Dantrium Capsules 100mg

2.           QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Each capsule contains 100 mg dantrolene sodium.

 

Dantrium 100mg capsules contain 100mg dantrolene sodium per capsule.

 

Excipients with known effect: contains lactose monohydrate 181.0mg and wheat start 33.0mg. 189.0mg.

 

 

3.        PHARMACEUTICAL form

 

Capsule, hard

Dantrium 100mg capsules are presented as white green orange/orange hard capsules. 

 

 

4.2          Posology and method of administration

 

Paediatric Population

 

Dosing table for children over 5 years (upwards of 25 kg body weight). For the individual patient the lowest dose compatible with optimal response is recommended. A recommended dosage titration schedule is provided below.

 

Week 1: 1 Dantrium 25 capsule once daily

Week 2: 1 Dantrium 25 capsules twice daily

Week 3: 1 Dantrium capsule 3 three times daily

Week 4: 2 Dantrium capsules twice daily

Week 5: 2 Dantrium capsules 3 three times daily

Week 6: 3 Dantrium 25 capsules 3 three times daily

 

 

4.3      Contraindications

 

Hypersensitivity to the active substance or to any of the excipients listed in 6.1,

 

Wheat allergy (other than coeliac disease) (see section 4.4).

 

4.4      Special warnings and precautions for use

 

At doses above 200 mg dantrolene per day, increased adverse reactions must be anticipated.

 

This medicine contains only very low levels of gluten (from wheat starch). It is regarded as ‘gluten-free’ and is very unlikely to cause problems in case of coeliac disease.

 

One capsule contains no more than 3.8 micrograms of gluten.

 

6.1      List of excipients

 

Capsule content

Wheat Maize starch

Talc

Magnesium stearate

Lactose monohydrate

 

 

Capsule Shell

Gelatin

Indigo Carmine (E132)

Titanium Dioxide (E171)

Iron Oxide (E172)

Erythrosine (E127)

 

6.4      Special precautions for storage

 

Store in blister packs, in the outer packaging, away from light and moisture.

Do not store above 30°C.

 

1. 5. Nature and contents of container

 

Polyvinyl chloride/aluminium blister packs of 100 capsules.

Dantrium 100mg Capsules are supplied in polyethylene containers of 100 capsules, with a polyethylene screw cap and packaged in an outer carton.

 

10.      DATE OF REVISION OF THE TEXT

20^th July 2021

29^th March 2022

2. What you need to know before you take Dantrium Capsules

 

Do not take Dantrium

-if you are if you are allergic to dantrolene sodium 3.5 H₂O, or any of the other ingredients of this medicine (listed in section 6),

-if you have liver disease,

-in cases where abnormally increased muscle tension is required to improve function, posture or movement balance,

-if you have impaired lung function,

-if you have severe heart muscle damage

- if you are pregnant or breast-feeding,

- If you are allergic (hypersensitive) to wheat, due to the presence of wheat starch.

 

Warnings and precautions

 

Doses of more than 200 mg dantrolene per day are more likely to cause side effects.

 

This medicine contains only very low levels of gluten (from wheat starch). It is regarded as ‘gluten-free’ and is very unlikely to cause problems if you have coeliac disease.

One Dantrium 25mg capsule contains no more than 3.8 micrograms of gluten.

One Dantrium 100mg capsule contains no more than 3.3 micrograms of gluten.

 

Driving and using machines

You must not drive or operate machinery without consulting your doctor.

When Dantrium or when other medicines that also affect the central nervous system are taken at the same time, central nervous system effects, such as drowsiness or confusion, can change the ability to react to such an extent that it reduces the ability to drive or operate tools and machines. This particularly applies at the start of treatment, when dosage is increased and when taken together with alcohol.

Important information about some of the ingredients of Dantrium

This medicine contains lactose and wheat starch. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

 

3. How to take Dantrium Capsules

Your doctor will slowly adjust the number of capsules you take until the optimal dose required for your treatment is reached. The lowest dose compatible with optimal response is recommended.

 

Adults

Unless prescribed otherwise by your doctor, the usual dose for adults at the beginning of treatment is 1 capsule daily. This dose should be increased weekly until the optimal dose is reached.

 

The dose should not be increased faster than as per the following schedule:

Week 1: 1 capsule of Dantrium 25 mg daily

Week 2: 1 capsule of Dantrium 25 mg 2 x daily

Week 3: 2 capsules of Dantrium 25mg 2 x daily

Week 4: 2 capsules of Dantrium 25 mg 3 x daily

 

Children

Unless prescribed otherwise by your doctor, the following dosage should be used for children aged 5 years and older (from 25 kg body weight):

 

Week 1: 1 Dantrium 25 capsule once daily

Week 2: 1 Dantrium 25 capsules twice daily

Week 3: 1 Dantrium 25 capsule 3 three times daily

Week 4: 2 Dantrium 25 capsules twice daily

Week 5: 2 Dantrium 25 capsules 3 three times daily

Week 6: 3 Dantrium 25 capsules 3 three times daily

 

5. How to store Dantrium Capsules

 

Keep out of the sight and reach of children.

 

Store capsules in the blister and outer packaging away from light and moisture a safe place at a temperature not above 30°C.

 

Do not use this medicine after the expiry date which is stated on the label outer carton and the blister after “EXP”. The expiry date refers to the last day of that month.

 

6. Contents of the pack and other information

 

What Dantrium Capsules contain

 

- The active substance is dantrolene sodium, 25 mg or 100 mg per capsule.

- The other ingredients are: lactose monohydrate,  wheat maize starch, talc and magnesium stearate (see section 2).

- The capsule shell of Dantrium 25mg and 100mg capsules contains gelatin and colouring agents titanium (E171), erythrosine (127) and iron oxide E110 sunset yellow (see end of section 2).

- The capsule shell of Dantrium 100mg capsules contains gelatin and colouring agents, titanium dioxide (E171),  iron oxide (E172) and indigo carmine (E132).

 

 

What Dantrium Capsules look like and contents of the pack:

- Dantrium 25 mg Capsules: The capsules are light brown white/orange. They capsules are supplied packed in blisters and available in packs plastic containers of 100 hard capsules with a snap on neck.

- Dantrium 100 mg Capsules: The capsules are white orange/green orange. They capsules are supplied packed in blisters and available in packs plastic containers of 100 hard capsules with polyethylene screw cap.

 

Marketing Authorisation Holder and Manufacturer:

Norgine B.V.

Antonio Vivaldistraat 150,

1083 HP Amsterdam

The Netherlands

 

Manufacturer:

Delpharm L’Aigle

Zone Industrielle N^o1

Route De Crulai

61300 L’Aigle

 

This leaflet was last revised in 07/2021 01/2022

4.1       Therapeutic Indications

 

For the treatment of chronic, severe spasticity resulting from such disorders as stroke, multiple sclerosis, spinal cord injury and cerebral palsy.

 

Dantrium capsules are indicated for the treatment of chronic, severe spasticity of skeletal muscle resulting from disorders such as stroke, spinal cord injury, cerebral palsy and multiple sclerosis in adults and children over the age of 5 years old weighing 25 kg or more.

 

4.2       Posology and method of administration

 

Posology

 

Adults and the elderly

The dosage should be titrated against clinical improvement and increased until the maximum benefit compatible with the patient's neurological deficit is achieved.  The lowest dose compatible with optimal response is recommended.

 

A recommended dosage increment scale is shown below:-

 

Week                     Recommended dosage

First                       One 25 mg capsule daily

Second One 25 mg capsule twice daily

Third                      Two 25 mg capsules twice daily

Fourth  Two 25 mg capsules three times daily

Fifth                       Three 25 mg capsules three times daily

Sixth                      Three 25 mg capsules four times daily

Seventh               One 100 mg capsule four times daily

 

Each dosage level should be maintained for seven days in order to determine the patient's response.  The maximum daily dose should not exceed 400 mg.  In view of the potential for hepatotoxicity in long term use, if no observable benefit is derived from the administration of Dantrium after a total of 45 days, therapy should be discontinued.

 

Many patients experience side-effects such as weakness and fatigue during the first four weeks of therapy whilst they adjust to the changes in muscle tone induced by the drug.  They are usually transient and mild in nature.  Should it be necessary, the dosage may be reduced and then gradually increased according to the patient's tolerance.

 

Paediatric population

 

Week                     Recommended dosage

First                       0.5 mg/kg twice daily

Second 1 mg/kg twice daily

Third                      2 mg/kg twice daily

Fourth  2 mg/kg three times daily

Fifth                       3 mg/kg three times daily

Sixth                      3 mg/kg four times daily

 

The safety of Dantrium in infants under the age of five years has not been established.

 

Method of administration

 

For oral use.

 

Each patient should be slowly titrated to the required individual dose. For the individual patient the lowest dose compatible with optimal response is recommended. A recommended dosage increment scale is shown below.

 

Adults:

 

Dantrium should be titrated no more rapidly than as per the following schedule:

 

Week 1: 25mg daily

Week 2: 25 mg twice daily

Week 3: 50 mg twice daily

Week 4: 50 mg three times daily

 

As soon as the optimal dose is reached, patients should receive their total daily dose divided over 2 to 4 individual doses to achieve as uniform plasma levels as possible and to minimise adverse reactions.

 

Doses higher than 200 mg should not be administered in long-term therapy with Dantrium. Temporarily, the dose can be gradually increased up to 400 mg per day if pressurised or stressful situations are anticipated in the patient.  The increased dose should be titrated as follows:

 

Week 5: 75 mg three times daily

Week 6: 75 mg four times daily

Week 7: 100 mg four times daily

 

However, doses above 200 mg per day should not be given for more than 2 months.

 

Paediatric Population

 

Dosing table for children over 5 years (upwards of 25 kg body weight) For the individual patient the lowest dose compatible with optimal response is recommended. A recommended dosage titration schedule is provided below.

 

Week 1:  1 Dantrium 25 capsule once daily

Week 2:  1 Dantrium 25 capsules twice daily

Week 3   1 Dantrium capsule 3 times daily

Week 4   2 Dantrium capsules twice daily

Week 5   2 Dantrium  capsules 3 times daily

Week 6:  3 Dantrium 25 capsules 3  times daily

 

For children weighing 50 kg or more, see dosage for adults.

The dose can be increased gradually up to 200 mg daily.

 

Dantrium is intended for long-term therapy.

If therapeutic success is still absent after 6-8 weeks of treatment, therapy should be discontinued.

 

As there is insufficient experience with the use of Dantrium in children under 5 years to assess its tolerability, it should not be used in this patient group.

 

Method of administration

 

For oral use.

 

4.3       Contraindications

 

Where spasticity is utilised to sustain upright posture and balance in locomotion, or whenever spasticity is utilised to obtain or maintain increased function.

 

In patients with evidence of hepatic dysfunction.

 

Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

 

Hypersensitivity to the active substance or to any of the excipients listed in 6.1,

- Hepatic disorders,

- Impaired respiratory function

- Severe impaired cardiac function due to myocardial disease

- In cases where abnormally increased tone is required to allow better function, an upright posture or balance during movement.

- Pregnancy and breastfeeding (see section 4.6)

 

 

4.4       Special warnings and precautions for use

 

There are isolated cases of possibly significant effects of Dantrium on cardiovascular and respiratory systems and therefore Dantrium should be used with caution in patients with cardiovascular or respiratory disease.

 

Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with Dantrium therapy.

 

Patients should be instructed to contact their physician should signs or symptoms of hepatotoxicity (e.g., discoloured faeces, generalized pruritus, jaundice, anorexia, nausea, vomiting) occur during therapy. 

 

Factors that may increase the risk of developing hepatotoxicity include:

• Higher daily doses (doses exceeding 400 mg daily)
• Duration of therapy (most frequently reported between 2 and 12 months of treatment)
• Female gender
• Age greater than 30 years
• Prior history of liver disease/dysfunction
• Receiving other hepatotoxic therapies concomitantly

 

Spontaneous reports also suggest a higher proportion of hepatic events with fatal outcome in elderly patients.

 

At the start of Dantrium therapy, liver function tests should be performed in all patients to establish a base-line, and exclude pre-existing liver disease.  These tests should be repeated upon hospital discharge or at six weeks after starting therapy.  Further tests may be carried out at appropriate intervals throughout treatment.  Generally, if these studies reveal abnormal values, therapy should not be commenced or should be discontinued.  In patients with symptoms compatible with hepatitis or where jaundice appears, Dantrium should be discontinued.  If a decision is made to restart treatment after recovery from hepatic dysfunction, liver function should be monitored and the drug discontinued if abnormal values are observed.

 

Dantrium must be used with caution in the following situations:

 

In cases of amyotrophic lateral sclerosis or in the presence of bulbar paralytic symptoms, as paresis can be enhanced by Dantrium.

Patients with cardiac disease, especially in patients with myocardial damage and/or cardiac arrhythmias, must receive particular medical surveillance.

Dantrolene leads to mild to severe liver damage in about 9 out of 100,000 treated patients, in whom mortality affects 10-20%.

The risk of liver damage seems to be particularly increased at daily doses higher than 300 mg, during prolonged therapy, in women, in patients over 30 years of age or with a history of liver damage and during concomitant use of other medicinal products that can damage the liver. Liver damage may run a lethal course, especially in elderly patients. In patients suffering from multiple sclerosis, the risk of serious liver damage seems to be further increased.

Before the start and during therapy with Dantrium, liver enzymes must be monitored at regular intervals; in particular, SGOT and SGPT must be monitored frequently. Patients in whom the risk of liver damage is increased must receive particularly close monitoring. If values are outside the norm or if symptoms of liver damage occur, Dantrium must be discontinued.

There are indications that, when liver damage occurs, high serum bilirubin levels correlate to severe progression.

To reduce the risk of liver damage, the lowest possible effective dantrolene dose must be used.

 

Dantrium can cause photosensitisation; patients should therefore protect themselves against strong sunlight during treatment.

Dantrium must be discontinued if patients have developed pleural or pericardial effusion or pleuropericarditis.

 

Patients with rare hereditary problems of galactose intolerance, the lactase deficiency or glucose-galactose malabsorption should not take Dantrium.

 

At doses above 200 mg dantrolene per day, increased adverse reactions must be anticipated.

 

4.5       Interaction with other medicinal products and other forms of interaction

 

The use of Dantrium with other potentially hepatotoxic drugs should be avoided.  There is also some evidence that hepatic injury is more likely in patients using concomitant oestrogen.

 

Although the primary pharmacological effect of Dantrium is exerted directly on skeletal muscle, caution should be exercised in the concomitant administration of tranquillising agents and alcohol.

 

Diazepam and phenobarbitone do not affect the metabolism of Dantrium.

 

The effects of non-depolarizing muscle relaxants may be potentiated in patients administered Dantrium.

 

Hyperkalemia and myocardial depression have been observed in malignant hyperthermia-susceptible patients receiving intravenous dantrolene and concomitant calcium channel blockers.

 

Concomitant intake of CNS depressants (such as benzodiazepine-type tranquillisers, antihistamines, sedatives) and alcohol consumption should be avoided, as the adverse reactions to Dantrium may be increased (particularly the depressant effect on the central nervous system and muscle weakness).

 

With concomitant administration of:

-oestrogens or other potentially hepatotoxic substances, there is an increased risk of liver damage.

-Dantrium and non-depolarising muscle relaxants (vecuronium), its effect can be enhanced.

-metoclopramide, the rate and speed of dantrolene absorption may be increased and thus lead to an increase in the effect and undesirable effects of dantrolene.

 

In patients predisposed to malignant hyperthermia who were receiving intravenous dantrolene, it was observed that co-administration of calcium antagonists and/or beta-blockers led to hyperkalaemia and heart failure.

 

4.6       Fertility, pregnancy and lactation

 

Pregnancy

Dantrolene crosses the placenta, Although teratological studies in animals have proved satisfactory, the use of Dantrium is not advised in pregnant women

 

Breast-feeding

Dantrolene has been detected in human milk so is not advised in nursing mothers.

 

Fertility

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

 

Pregnancy

There are no or limited amount of data from the use of dantrolene sodium in pregnant women. Dantrolene crosses the placenta and can induce muscle hypotonia, especially in the uterus. Studies in animals are insufficient with respect to reproductive toxicity (see section 5.3). The use of Dantrium during pregnancy is contraindicated.

 

Breastfeeding

Dantrium is contraindicated during breastfeeding, as the active substance, dantrolene, is excreted in human milk and undesirable effects on the breast-fed infant cannot be excluded, particularly during long-term therapy with Dantrium. If treatment of nursing mothers with Dantrium is required, breastfeeding must be discontinued.

 

Fertility

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

 

4.7       Effects on ability to drive and use machines

 

Patients should be advised not to drive a motor vehicle or participate in hazardous occupations because some patients experience drowsiness and dizziness.

 

During oral use of Dantrium, central nervous effects such as drowsiness or confusion can alter responsiveness to such an extent that the ability to drive actively or operate tools and machinery is reduced. This applies particularly at the start of treatment, when increasing the dose and in combination with alcohol or other medicinal products that depress the central nervous system.

 

1. 8. Undesirable effects

 

Other undesirable effects reported commonly (≥1%) or less commonly (≤1%) in post-marketing are:

The frequency terminology ‘Unknown’ is defined as, cannot be established from the available data.

 

Tabulated list of adverse reactions

 

System Organ Class	Frequency	Adverse Drug Reaction
Metabolism and nutrition disorders	Common:	Anorexia
Psychiatric disorders	Common:	Mental depression, mental confusion
Nervous system disorders	Common:	Seizure, visual disturbances, speech disturbance, headache, drowsiness, dizziness
Cardiac disorders	Common:   Less common:           Unknown	Pericarditis   Exacerbation of pre-existing cardiac insufficiency, tachycardia         Bradycardia
Vascular Disorder	Less common	Labile blood pressure
Respiratory, thoracic and mediastinal disorders	Common:       Less common	Pleural effusion with associated eosinophilia, respiratory depression,     Dyspnoea
Gastrointestinal disorders	Common:       Less Common:         Unknown	Nausea and/or vomiting, abdominal pain, diarrhoea (may be severe and may necessitate temporary withdrawal of dantrolene therapy),     Swallowing difficulties, constipation (rarely progressing to signs of intestinal obstruction       Gastrointestinal bleeding
Hepatobiliary disorders	Common:         Less common             Unknown:	Hepatotoxicity (see  section 4.4), liver function test abnormal     Overt hepatitis (occurs at varying intervals after initiation of therapy, most frequently been observed between the 2nd and 12th month of treatment)         Jaundice
Skin and subcutaneous disorders	Common:     Less common:	Acne-like rash, skin eruptions     Sweating
Renal and urinary disorders	Less common:	Incontinence, increased urinary frequency, urinary retention, haematuria, crystalluria
General disorders and administration site conditions	Common:	Chills and/or fever, weakness, fatigue, general malaise

 

Tabulated list of adverse reactions

 

System Organ Class	Frequency	Adverse Drug Reactions
Neoplasms benign, malignant and unspecified (incl 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[
	Uncommon	Hallucination
	Common	Insomnia
	Unknown	Disorientation
Nervous system disorders	Very common	Dizziness
	Very common	Somnolence
	Common	Headache[
	Common	Speech disorder[
	Common	Seizures
	Uncommon	Enhanced paresis in cases of amyotrophic lateral sclerosis or in the presence of bulbar paralytic symptoms
	Uncommon	Dysgeusia
	Unknown	Hypotonia
Eye disorders	Uncommon	Diplopia
	Uncommon	Lacrimation increased
	Common	Visual impairment
	Uncommon	Cardiac failure
	Uncommon	Tachycardia
	Common	Pericarditis
	Uncommon	Pleuropericarditis
	Unknown	Bradycardia
Vascular disorders	Uncommon	Phlebitis
	Uncommon	Blood pressure fluctuation
Respiratory, thoracic and mediastinal disorders	Common	Respiratory depression
	Common	Respiratory failure
	Very rare	Suffocation feeling
	Uncommon	Dyspnoea
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	Abdominal pain upper
	Uncommon	Salivary hypersecretion
	Unknown	Dyspepsia
	Unknown	Dry Mouth
Hepatobiliary disorders	Common	Hepatotoxicity/hepatitis
	Common	Jaundice
	Common	Cholestasis
Skin and subcutaneous tissue disorders	Common	Rash
	Common	Dermatitis acneiform/acne like rash/acne
	Uncommon	Hyperhidrosis
	Uncommon	Hair growth abnormal
	Uncommon	Pruritus
	Uncommon	Photosensitivity reaction
	very rare	Urticaria
	very rare	Eczema
Musculoskeletal and connective tissue disorder	Common	Muscular weakness
	Uncommon	Back pain
	Uncommon	Myalgia
Renal and urinary disorders	Uncommon	Urinary incontinence
	Uncommon	Pollakiuria
	Uncommon	Crystalluria
	Uncommon	Haematuria
	Uncommon	Urinary retention
	Unknown	Nocturia
	very rare	Micturition disorder
	Unknown	Chromaturia
Reproductive system and breast disorders	very rare	Erectile dysfunction
General disorders and administration site conditions	Very common	Fatigue
	Very common	Malaise
	Common	Chills
	Common	Pyrexia
	Very common	Asthenia
Investigations	Common	Liver function tests abnormal

 

In addition, the following specific undesirable effects have been noticed with the use of Dantirum Capsules:

• Precipitation of cerebral seizures, especially in children with cerebral palsy;
• pleuropericarditis and pericardial effusion, (accompanied by eosinophilia)
• pleural effusion (with associated eosinophilia),
• Diarrhoea (may be severe and may necessitate temporary withdrawal of dantrolene therapy).

 

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

 

4.9       Overdose

 

There is no known constellation of symptoms with acute overdose. Symptoms that may occur include, but are not limited to, muscular weakness, alterations in the state of consciousness (e.g. lethargy, coma), vomiting, and diarrhoea. For acute overdosage, general supportive measures should be employed along with immediate gastric lavage. Fluids should be administered in large quantities to avert the theoretical possibility of crystalluria. The value of dialysis in dantrolene overdose is not known.

 

Symptoms which may occur in case of overdose are: muscular weakness, troubling hypotonia vision disorders (diplopia), changes in consciousness (lethargy, coma), fatigue, dizziness, vomiting, diarrhoea tachycardia, hypo- or hypertension, pruritus, adverse hepatotoxic reactions.

 

In case of intoxication, if possible, gastric emptying should be performed and general measures for cardiac support and respiratory assistance should be planned. Dilution solution should be infused intravenously to avert the possibility of crystalluria.

The value of dialysis in dantrolene overdose is not known and there is no specific antidote for dantrolene overdose.

 

5.1      Pharmacodynamic properties

 

Pharmacotherapeutic group ATC code: M03CA01, muscle relaxants, directly acting agents.

 

Mechanism of action

 

Dantrium is classified as a direct-acting skeletal muscle relaxant.  In isolated nerve-muscle preparation, Dantrium has been shown to produce relaxation by affecting the contractile response of the skeletal muscle at a site beyond the myoneural junction, directly on the muscle itself.

 

Pharmacodynamic effects

In skeletal muscle, Dantrium dissociates the excitation-contraction coupling, probably by interfering with the release of Ca++ from the sarcoplasmic  reticulum.
This effect appears to be more pronounced in fast muscle fibres as compared to slow ones, but generally affects both.

 

Clinical efficacy and safety

A central nervous system effect occurs, with drowsiness, dizziness, and generalised weakness occasionally present.  Although Dantrium does not appear to directly affect the CNS, the extent of its indirect effect is unknown.

 

Pharmacotherapeutic group: direct-acting muscle relaxants,  ATC code: M03CA01

Dantrolene decouples nerve stimulation and contraction in skeletal muscle probably by interfering with calcium release from the sarcoplasmic reticulum. Its action is selective and has no influence on neuromuscular transmission or any measurable effect on the excitable surface membrane.

Within the therapeutic dose range, smooth muscle and cardiac muscle are generally not affected by Dantrium. In vitro animal trials have indicated that effects on smooth muscle and heart muscle may occur at doses well above the therapeutic range; however, with conflicting results, so that no definitive statements can be made regarding such effects in humans.

 

5.2       Pharmacokinetic properties

 

Absorption

The absorption of Dantrium after oral administration in humans is incomplete and slow but consistent, and dose-related blood levels are obtained.  The duration and intensity of skeletal muscle relaxation is related to the dosage and blood levels. 

 

Distribution

The mean biologic half-life of Dantrium in adults is 8.7 hours after a 100-mg dose.  Specific metabolic pathways in the degradation and elimination of Dantrium in human subjects have been established.

 

Biotransformation

Metabolic patterns are similar in adults and children.  In addition to the parent compound, dantrolene, which is found in measurable amounts in blood and urine, the major metabolites noted in body fluids are the 5-hydroxy analogue and the acetamido analogue.  Since Dantrium is probably metabolised by hepatic microsomal enzymes, enhancement of its metabolism by other drugs is possible. 

However, neither phenobarbital nor diazepam appears to affect Dantrium metabolism.  Binding to plasma protein is not significantly altered by diazepam, diphenylhydantoin, or phenylbutazone.  Binding to plasma proteins is reduced by warfarin and clofibrate and increased by tolbutamide.

 

Absorption:

The gastrointestinal absorption of dantrolene sodium is approximately 70% and leads to dose-dependent plasma concentrations. After administration of 25 mg dantrolene sodium 3.5•H2O, peak plasma concentrations were reached after 3 4 hours and were 0.22 µg/mL. The absolute bioavailability was 83.6% on average.

 

Distribution:

Dantrolene is reversibly bound to plasma albumin; as an in vitro binding constant, a value of 4.3x10^-4 M^-1 was established. For the transplacental passage of dantrolene, a factor of 0.4 was found.

 

Metabolism:

Metabolism in the liver takes place via 5-hydroxylation at the hydantoin ring, as well as via reduction of the nitro group to the amine with subsequent acetylation.

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

 

Elimination:

Renal clearance (5-OH-dantrolene) is 1.8-7.8 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 h was found.

 

Duration and intensity of skeletal muscle relaxation in patients is dependent on blood levels.

 

5.3          Preclinical safety data

 

Carcinogenicity

 

Dantrolene sodium showed some evidence of tumourgenicity at high dose levels in Sprague-Dawley female rats.  However, these effects were not seen in other studies in Fischer 344 rats or HaM/ICR mice.  There is no clinical evidence of carcinogenicity in humans, however, this possibility cannot be absolutely excluded.

 

Mutagenicity

Dantrolene sodium has produced positive results in a bacterial mutagenesis assay.

 

Reproductive toxicity:

In reproduction toxicity studies in rats, dantrolene sodium showed no adverse effects on fertility or general reproductive performance.

 

Acute toxicity

Non clinical data for intravenous administration are not available.  Following intraperitoneal administration, the LD50 is around 800 mg/kg body weight in rats (human equivalent dose 128 mg/kg) and following oral administration the LD50 is around 3 g/kg in newborn rats (human equivalent dose 480 mg/kg). No LD50 values could be determined following oral administration to adult animals, due to a lack of mortality.

 

With subacute intravenous administration of dantrolene at doses of up to 20 mg/kg/day, the sole observations were reduced body weight gain 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 rats, dogs and monkeys oral administration of >30 mg/kg/day (human equivalent dose 4.8 mg/kg, 16.2 mg/kg and 9.6 mg/kg, respectively) for 12 months led to a reduction of growth or body weight gain. Hepatotoxic effects and possibly renal obstruction were observed, which were reversible.

 

Mutagenicity

Dantrolene yielded positive results in the Ames S. typhimurium test both in the presence and absence of a liver activating system.

 

Carcinogenicity

Dietary doses of dantrolene sodium in rats at doses of up to 60 mg/kg/day (human equivalent dose 9.6 mg/kg) for to 18 months resulted in increases in benign hepatic lymphatic neoplasms, increased hepatic lymphangiomas and hepatic angiosarcomas, and in females only, an increase in mammary tumours.

The relevance of these data for clinical use of dantrolene is not known.

 

Reproductive toxicity

In male and female adult rats dantrolene up to an oral dose of 45 mg/bodyweight/day (human equivalent dose 7.3 mg/kg/day) did not have any adverse effects on fertility or general reproductive capability. Administration of dantrolene to pregnant rats (at 20 mg/kg/day or above; human equivalent dose 3.2 mg/kg/day) and rabbits (45 mg/kg/day; human equivalent dose 14.5 mg/kg/day) led to increased formation of unilateral or bilateral supernumerary ribs in the pups.

 

10.          DATE OF REVISION OF THE TEXT

 

January 2019 July 2021

1.What Dantrium Capsules are and what they are used for

 

Dantrium Capsules are available in two strengths, containing either 25 mg or 100 mg of the active ingredient dantrolene sodium.

 

Dantrolene sodium is a muscle relaxant and Dantrium Capsules are used for the treatment of long-term, severe spasticity which may arise from disorders such as stroke, multiple sclerosis, spinal cord injury and cerebral palsy.

 

Dantrium is a medicine that reduces increased muscle tension.

 

Dantrium is used for spastic movement disorders with abnormally increased muscle tension due to various causes in adults and children over the age of 5 years old weighing 25 kg or more.

 

2. What you need to know before you take DANTRIUM Capsules

 

Do not take Dantrium Capsules if:

 

∙ your muscles have suddenly gone rigid (acute skeletal muscle spasm).

∙ you need extra tension in your muscles to stand up, walk and cope with daily activities.

• you have liver disease

∙ you have been told by your doctor that you are unable to take some sugars such as lactose

• you are allergic to dantrolene sodium or any of the other  ingredients of this medicine ( listed in section 6.)

 

Talk to your doctor or pharmacist before taking Dantrium Capsules if

 

• You have liver, heart or lung problems
• You have any signs of liver damage ( e.g. discoloured faeces, itching, jaundice, weight loss, nausea or vomiting)

 

Some factors may increase the risk of developing liver problems, these include:

• if you are female
• if you are greater than 30 years of age
• if you have a prior history of liver disease or dysfunction

 

if you need to take higher doses of this medicine ( doses exceeding 400mg daily ) or have to take the medicine for prolonged period of time

 

 

Children

 

Children under the age of five years should not be given Dantrium Capsules.

Other medicines and Dantrium Capsules

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines such as :

• medicines that treat your liver
• oestrogen (found in most oral contraceptive pills and hormone replacement therapy)
• tranquillisers
• Medicines used to treat abnormal heartbeat, angina or high blood pressure

 

Dantrium Capsules with food and drink

 

Dantrium Capsules should not be taken with alcohol as they can cause drowsiness.

 

 

Pregnancy, breast-feeding and fertility

 

Do not take Dantrium capsules if  you are pregnant or breast-feeding unless advised otherwise by your doctor.

 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before taking this medicine.

 

Driving and using machines

 

You should not drive or get involved in hazardous activities because some people experience drowsiness, dizziness and weakness when taking Dantrium capsules .

Alcohol  and other depressant drugs may make the drowsiness, dizziness and weakness worse.

 

Dantrium Capsules contain Lactose

 

If you have been told by your doctor that you have an  intolerance to some sugars, speak to your doctor before taking this medicine.

 

The capsule shell of Dantrium 25 mg Capsules contains Sunset Yellow (E110) which may cause allergic reactions

 

Do not take Dantrium

• if you are allergic to dantrolene sodium 3.5 H₂O, or any of the other ingredients of this medicine (listed in section 6),
• if you have liver disease,
• in cases where abnormally increased muscle tension is required to improve function, posture or movement balance,

• if you have impaired lung function,
• if you have severe heart muscle damage,
• if you are pregnant or breast-feeding.

Warnings and precautions
Talk to your doctor or pharmacist before taking Dantrium.

Take special care with Dantrium

• if you suffer from amyotrophic lateral sclerosis (ALS, a disorder of the nervous system), if you have symptoms of bulbar paralysis (symptoms caused by damage to certain cranial nerves), as Dantrium can exacerbate symptoms of paralysis,
• if you have heart disease, particularly heart damage and/or heart arrhythmia. Your doctor will carefully monitor you for heart disease.

Before and during treatment with Dantrium your doctor will carry out regular blood tests to check your liver function. If the values are outside the normal range, treatment with Dantrium must be discontinued.

If you notice any signs that might indicate liver damage, such as unusual fatigue, light stools, itching all over the body, yellowing of the skin or eyes, loss of appetite, nausea and vomiting, you should seek medical attention immediately.

The risk of liver damage appears to be particularly high at daily doses of more than 300 mg, with prolonged treatment, in female patients over 30 years of age, with a history of liver damage and concomitant use of other medicines that can cause liver damage. Liver damage can be life-threatening, especially in the elderly.

If you suffer from multiple sclerosis, the risk of serious liver damage appears to be even higher.

Dantrium may cause the skin to become sensitive to light (photosensitisation), so you should protect yourself from strong sunlight during treatment.

Administration of Dantrium must be discontinued if patients have developed cardiac and pleural reactions with fluid accumulation (pleural or pericardial effusion or pleuropericarditis).

Doses of more than 200 mg dantrolene per day are more likely to cause side effects.

 

Children

Dantrium can be used in children over 5 years of age under supervision from your doctor

Dantrium should not be given to children under 5 years of age as there is insufficient experience with the use of Dantrium in this patient group to determine tolerability.

Other medicines and Dantrium

Tell your doctor or pharmacist if you are taking/using or have recently taken/used any other medicines, even if they are not prescription medications.

If taken at the same time as

• oestrogens (certain hormones) or other potentially liver-damaging substances there is an increased risk of liver damage,
• vecuronium (muscle relaxant drug) its effect can be amplified,
• metoclopramide (a medicine used to treat certain gastrointestinal disorders), the absorption of the active ingredient of Dantrium in the body may be increased, leading to an increase in the effect and side effects of dantrolene.

Simultaneous use of medicines that depress the central nervous system (sedatives, such as benzodiazepines, antihistamines) and alcohol is to be avoided as the side effects of Dantrium may be increased (in particular the central nervous system depressant effect and muscle weakness).

In patients predisposed to malignant hyperthermia (certain complications of anaesthesia) who received intravenous dantrolene, it has been observed that simultaneous administration of calcium antagonists and/or beta-blockers (antihypertensive/heart disease drugs) resulted in elevated potassium levels and cardiac insufficiency.

Dantrium with food and drink

Do not drink alcohol while taking Dantrium.

Pregnancy and breast-feeding

Dantrium should not be used during pregnancy, as the safety of Dantrium for use during pregnancy has not been established.

The active substance of Dantrium passes into breast milk. Dantrium should not be used while breast-feeding, since adverse effects on the breastfed child cannot be excluded, particularly under long-term treatment with Dantrium. Breast-feeding must be discontinued if treatment is required while breast-feeding.

Ask your doctor or pharmacist for advice before taking/using any medicine.

Driving and using machines

You must not drive or operate machinery without consulting your doctor.

When Dantrium or when other medicines that also affect the central nervous system are taken at the same time, central nervous system effects, such as drowsiness or confusion, can change the ability to react to such an extent that it reduces the ability to drive or operate tools and machines. This particularly applies at the start of treatment, when dosage is increased and when taken together with alcohol.

Important information about some of the ingredients of Dantrium

This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

 

3. How to take Dantrium Capsules

 

Always take use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

 

Adults and Elderly:

The dose of Dantrium Capsules varies from one person to another. It is usual to start on one 25 mg capsule a day. If there is no improvement, your doctor may increase your dose every week until the right dose for you is reached. The normal maximum dose is one 100 mg capsule four times a day.

It is important to take the lowest dose which works for you. If there is no improvement after about 45 days, then your medication will be stopped by your doctor.

 

Use in children

Consult your doctor to establish the correct dose of Dantrium Capsules for children.

Children under the age of five years should not be given Dantrium Capsules.

 

Dantrium Capsules are to be taken by mouth. Swallow the capsules with a glass of water.

 

If you take more Dantrium Capsules than you should

 

If you take too much medicine contact your doctor or your nearest hospital emergency department.

 

If you forget to take Dantrium Capsules

If you miss a dose do not take an extra capsule, just continue as normal with the next dose at the correct time.

Do not take a double dose to make up for a forgotten dose.

 

Always take Dantrium exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

 

Your doctor will slowly adjust the number of capsules you take until the optimal dose required for your treatment. The lowest dose compatible with optimal response is recommended.

 

Adults

Unless prescribed otherwise by your doctor, the usual dose for adults at the beginning of treatment is 1 capsule daily. This dose should be increased weekly until the optimal dose is reached.

 

The dose should not be increased faster than as per the following schedule:

Week 1: 1 capsule Dantrium 25 mg daily

Week 2: 1 capsule Dantrium 25 mg 2 x daily

Week 3: 2 capsule Dantrium 25 mg 2 x daily

Week 4: 2 capsule Dantrium 25 mg 3 x daily

Once the optimal dose is reached, the patient should take their total daily dose subdivided between 2 to 4 individual doses.

Doses of more than 200 mg should not be given in long-term Dantrium treatment, as doses of more than 200 mg of dantrolene per day are more likely to result in side effects.

If it is foreseeable that the patient will face stress or stressful situations, the dose can be increased temporarily and gradually up to 400 mg per day. The increased dose should be titrated as follows:

 

 

Week 5: 75 mg three times daily

Week 6: 75 mg four times daily

Week 7: 100 mg four times daily

 

Doses of more than 200 mg per day should not be given for more than 2 months.

 

Children

Unless prescribed otherwise by your doctor, the following dosage should be used for children aged 5 years and older (from 25 kg body weight):

 

Week 1: 1 Dantrium 25 capsule once daily

Week 2: 1 Dantrium 25 capsules twice daily

Week 3: 1 Dantrium 25 capsule  3 times daily

Week 4: 2 Dantrium 25 capsules twice daily

Week 5: 2 Dantrium  25 capsules 3 times daily

Week 6: 3 Dantrium 25 capsules 3  times daily

 

Children weighing  50 kg or more:

See dosage for adults.

The dose can be gradually increased up to 200 mg daily.

Please take the capsules whole with plenty of liquid (preferably with a glass of water).

If no improvement is achieved after a total of 6-8 weeks, treatment should be discontinued by the doctor.

Please talk to your doctor or pharmacist if you feel that the effect of Dantrium is too strong or too weak.

If you take more Dantrium than you should

Tell your doctor immediately. He or she will take the necessary measures. Signs of overdose may include disorders of consciousness (e.g. lethargy, coma), muscle weakness, fatigue, dizziness, weakness, impaired vision, rapid heartbeat, itching, loss of appetite, nausea, vomiting, diarrhoea, light stools, yellowing of the skin or eyes.

If you forget to take Dantrium

Do not take a double dose to make up for an omitted dose. Take the same number of capsules as prescribed, when your next dose is due. If you are unsure what to do, please talk to your doctor.

If you stop taking Dantrium

If you temporarily want to stop treatment or stop it early, e.g. because the side effects appear too severe, please talk to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

 

4. Possible side effects

 

Like all medicines, this medicine can cause side effects although not everybody gets them

 

Minor side effects are sometimes seen for the first four weeks as the body gets used to the effect of Dantrium.

 

You may suffer an allergic reaction, symptoms of which include rash, itching, difficulty in breathing or swelling of the face, lips, throat or tongue. If this happens to you, stop taking the capsules immediately and seek urgent medical attention.

 

Immediately inform your health care provider if you have discoloured stool, generalised itch, yellowing of skin and eyes, loss of appetite, feeling sick, abnormal blood tests, as this may be signs of a serious liver disorder.

 

Common side effects include :

effects on the central nervous system such as depression and confusion,

abnormal weight loss ( anorexia ),

skin rashes, acne,

allergic-type reactions including asthma which may be caused by the colouring agent Sunset Yellow E110 (Dantrium 25mg Capsules only); this is more common in people who are allergic to aspirin.

seizures,

speech problems,

visual problems,

headache,

drowsiness,

dizziness

inflammation of the membrane around the heart (pericarditis),

difficulty in breathing,

fluid in the lungs,

abdominal pain,

 

nausea (feeling sick) and vomiting (being sick),

liver toxicity (signs may include generalised itching, yellowing of skin and eyes, loss of appetite), problems with liver function (abnormal blood tests)

fever and or chills,

weakness

feeling generally unwell,

fatigue, 

 

Less common side effects include:

swallowing difficulties,

heart problems,

constipation,

shortness of breath,

sweating,

unstable blood pressure,

blood in the urine,

crystals in the urine,

increased urination,

difficulty in passing urine,

difficulty in controlling the bladder (incontinence).

fast heartbeat,

 

Unknown side effects include:

slow heartbeat,

bleeding in the gut,

yellowing of the skin,

 

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The frequencies for the following list of adverse drug reactions are based on estimates after reports of adverse drug reactions to the approved drug.

Very common (may affect more than 1 in 10 people): Fatigue, weakness, malaise, dizziness, drowsiness and diarrhoea. In persistent diarrhoea, the medicinal product must be discontinued.

Common (may affect up to 1 in 10 people): In patients treated with Dantrium, the following occurred: Headache, speech disorders, seizures, loss of appetite, impaired vision, abdominal cramps, nausea, vomiting, skin rashes, acne-like skin reactions, muscle weakness, which may cause functional impairment and coordination disorders, chills, fever, depression, confusion, nervousness, insomnia, respiratory failure, Abnormal liver function test, liver damage: Even daily doses of up to 200 mg can cause liver-damaging side effects, usually as inflammation of the liver with jaundice.

Uncommon (may affect up to 1 in 100 people): In patients treated with Dantrium, the following occurred: Reduction of red blood cells due to impaired or lack of production (aplastic anaemia), reduction of white blood cells (leukopaenia), lymph node cancer (lymphocytic lymphoma), thrombocytopaenia, allergic reaction, acute allergic reaction (anaphylaxis) hallucinations, triggering of cerebral seizures, particularly in children with cerebral palsy; aggravation of paralysis in amyotrophic lateral sclerosis (ALS, a disorder of the nervous system) or presence of symptoms of bulbar paralysis (symptoms caused by damage to certain cranial nerves). Double vision, increased tear-flow, increased heart rate, insufficient cardiac output (heart failure); phlebitis, fluctuations in blood pressure, constipation, in rare cases including intestinal obstruction; difficulty swallowing, taste disorders, shortness of breath, bleeding in the gastrointestinal tract, abdominal pain, increased salivation.

Increased sweating, abnormal hair growth, itching, photosensitivity, muscle and back pain, excretion of crystals or red blood cells in the urine (crystalluria, haematuria), involuntary urinary incontinence, urinary retention or increased urinary frequency, Cardiac and pleural reactions with fluid accumulation (pleural or pericardial effusion or pleuropericarditis), accompanied by eosinophilia (proliferation of certain cells in the blood) has been reported, as well as respiratory disorders, presumably due to weakening of the respiratory muscles.

Very Rare

Feeling of suffocation, skin rash with red swollen bumps, eczema, Micturition disorder, Erectile dysfunction.

Not known (frequency cannot be estimated from the available data):

Decreased heart rate, disorientation. Reduced muscle tone, dry mouth, nocturnal urination (nocturia), discoloured urine, indigestion.

 

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

 

6. Contents of the pack and other information

 

This leaflet was last revised in 11/2020 07/2021

 

The following changes have been made:

 

QRD updates throughout the SPC

 

Section 4.8 has been tabulated in line with QRD and additional ADRs have been listed as unknown

 

Revision date

The following changes have been made:

 

QRD updates throughout the SPC

 

Section 4.8 has been tabulated in line with QRD and additional ADRs have been listed as unknown

 

Revision date

2.            QUALITATIVE AND QUANTITATIVE COMPOSITION

Dantrium capsules 100 mg Capsules contains 100 mg dantrolene sodium per capsules capsule.

Excipients: Contains Lactose Monohydrate 189.0 mg and Sunset Yellow (E110).

For a full list of excipients, see section 6.1.

 

3.        PHARMACEUTICAL form

Capsule, hard

Dantrium capsules are presented in orange/light brown hard capsules. The 100 mg capsule carries the monogram ‘Dantrium 100 mg’ on the cap and ‘0149’, ‘0033’ and triple coding bars on the body. white/green hard capsules.

 

4.2      Posology and method of administration

Each dosage level should be maintained for seven days in order to determine the patient's response. The maximum daily dose should not exceed 400 mg. In view of the potential for hepatoxicity hepatotoxicity in long term use, if no observable benefit is derived from the administration of Dantrium after a total of 45 days, therapy should be discontinued.

4.4         Special warnings and precautions for use

At the start of Dantrium therapy, liver function tests should be performed in all patients to establish a base-line, and exclude pre-existing liver disease. These tests should be repeated upon hospital discharge or at 6 six weeks after staring starting therapy. Further tests should may be carried out at appropriate intervals throughout treatment. Generally, if these studies reveal abnormal values, therapy should not be commenced or should be discontinued. In patients with symptoms compatible with hepatitis or where jaundice appears, Dantrium should be discontinued. If a decision is made to restart treatment after recovery from hepatic dysfunction, liver function should be monitored and the drug discontinued if abnormal values are observed.

4.5         Interaction with other medicinal products and other forms of interaction

 

The effects of non-depolarizing muscle relaxants may be potentiated in patients administered Dantrium. Hyperkalemia and myocardial depression have been observed in malignant hyperthermia-susceptible patients receiving intravenous dantrolene sodium and concomitant calcium channel blockers.

4.6      Pregnancy Fertility, pregnancy and lactation

Dantrolene sodium crosses the placenta, and has been detected in human milk. Although teratological studies in animals have proved satisfactory, the use of Dantrium is not advised in pregnant or nursing mothers.

 

4.8 Undesirable effects

 

Nervous system disorders:

Common: Seizure, visual disturbances, speech disturbance, headache

 

 

VasularVascular disorders:

Less common: Labile blood pressure

The colouring agent E110 can cause allergic-type reactions including asthma. Allergy is more common in those people who are allergic to aspirin.

5.2      Pharmacokinetic properties

The absorption of Dantrium after oral administration in humans in is incomplete and slow but consistent, and dose-related blood levels are obtained. The duration and intensity of skeletal muscle relaxation is related to the dosage and blood levels. The mean biologic half-life of Dantrium in adults is 8.7 hours after a 100-mg dose. Specific metabolic pathways in the degradation and elimination of Dantrium in human subjects have been established.

 

 

6.1    List of excipients

 

Capsule Fill:Maize starch

Talc

Magnesium Stearate

Lactose monohydrate Monohydrate

 

Capsule Shell:

 

Sunset Yellow (E110)

Gelatin

Indigo Carmine (E132)

Titanium Dioxide (E171)

Iron Oxide (E172)

Edible Black Ink (Shellac, Iron Oxide E172).

 

 

6.5         Nature and contents of container

 

Dantrium 100 mg Capsules are supplied in polypropylene or  polyethylene containers of 100 capsules, with a polyethylene screw cap and packaged in an outer carton.

 

7.        MARKETING AUTHORISATION HOLDER

 

SpePharm Holding Norgine B.V.

Kingsfordweg 1511043 GR Hogehilweg 7

1101CA  Amsterdam ZO

The Netherlands

 

8.        MARKETING AUTHORISATION NUMBER(S)

 

PA 1556/1/2 1336/004/002

 

 

10.      DATE OF REVISION OF THE TEXT

 

July 2010 September 2014

 

2.            QUALITATIVE AND QUANTITATIVE COMPOSITION

Dantrium capsules 100 mg Capsules contains 100 mg dantrolene sodium per capsules capsule.

Excipients: Contains Lactose Monohydrate 189.0 mg and Sunset Yellow (E110).

For a full list of excipients, see section 6.1.

 

3.        PHARMACEUTICAL form

Capsule, hard

Dantrium capsules are presented in orange/light brown hard capsules. The 100 mg capsule carries the monogram ‘Dantrium 100 mg’ on the cap and ‘0149’, ‘0033’ and triple coding bars on the body. white/green hard capsules.

 

4.2      Posology and method of administration

Each dosage level should be maintained for seven days in order to determine the patient's response. The maximum daily dose should not exceed 400 mg. In view of the potential for hepatoxicity hepatotoxicity in long term use, if no observable benefit is derived from the administration of Dantrium after a total of 45 days, therapy should be discontinued.

4.4         Special warnings and precautions for use

At the start of Dantrium therapy, liver function tests should be performed in all patients to establish a base-line, and exclude pre-existing liver disease. These tests should be repeated upon hospital discharge or at 6 six weeks after staring starting therapy. Further tests should may be carried out at appropriate intervals throughout treatment. Generally, if these studies reveal abnormal values, therapy should not be commenced or should be discontinued. In patients with symptoms compatible with hepatitis or where jaundice appears, Dantrium should be discontinued. If a decision is made to restart treatment after recovery from hepatic dysfunction, liver function should be monitored and the drug discontinued if abnormal values are observed.

4.5         Interaction with other medicinal products and other forms of interaction

 

The effects of non-depolarizing muscle relaxants may be potentiated in patients administered Dantrium. Hyperkalemia and myocardial depression have been observed in malignant hyperthermia-susceptible patients receiving intravenous dantrolene sodium and concomitant calcium channel blockers.

4.6      Pregnancy Fertility, pregnancy and lactation

Dantrolene sodium crosses the placenta, and has been detected in human milk. Although teratological studies in animals have proved satisfactory, the use of Dantrium is not advised in pregnant or nursing mothers.

 

4.8 Undesirable effects

 

Nervous system disorders:

Common: Seizure, visual disturbances, speech disturbance, headache

 

 

VasularVascular disorders:

Less common: Labile blood pressure

The colouring agent E110 can cause allergic-type reactions including asthma. Allergy is more common in those people who are allergic to aspirin.

5.2      Pharmacokinetic properties

The absorption of Dantrium after oral administration in humans in is incomplete and slow but consistent, and dose-related blood levels are obtained. The duration and intensity of skeletal muscle relaxation is related to the dosage and blood levels. The mean biologic half-life of Dantrium in adults is 8.7 hours after a 100-mg dose. Specific metabolic pathways in the degradation and elimination of Dantrium in human subjects have been established.

 

 

6.1    List of excipients

 

Capsule Fill:Maize starch

Talc

Magnesium Stearate

Lactose monohydrate Monohydrate

 

Capsule Shell:

 

Sunset Yellow (E110)

Gelatin

Indigo Carmine (E132)

Titanium Dioxide (E171)

Iron Oxide (E172)

Edible Black Ink (Shellac, Iron Oxide E172).

 

 

6.5         Nature and contents of container

 

Dantrium 100 mg Capsules are supplied in polypropylene or  polyethylene containers of 100 capsules, with a polyethylene screw cap and packaged in an outer carton.

 

7.        MARKETING AUTHORISATION HOLDER

 

SpePharm Holding Norgine B.V.

Kingsfordweg 1511043 GR Hogehilweg 7

1101CA  Amsterdam ZO

The Netherlands

 

8.        MARKETING AUTHORISATION NUMBER(S)

 

PA 1556/1/2 1336/004/002

 

 

10.      DATE OF REVISION OF THE TEXT

 

July 2010 September 2014

 

4.4     Special warnings and precautions for use

 

There are isolated cases of possibly significant effects of Dantrium on cardiovascular and respiratory systems and therefore Dantrium should be used with caution in patients with cardiovascular or respiratory disease.

 

Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with Dantrium therapy.

 

Patients should be instructed to contact their physician should signs or symptoms of hepatotoxicity (e.g., discoloured faeces, generalized pruritus, jaundice, anorexia, nausea, vomiting) occur during therapy. 

 

Factors that may increase the risk of developing hepatotoxicity include:

-                 Higher daily doses (doses exceeding 400 mg daily)

-                 Duration of therapy (most frequently reported between 2 and 12 months of treatment)

-                 Female gender

-                 Age greater than 30 years

-                 Prior history of liver disease/dysfunction

-                 Receiving other hepatotoxic therapies concomitantly

 

Spontaneous reports also suggest a higher proportion of hepatic events with fatal outcome in elderly patients.

 

At the start of Dantrium therapy, liver function tests should be performed in all patients to establish a base-line, and exclude pre-existing liver disease.  These tests should be repeated upon hospital discharge or at 6 weeks after staring therapy.  Further tests should be carried out at appropriate intervals throughout treatment.  Generally, if these studies reveal abnormal values, therapy should not be commenced or should be discontinued.  In patients with symptoms compatible with hepatitis or where jaundice appears, Dantrium should be discontinued.  If a decision is made to restart treatment after recovery from hepatic dysfunction, liver function should be monitored and the drug discontinued if abnormal values are observed.

 

Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

6.1     List of excipients

 

Maize starch

Talc

Magnesium Stearate

Lactose monohydrate

Capsule shell

Sunset Yellow (E110)

Gelatin

Titanium Dioxide (E171)

Iron Oxide (E172)

Edible Black Ink (Shellac, Iron Oxide E172).

6.5         Nature and contents of container

 

Dantrium 100 mg Capsules are supplied in polypropylene or polyethylene containers of 100 capsules.

7.       MARKETING AUTHORISATION HOLDER

 

SpePharm Holding B.V.

Kingsfordweg 151

1043 GR Amsterdam

The Netherlands

 

 

8.       MARKETING AUTHORISATION NUMBER(S)

 

PA 1556/1/2

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 19 March 1975.

 

Date of last renewal: 19 March 2010.

 

 

10.     DATE OF REVISION OF THE TEXT

 

July 2010

4.4     Special warnings and precautions for use

 

There are isolated cases of possibly significant effects of Dantrium on cardiovascular and respiratory systems and therefore Dantrium should be used with caution in patients with cardiovascular or respiratory disease.

 

Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may occur with Dantrium therapy.

 

Patients should be instructed to contact their physician should signs or symptoms of hepatotoxicity (e.g., discoloured faeces, generalized pruritus, jaundice, anorexia, nausea, vomiting) occur during therapy. 

 

Factors that may increase the risk of developing hepatotoxicity include:

-                 Higher daily doses (doses exceeding 400 mg daily)

-                 Duration of therapy (most frequently reported between 2 and 12 months of treatment)

-                 Female gender

-                 Age greater than 30 years

-                 Prior history of liver disease/dysfunction

-                 Receiving other hepatotoxic therapies concomitantly

 

Spontaneous reports also suggest a higher proportion of hepatic events with fatal outcome in elderly patients.

 

At the start of Dantrium therapy, liver function tests should be performed in all patients to establish a base-line, and exclude pre-existing liver disease.  These tests should be repeated upon hospital discharge or at 6 weeks after staring therapy.  Further tests should be carried out at appropriate intervals throughout treatment.  Generally, if these studies reveal abnormal values, therapy should not be commenced or should be discontinued.  In patients with symptoms compatible with hepatitis or where jaundice appears, Dantrium should be discontinued.  If a decision is made to restart treatment after recovery from hepatic dysfunction, liver function should be monitored and the drug discontinued if abnormal values are observed.

 

Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

6.1     List of excipients

 

Maize starch

Talc

Magnesium Stearate

Lactose monohydrate

Capsule shell

Sunset Yellow (E110)

Gelatin

Titanium Dioxide (E171)

Iron Oxide (E172)

Edible Black Ink (Shellac, Iron Oxide E172).

6.5         Nature and contents of container

 

Dantrium 100 mg Capsules are supplied in polypropylene or polyethylene containers of 100 capsules.

7.       MARKETING AUTHORISATION HOLDER

 

SpePharm Holding B.V.

Kingsfordweg 151

1043 GR Amsterdam

The Netherlands

 

 

8.       MARKETING AUTHORISATION NUMBER(S)

 

PA 1556/1/2

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation: 19 March 1975.

 

Date of last renewal: 19 March 2010.

 

 

10.     DATE OF REVISION OF THE TEXT

 

July 2010