DANTRIUM 25 mg Gél Plq/5x10 (50)

Capsule (light orange-brown).
Box of 50, under blister packs.

Per capsule :

Dantrolene sodium: 0,025 g

Excipients with known effect: Lactose monohydrate, wheat starch.

Excipients:

DANTRIUM is indicated for the treatment of chronic and severe forms of skeletal muscle spasticity resulting from conditions such as stroke, spinal cord injury, cerebral palsy and multiple sclerosis in adults and in children over 5 years weighing 25 kg or more.

Dosage

For each patient, treatment initiation must be gradual until the optimal individual dose is reached. For each patient, it is recommended to seek the minimum dose providing optimal efficacy. The recommended dose escalation schedule is presented below.

Adults

The dose escalation of DANTRIUM must follow the schedule below and must not be faster:

• Week 1: 25 mg once daily
• Week 2: 25 mg twice daily
• Week 3: 50 mg twice daily
• Week 4: 50 mg three times daily

Once the optimal dose is reached, the patient's total daily dose should be divided into 2 to 4 individual doses in order to obtain plasma levels that are as uniform as possible and to minimise adverse effects.

Doses higher than 200 mg must not be administered during long-term treatment with DANTRIUM. Temporarily, the dose may be gradually increased up to 400 mg per day if situations of tension or stress are anticipated in the patient.

The dose should be increased as follows:

• Week 5: 75 mg three times daily
• Week 6: 75 mg four times daily
• Week 7: 100 mg four times daily

However, administration of doses higher than 200 mg per day must not exceed a duration of 2 months.

Paediatric population

Dosage schedule for children over 5 years (from 25 kg body mass).

For each patient, it is recommended to seek the minimum dose providing optimal efficacy. The recommended dose escalation schedule is presented below:

• Week 1: 1 capsule of 25 mg once daily
• Week 2: 1 capsule of 25 mg twice daily
• Week 3: 1 capsule of 25 mg three times daily
• Week 4: 2 capsules of 25 mg twice daily
• Week 5: 2 capsules of 25 mg three times daily
• Week 6: 3 capsules of 25 mg three times daily

For children weighing 50 kg or more, refer to the adult dosage.

The dose may be gradually increased up to 200 mg per day.

DANTRIUM is a long-term treatment.

If no improvement is observed after 6 to 8 weeks, treatment must be discontinued.

Due to insufficient experience regarding its use and assessment of its tolerability, DANTRIUM must not be used in children under 5 years of age.

Method of administration

Oral use.

• Hypersensitivity to the active substance or to any of the excipients listed in section Composition.
• Hepatic disorders.
• Respiratory insufficiency.
• Severe heart failure due to myocardial disease.
• In cases where an abnormally high muscle tone is needed to allow better function, upright posture or balance during movement.
• Pregnancy and breastfeeding (see section Fertility, pregnancy and breastfeeding).
• This medicine is contraindicated in patients with an allergy to wheat (other than coeliac disease) (see section Warnings and precautions).

DANTRIUM should be used with caution in the following situations:

In cases of amyotrophic lateral sclerosis or in the presence of symptoms of bulbar palsy, as the paresis may be aggravated by DANTRIUM.

Patients suffering from heart disease, in particular those with myocardial lesions and/or cardiac arrhythmias, require particular medical monitoring.

Dantrolene causes hepatic lesions ranging from mild to severe in approximately 9 patients treated out of 100 000, for whom the mortality rate is 10 to 20 %.

The risk of hepatic lesions appears to be particularly increased at daily doses above 300 mg, during prolonged therapy, in women, in patients over 30 years of age or with a history of hepatic lesions, and during concomitant use of other medicines that may damage the liver. Hepatic lesions may be fatal, particularly in elderly patients. In patients with multiple sclerosis, the risk of severe hepatic lesions appears to be increased.

Before starting and during treatment with DANTRIUM, liver enzymes must be monitored at regular intervals; in particular, AST and ALT, which must be measured frequently. Patients for whom the risk of hepatic lesions is increased must be monitored particularly closely. If the values are outside the normal range or if symptoms of hepatic lesions appear, DANTRIUM must be discontinued.

Some data show that when hepatic lesions occur, high serum bilirubin levels are correlated with severe progression.

To reduce the risk of hepatic lesions, the lowest effective dose of DANTRIUM possible must be used.

DANTRIUM may cause photosensitisation; therefore, patients must protect themselves against strong sun exposure during treatment.

Treatment must be discontinued if patients develop pleural or pericardial effusion or pleuropericarditis.

Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases) must not take DANTRIUM.

At doses above 200 mg of dantrolene sodium per day, an increase in undesirable effects is expected.

This medicine contains a very low gluten content (from wheat starch). It is considered "gluten-free" and is therefore unlikely to cause problems in cases of coeliac disease.

A capsule contains no more than 3,8 micrograms of gluten.

Concomitant intake of central nervous system depressants (such as benzodiazepine-type tranquilisers, antihistamines, sedatives) and alcohol consumption should be avoided, as the undesirable effects with DANTRIUM may be increased (in particular the depressant effect on the central nervous system and muscle weakness).

With concomitant administration:

• of oestrogens or other potentially hepatotoxic substances, the risk of liver damage is increased.
• of non-depolarising muscle relaxants (vecuronium), the effect of DANTRIUM may be potentiated.
• of metoclopramide, the rate and speed of absorption of DANTRIUM may be increased and thus lead to an increase in the therapeutic effect and undesirable effects of DANTRIUM.

In patients with a predisposition to malignant hyperthermia who were receiving intravenous dantrolene sodium, co-administration of calcium antagonists and/or beta-blockers was observed to result in hyperkalaemia and cardiac failure.

Pregnancy

There are no or few data on the use of dantrolene sodium in pregnant women. Dantrolene crosses the placental barrier and may induce muscular hypotonia, particularly in the uterus. Animal studies are insufficient with regard to reproductive toxicity (see section Preclinical safety). Use during pregnancy is contraindicated.

Breast-feeding

This medicinal product is contraindicated during breast-feeding, as its active substance, dantrolene, is excreted in breast milk and undesirable effects in the breast-fed infant cannot be excluded, particularly during long-term treatment with DANTRIUM. If treatment of the breast-feeding mother with DANTRIUM is necessary, breast-feeding must be stopped.

Fertility

There are no data on the effects of dantrolene on fertility in humans.

When administered orally, the effects of DANTRIUM on the central nervous system, such as drowsiness or confusion, may impair responsiveness to the point of reducing the ability to drive or use machines. This applies in particular at the start of treatment, when the dose is increased, and in combination with alcohol or other central nervous system depressant medicines.

Undesirable effects are presented below by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1 000, < 1/100), rare (≥ 1/10 000, < 1/1 000), very rare (< 1/10 000) and not known (cannot be estimated from the available data).

System organ class	Frequency	Adverse effects
Benign, malignant and unspecified tumours (including cysts and polyps)	Uncommon	Lymphocytic lymphoma
	Uncommon	Lymphoma
Blood and lymphatic system disorders	Uncommon	Aplastic anaemia
	Uncommon	Anaemia
	Uncommon	Leukopenia
	Uncommon	Thrombocytopenia
Immune system disorders	Uncommon	Hypersensitivity
	Uncommon	Anaphylactic reaction
Metabolism and nutrition disorders	Common	Decreased appetite
Psychiatric disorders	Common	Depression
	Common	Confusional state
	Common	Nervousness
	Common	Insomnia
	Uncommon	Hallucination
	Frequency not known	Disorientation
Nervous system disorders	Very common	Vertigo
	Very common	Somnolence
	Common	Headache
	Common	Speech disturbances
	Common	Convulsions
	Uncommon	Increased paresis in cases of amyotrophic lateral sclerosis or in the presence of bulbar palsy symptoms
	Uncommon	Dysgeusia
	Frequency not known	Hypotonia
Eye disorders	Common	Visual impairment
	Uncommon	Diplopia
	Uncommon	Increased lacrimation
Cardiac disorders	Common	Pericarditis
	Uncommon	Heart failure
	Uncommon	Tachycardia
	Uncommon	Pleuropericarditis
	Frequency not known	Bradycardia
Vascular disorders	Uncommon	Phlebitis
	Uncommon	Fluctuation of blood pressure
Respiratory, thoracic and mediastinal disorders	Common	Respiratory depression
	Common	Respiratory insufficiency
	Uncommon	Dyspnoea
	Very rare	Sensation of suffocation
Gastrointestinal disorders	Very common	Diarrhoea
	Common	Abdominal cramps
	Common	Nausea
	Common	Vomiting
	Uncommon	Constipation (rarely progressing to signs of intestinal obstruction)
	Uncommon	Dysphagia
	Uncommon	Gastrointestinal haemorrhage
	Uncommon	Upper abdominal pain
	Uncommon	Hypersalivation
	Frequency not known	Dyspepsia
	Frequency not known	Dry mouth
Hepatobiliary disorders	Common	Hepatotoxicity/hepatitis
	Common	Jaundice
	Common	Cholestasis
Skin and subcutaneous tissue disorders	Common	Skin rash
	Common	Acneiform dermatitis/acne-like rash/acne
	Uncommon	Hyperhidrosis
	Uncommon	Abnormal hair growth
	Uncommon	Pruritus
	Uncommon	Photosensitivity reaction
	Very rare	Urticaria
	Very rare	Eczema
Musculoskeletal and connective tissue disorders	Common	Muscle weakness
	Uncommon	Back pain
	Uncommon	Myalgia
Renal and urinary disorders	Uncommon	Urinary incontinence
	Uncommon	Pollakiuria
	Uncommon	Crystalluria
	Uncommon	Hematuria
	Uncommon	Urinary retention
	Very rare	Micturition disorders
	Frequency not known	Chromaturia
	Frequency not known	Nocturia
Disorders of the reproductive system and breast	Very rare	Erectile dysfunction
General disorders and administration site conditions	Very common	Fatigue
	Very common	Malaise
	Very common	Asthenia
	Common	Chills
	Common	Fever
Investigations	Common	Abnormal liver function tests

In addition, the following specific adverse effects have been observed with the use of DANTRIUM:

• Onset of cerebral convulsions, particularly in children with cerebral palsy;
• Pleuropericarditis and pericardial effusion (with associated eosinophilia)
• Pleural effusion (with associated eosinophilia),
• Diarrhea (which may be severe and require temporary discontinuation of treatment).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr

Symptoms that may occur in case of overdose are as follows: muscle weakness, troublesome hypotonia, visual disturbances (diplopia), disturbances of consciousness (lethargy, coma), fatigue, dizziness, vomiting, diarrhea, tachycardia, hypo- or hypertension, pruritus, undesirable hepatotoxic reactions.

In case of poisoning, if possible ensure gastric emptying and provide general measures of cardiac and respiratory support. Administer diluting solutions by intravenous infusion so as to avoid a risk of crystalluria.

In case of overdose with dantrolene, the benefit of dialysis is not known and there is no specific antidote.

Pharmacotherapeutic class: direct-acting muscle relaxants, ATC code: M03CA01.

Dantrolene sodium uncouples nerve excitation and contraction of skeletal muscles, probably by interfering with calcium release at the level of the sarcoplasmic reticulum.

Its action is selective and has no influence on neuromuscular transmission nor any measurable effect on the excitable membrane.

At therapeutic doses, smooth muscles and the myocardium are not affected by DANTRIUM.

Studies in vitro in animals indicated that effects on smooth muscles and the myocardium may occur at doses well above therapeutic doses; however, as the results are contradictory, no definitive conclusion can be drawn regarding such effects in humans.

Absorption

Gastrointestinal absorption of dantrolene sodium is approximately 70% and leads to dose-dependent plasma concentrations. After administration of 25 mg of dantrolene sodium, maximum plasma concentrations were reached after 3 to 4 hours and were 0,22 μg/mL. Absolute bioavailability was 83,6% on average.

Distribution

Dantrolene is reversibly bound to plasma albumin; the in vitro binding constant value was established at 4,3 x 10^-4M^-1. For transplacental passage of dantrolene, a factor of 0,4 was measured.

Biotransformation

Metabolism in the liver occurs by 5-hydroxylation at the hydantoin ring, as well as by reduction of the nitro group to an amine group followed by acetylation.

The parent substance and metabolites are mainly excreted via the renal and biliary routes, renal excretion occurring at a ratio of 79% of 5-hydroxy-dantrolene, 17% of acetylamino-dantrolene and 1 to 4% of unchanged dantrolene. The metabolite 5-hydroxy-dantrolene is pharmacologically active, whereas acetylamino-dantrolene has no muscle relaxant effect.

Elimination

Renal clearance (5-OH-dantrolene) is 1,8 to 7,8 L/h. The mean biological half-life in adults is 8,7 hours after an oral dose of 100 mg. In children with chronic spasticity, an elimination half-life of 7,3 hours has been observed.

The duration and intensity of skeletal muscle relaxation in patients depend on blood concentrations of dantrolene sodium.

Acute toxicity

Non-clinical data on intravenous administration are not available. Following intraperitoneal administration, the LD50 is approximately 800 mg/kg body mass in rats (human equivalent dose 128 mg/kg) and following oral administration, the LD50 is approximately 3 g/kg in newborn rats (human equivalent dose 480 mg/kg). No LD50 value could be determined following oral administration in adult animals, due to insufficient mortality.

With subacute intravenous administration of dantrolene at doses up to 20 mg/kg/day, the only observations were a lower gain in body mass in rats (human equivalent dose 3,2 mg/kg) and hepatic changes in dogs (human equivalent dose 10,8 mg/kg).

Chronic toxicity

In chronic toxicity studies in rats, dogs and monkeys, oral administration of more than 30 mg/kg/day (human equivalent dose 4,8 mg/kg, 16,2 mg/kg and 9,6 mg/kg respectively) for 12 months resulted in reduced growth or body mass gain. Hepatotoxic effects and potentially renal obstruction were observed; these were reversible.

Mutagenicity

Dantrolene sodium produced positive results in the Ames test with S. typhimurium both in the presence and in the absence of hepatic activation.

Carcinogenicity

Doses of dantrolene sodium up to 60 mg/kg/day (human equivalent dose 9,6 mg/kg) for 18 months led to an increase in benign hepatic neoplasms, an increase in hepatic lymphangiomas and hepatic angiosarcomas, and, in females only, an increase in mammary tumours.

The relevance of these data to clinical practice is not known.

Reproductive toxicity

In adult male and female rats, orally administered dantrolene up to 45 mg/kg/day (human equivalent dose 7,3 mg/kg/day) had no negative effects on fertility or general reproductive capacity. Administration of dantrolene to pregnant female rats (at 20 mg/kg/day or more; human equivalent dose 3,2 mg/kg/day) and pregnant female rabbits (at 45 mg/kg/day; human equivalent dose 14,5 mg/kg/day) resulted in an increase in the unilateral or bilateral formation of supernumerary ribs in the offspring.

3 years.

To be stored in the blister packs, in the outer packaging, protected from light and moisture.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400932156009 (Blister/5x10 (50)).

Price:

5,25 euros (Blister/5x10 (50)).

Social Security reimbursement at 30%. Collective.

 

Marketing authorisation holder: NORGINE B.V., Antonio Vivaldistraat 150, 1083 HP Amsterdam, Netherlands.