becomes less excitable.

Indirect antagonism of flupirtine in respect of NMDA receptors protects neurons from the arrival of calcium ions. Thus softened by the sensitizing effect of increasing the intracellular concentration of calcium ions.

Consequently, when excitation of a neuron is the inhibition of the ascending transmission of nociceptive impulses

Muscle relaxant effect

Pharmacological effects described for the analgesic effect, functionally supported by increasing absorption of calcium ions by mitochondria, which occurs at therapeutically relevant concentrations. Muscle relaxant effect occurs as a result of concomitant inhibition of transmission of impulses to motor neurons and corresponding effects of neuronal inserted. Thus, this effect is manifested mainly in relation to the entire musculature as a whole.

The effect of the processes of chronification

The process of chronification should be seen as processes of neuronal conduction due to the plasticity of neuronal function.

Through the induction of intracellular processes elasticity functions of neurons creates conditions for the implementation of mechanisms such as “inflation” that leads to the strengthening of the response to each successive pulse. The launch of such changes, largely responsible NMDA receptors (expression of genes). Indirect blockade of these receptors under the action of flupirtine to suppress these effects. This creates unfavorable conditions for clinically relevant chronic pain, and in the case of the previously present chronic pain to “erase” the pain of memory through stabilizing membrane potential, which leads to lower pain sensitivity.

Pharmacokinetics

Suction

Once inside almost completely (90%) and rapidly absorbed from the gastrointestinal tract.

The concentration of active substance in blood plasma is proportional to dose.

Metabolism

Metabolized in the liver (up to 75% of the dose) with the formation of the active metabolite M1 (2-amino-3-acetamino-6-[4-fluoro]-benzylaminopurine) and M2. The active metabolite M1 is formed by hydrolysis of urethane structure (1 phase reaction) and subsequent acetylation (2 phase reaction). This metabolite provides on average 25% analgesic activity flupirtine. The other metabolite (M2 – biologically inactive) formed by the oxidation reaction (phase 1) pair of Formentera with subsequent conjugation (phase 2) pair-fermenting acid with glycine.

Study about what is the isozyme primarily involved in the oxidative pathway of degradation, was conducted. It is expected that flupirtine will have only a marginal ability to interact.

Excretion

T1/2 is about 7 h (10 h for basic substance and metabolite M1) that is sufficient to provide an analgesic effect.

Write mainly kidneys (69%): 27% output unchanged, 28% – in the form of metabolite, M1 (acetyl-metabolite), 12% – in the form of metabolites M2 (para-persipura acid) and 1/3 of the administered dose was excreted as metabolites with outstanding structure. A small part of the dose excreted in bile and feces.

Pharmacokinetics in special clinical cases

At patients of elderly age (over 65 years) compared to younger patients observed increase in T1/2 (up to 14 hrs in single dose and up to 18.6 hours when taken for 12 days) and Cmax, respectively, in plasma above 2-2.5 times.

Side effects

Adverse reactions are categorized by frequency as follows: very common (>,1/10), often (>,1/100, but <,1/10), infrequently (>,1 / 1000th, but the <1/100), rare (>,000 1/10, but <,1/1000), very rare (1/10 000) frequency unknown (cannot be evaluated on the basis of available data).

The immune system: infrequently – hypersensitivity to the drug, allergic reactions (in some cases accompanied by increased body temperature, skin rash, urticaria, pruritus).

From the nervous system: often – insomnia, depression, anxiety/nervousness, dizziness, tremor, headache, rarely – confusion.

On the part of the organ of vision: often – blurred vision.

From the digestive system: often – neuralgia, nausea, vomiting, pain in the stomach, constipation, abdominal pain, dryness of the mucous membrane of the mouth, flatulence, diarrhea.

The liver and biliary tract: very common – increase in liver transaminases, frequency unknown – hepatitis, liver failure.

The skin and subcutaneous tissue: often – sweating.

Other: often – fatigue/weakness (15% of patients), especially at the beginning of treatment, lack of appetite.

Side effects mainly depend on the dose (except allergic reactions). In many cases, they disappear by themselves in the course of or after the end of treatment.

Special conditions

The drug should be used if treatment with other analgesics (e.g., NSAIDs or opioid drugs) are contraindicated.

When used in patients with reduced kidney function should monitor the concentration of creatinine in the blood.

In patients older than 65 years or with severe renal failure or hypoalbuminemia requires correction of the dose.

During drug treatment should Nolodatac 1 time per week to monitor the status of liver function, since during therapy with flupirtine may increase the activity of transaminases, the development of hepatitis and liver failure. If the findings of liver function are abnormal or the clinical symptoms that indicate liver injury should stop using the product

Patients should be warned that during treatment it is necessary to pay attention to any symptoms of liver injury (e.g., lack of appetite, nausea, vomiting, stomach pain, fatigue, dark urine, jaundice, itching). The manifestation of such symptoms should stop taking the drug and immediately consult a doctor.

In the treatment of flupirtine possible false-positive reaction with the diagnostic test strips for bilirubin, urobilinogen and protein in the urine. A similar reaction is possible in the quantitative determination of the concentration of bilirubin in plasma.

In applying the drug in high doses in some cases may be urine staining in green, that is not a clinical symptom of any disease.

Effects on ability to drive vehicles and management mechanisms

In applying the drug Nolodatac should refrain from driving vehicles and management mechanisms, due to the fact that patients may develop drowsiness and dizziness that may affect the concentration and speed of psychomotor reactions. This is especially important to remember in case of simultaneous use of alcohol.

Testimony

Nolodatac intended for the treatment of acute and chronic pain of mild and moderate intensity.

Contraindications

• patients with risk of development of hepatic encephalopathy and cholestasis (may develop encephalopathy or worsening of an existing encephalopathy or ataxia),
• myasthenia gravis (due to muscle relaxant action flupirtine),
• liver disease
• alcoholism,
• tinnitus (including recent cured),
• the simultaneous use of flupirtine with other medicinal preparations have hepatotoxic effects,
• child and adolescence to 18 years,
• hypersensitivity to the active substance or any component of the drug.

With caution designate of renal failure, hypoalbuminemia, elderly patients (over 65 years).

Insufficient data on the use of flupirtine during pregnancy. In experimental studies in animals flupirtine showed reproductive toxicity, but not teratogenicity. The potential risk for humans is unknown. Nolodatac the drug should not be used during pregnancy, except in those cases where the benefit to the mother outweighs the potential risk to the fetus.

According to studies, flupirtine in small quantities enters breast milk. In this regard, it should not be used in breastfeeding with the exception of those cases where the drug is an emergency. If necessary, use of the drug during lactation should stop breastfeeding.