Tolperison-HCl  150mg tablets Taj Pharma

1. NAME OF THE MEDICINAL PRODUCT

Tolperison-HCl  50mg tablets Taj Pharma
Tolperison-HCl  150mg tablets Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 50 mg Tolperisone hydrochloride.
Each film-coated tablet contains 150 mg Tolperisone hydrochloride.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet

4. CLINICAL PARTICULARS

• 1 Therapeutic indication

Spasticity of the skeletal muscles

4.2    Posology and method of administration

Adults and adolescents from age 15: daily dose is 150 mg – 450 mg per os divided into 3 doses, according to the individual requirements and tolerance of the patients. This dosage can also be applied for long-term treatment (several months or years) without dose reduction.

In the elderly dose modification or reduction is not necessary; the doses recommended are well tolerated.

According to the available data no special dosage adjustment is required in renal or liver insufficiency.

For doses not realisable/practicable with this strength another strength of this medicinal product is available.

For oral use.

It is recommended to take Tolperison-HCl tablets after meals.

4.3    Contraindications

• Hypersensitivity to the active substance or to any of the excipients.
• Myasthenia gravis.

4.4    Special warnings and precautions for use

The medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose-malabsorption should not take this medicine.

Special attention is required in treatment of patients who already receiving antihypertensive therapy, since according preliminary clinical observations tolperisone may cause decreased blood pressure of approximately 10 to 30 Hgmm in transient after a single dose or in case of long-term therapy as well.

There is no need of reduction or modification of dosages in special treatment groups such as elderly people, however as it is known that interindividual variations may require attention and the oral doses of tolperisone might need to be individualized.

Interindividual differences may be observed in all treatment groups, based on the metabolism, which takes place primarily in the liver. Tolperisone undergoes an extensive first pass effect, and only 20% of an administered dose appear unchanged in the blood. The metabolism is NADPH-dependent, since the omission of this coenzyme completely abolished the consumption of tolperisone. It has been demonstrated that both P450- dependent and P450-independent microsomal biotransformations are involved in tolperisone metabolism, in vitro. Hydroxymethyl metabolite formation revealed to be the main P450-mediated metabolic pathway. CYP2D6 was identified as the key enzyme in metabolism, however involvement of CYP2C19 and CYP1A2 were also shown in a lesser extent. It was evidenced that P450-independent metabolism was mediated to a small extent by FMO3. Metabolites detected and indirect evidences from inhibition studies pointed toward the substantial involvement of presumable microsomal carbonyl reductase in the metabolism of tolperisone.

4.5    Interaction with other medicinal products and other forms of interaction

No interaction between tolperisone and medications prescribed for concomitant diseases has been observed that would restrict the administration of tolperisone. However, tolperisone is metabolised by

the cytochrome P450 system, in particular CYP2D6. Therefore, interactions with drugs that are metabolised by the same system cannot be excluded. Tolperisone does not affect cortical functions and the arousal level; therefore, it can be given together with hypnotics, sedatives and tranquillizers. However, dose reduction may be considered when Tolperison-HCl  tablets are administered concomitantly with other centrally acting muscle relaxants. On the basis of clinical trials, it can be concluded that tolperisone potentiates the effect of NSAIDs.

Additional that has described in 4.4, in treatment of patients who already receiving antihypertensive therapy, possible interactions may be considered, however there is no direct evidences of clinical observations reported. Based on the current data tolperisone inhibits reflexes by two main mechanisms: on the one hand by influencing the inhibition of voltage-dependent sodium channels, and on the other hand by influencing synaptic transmission through inhibiting sodium and calcium channels. However, additional mechanisms can not be completely excluded (e. g. effects through alpha receptors). A theoretical sites of interference can not be ruled out due the direct inhibition of tolperisone, on the Na2+ and in lesser extent on the Ca2+ channels in experimental conditions. However, reports showed that the Ca2+ antagonistic action occurring generally in higher concentrations, compared to the action on Na2+ channels. The sites and extent of possible intercations need to be elucidated.

Tolperison-HCl  tablets do not cause either somatic or psychical dependency.

On the basis of human investigations, effects of alcohol on the functions of the central nervous system are not enhanced or altered by tolperisone.

According to present data Tolperison-HCl  tablets do not have any influence on the results of clinical laboratory examinations.

4.6    Pregnancy and lactation

Pregnancy

No teratogenic effect of tolperisone was noted in any animal studies. Since there are no human study results available, tolperisone should only be used in pregnancy (especially in the first trimester), if the expected therapeutic benefits are unambiguously higher than the foetal risk.

Lactation

Since there are no data available whether tolperisone is excreted into breast milk, it must not be used

during lactation.

4.7    Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8    Undesirable effects

Undesirable effects of Tolperison-HCl  are transient, and decrease or even stop by reducing the dose.

Adverse events are listed below by frequency as follows.

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

Immune system dysorders:

Rare:                                   hypersensitivity reaction with erythema, exanthema, pruritus, blood pressure

decreased and increased heart rate

Very rare:                          hypersensitivity reaction with urticaria, dyspnoea, angioneurotic oedema in

single cases, anaphylactic shock

In cases of any hypersensitivity reaction, the administration of Tolperison-HCl  should be discontinued.

4.9    Overdose

There are limited data available on the overdose of tolperisone. The therapeutic index of tolperisone is wide and there are literature reports of oral administration of 600 mg tolperisone in children without any severe toxic symptom. In some children 300 – 600 mg/day tolperisone administered orally was associated with irritability. Tolperisone has no specific antidote. In tolperisone overdose general symptomatic and supportive measures should be taken.

5. PHARMACOLOGICAL PROPERTIES

• 1 Pharmacodynamic properties

Pharmacotherapeutic group: other centrally acting agents.

Tolperisone is a centrally acting muscle relaxant with properties similar to local anaesthetics. The precise mechanism of action of tolperisone is not fully known. It possesses high affinity for nervous tissue, reaching the highest concentration in the brain stem, spinal cord and peripheral nerve tissue. The chemical structure of tolperisone is similar to that of lidocaine and, similarly to lidocaine, tolperisone has membrane stabilising effects. Tolperisone reduces the sodium influx through the isolated nerve membrane in a dose dependent way, thus amplitude and frequency of action potentials are reduced. Furthermore, inhibitory effects on voltage dependent Ca²⁺-channels have been demonstrated, suggesting that tolperisone might also reduce the transmitter release in addition to its membrane stabilising effect.

Tolperisone exerts its action at 3 levels:

• Peripheral level – Tolperisone stabilises the cell membrane of neurons, and consequently suppresses the amplitude and frequency of the action potentials. It is capable of inhibiting the pathological peripheral impulse condition induced by pain, which could start various motoric or vegetative reflexes that would lead to increased muscular tone.
• Central-spinal level – Tolperisone reduces the increased mono- and polysynaptic reflex activity in a dose-dependent manner to the physiological level. This effect is well demonstrated in several animal models.
• Central-reticular level – An imbalance between supraspinal facilitatory and inhibitory control can also lead to an enhanced reflex activity and an increased muscle tone. Tolperisone reduces the reticulospinal facilitation in the brainstem and has been shown to be effective in alleviating experimental gamma-rigor of reticular origin.

The blood flow enhancing effect of tolperisone is still not understood. Involvement of calcium-antagonistic, slight spasmolytic or slight anti-adrenergic effects have been proposed.

5.2     Pharmacokinetic properties

Absorption

The absorption of orally administered tolperisone from the small intestine is good. Peak plasma concentration is observed 0,5 – 1 hour after the oral intake. Bioavailability is about 20% due to significant first-pass metabolism.

Biotransformation

Tolperisone is extensively metabolised in the liver and kidneys. There are no observations that suggest a pharmacological activity of the metabolites.

In animal studies on distribution, relative accumulation of tolperisone was observed in the diencephalon, pons and medulla oblongata, as well as in the main organs of elimination such as liver and kidney.

Elimination

Tolperisone and its metabolites are excreted almost entirely through the kidneys. 98% of the administered dose is excreted with the urine within 24 hours. Less than 0.1% of the dose is eliminated in the intact form. When administered orally, the elimination half -life of tolperisone in men was calculated to be approximately 2-4 hours with a large inter-individual variation.

Tolperisone is reported to have a relatively high volume of distribution (5l/kg b.w.); the total plasma clearance is 1.9±0.4 l/h/kg. The overall binding rate of tolperisone racemate to human plasma proteins is 95%.

Food increases the bioavailability. Therefore, it is recommended to take Tolperison-HCl  tablets after meals.

5.3    Preclinical safety data

In acute animal toxicity studies large doses of tolperisone caused ataxia, tonic-clonic seizures, dysnpoe and respiratory failure were reported. Based on animal studies tolperisone is not teratogenic. Embryotoxic variations were observed in rats at 500 mg/kg and in rabbits at 250 mg/kg oral doses. These doses were multiple times higher than the doses applied in humans.

6. PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Core: Talc, Stearic acid, Crospovidone, Betaine hydrochloride, Mannitol, Microcrystalline cellulose.

Film coating: Opadry II. White, Titanium dioxide E 171, Macrogol 4000, Hypromellose, Lactose monohydrate.

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 Years

6.4     Special precautions for storage

Do not store above 30^oC.

Store in the original package.

6.5    Nature and contents of container

20 or 30 or 50 or 100 film-coated tablets in colourless, transparent PVC/Al by blister and carton box.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal <and other handling>

Any unused product or waste material should be disposed of in accordance with local requirements.

7.Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com