DANTRIUM CAPSULES 25 MG - summary of medicine characteristics

Dantrium Capsules 25mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 25 mg dantrolene sodium.

Excipient with known effect: lactose monohydrate and wheat starch..

For a full list of excipients, see section 6.1.

Hard capsule for oral use

DANTRIUM capsules 25 mg are presented as light brown orange capsules

4.1 Therapeutic indications

Dantrium Capsules are indicated for the treatment of chronic, severe spasticity of skeletal muscle in adults.

4.2 Posology and method of administration

Posology

Dosage for Use in Spasticity for Adults

For the individual patient the lowest dose compatible with optimal response is recommended. A recommended dosage increment scale is shown below:

1st week One 25 mg capsule daily

Each dosage level should be maintained for seven days in order to determine the patient's response. Therapy with a dose four times daily may offer maximum benefit to some patients. Maximum daily dose should not exceed 400 mg. In view of the potential for hepatotoxicity with long term use, if no observable benefit is derived from the administration of Dantrium after a total of 6–8 weeks, therapy should be discontinued.

Elderly

A similar dosage titration schedule should be used with the elderly.

Paediatric population

Dantrium is not recommended for use in children.

Method of administration

For oral use.

4.3 Contraindications

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)

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

4.4 Special warnings and precautions for use

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.

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.

4.5 Interaction with other medicinal products and other forms of interaction

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

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

4.6 Fertility, pregnancy and lactation

Pregnancy

Although teratological studies in animals have proved satisfactory, Dantrolene sodium does cross the placenta and therefore the use of Dantrium is not advised during pregnancy.

Breast-feeding

Dantrolene sodium has been detected in human milk. Therefore, the use of Dantrium is not advised in nursing mothers.

Fertility

There is no data on the effects of Dantrium on human fertility.

4.7 Effects on ability to drive and use machines

Patients should be advised not to drive a motor vehicle or undertake potentially dangerous work until dantrium therapy has been stabilised, because some patients experience drowsiness and dizziness.

4.8 Undesirable effectsSummary of the safety profile

The most frequently reported unwanted effects associated with the use of Dantrium have been drowsiness, dizziness, weakness, general malaise, fatigue and diarrhoea. These effects are generally transient, occur early in treatment, and can often be obviated by careful determination and regulation of the dosage. Diarrhoea may be severe, and may necessitate temporary withdrawal of Dantrium. If diarrhoea recurs upon re-introduction of Dantrium, then Dantrium therapy should probably be withdrawn permanently.

Dantrium has a potential for hepatotoxicity. Symptomatic hepatitis (fatal and non-fatal) has been reported at various dose levels although the incidence is greater in patients taking more than 400 mg/day. Liver dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme elevation) has been observed in patients exposed to Dantrium for varying periods of time.

Overt hepatitis has occurred at varying intervals after initiation of therapy, but has most frequently been observed between the second and twelfth month of treatment. The risk of hepatic injury appears to be greater in females, in patients over 30 years old and in patients taking concomitant medication. There is some evidence that hepatic injury is more likely in patients using concomitant oral oestrogen.

Tabulated list of adverse reactions

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 Yellow Card Scheme Website:

www.mhra.gov.uk/y­ellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 and gastric lavage should be employed as well as measures to reduce the absorption of Dantrium. The theoretical possibility of crystalluria in overdose has not been reported for Dantrium, but would be treated according to general principles, including administration of fluids. The value of dialysis in dantrolene overdose is not known.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Muscle relaxants, directly acting agents, ATC code: M03CA01

The receptor molecule for dantrolene sodium has not been identified. Radiolabelled dantrolene sodium binds to specific components of the striated muscle cell, namely the t-tubules and the sarcoplasmic reticulum; however the kinetics of binding varies between these two organelles. The binding of ryanodine is thought to compete with the binding of calcium in these organelles; further evidence for the specificity of binding is that dantrolene sodium inhibits the binding of the insecticide ryanodine to heavy sarcoplasmic reticulum vesicles from rabbit skeletal muscle. Under some conditions, dantrolene sodium will lower intra-sarcoplasmic calcium concentrations in the resting state. This may be more important in diseased muscle (e.g. in malignant hyperthermia in humans and swine stress syndrome) than in muscle with normal function.

Dantrolene sodium does not bind to the same sites as calcium channel blocking drugs such as nitrendipine or calmodulin. There is no electrophysio­logical evidence that dantrolene sodium interferes with the influx of calcium from outside the cell. This may be one reason why paralysis by dantrolene sodium has never been reported in animals or man; the muscle cell has alternative sources of calcium which are not influenced by dantrolene sodium.

Whatever the molecular mechanism, the cardinal property of dantrolene sodium is that it lowers intracellular calcium concentration in skeletal muscle. Calcium concentrations may be lower in both the quiescent state, and as a result of a reduction in the release of calcium form the sarcoplasmic reticulum in response to a standard stimulus. This effect has been observed in striated muscle fibres from several species, and is not seen in myocardium. Fast fibres may be more sensitive than slow fibres to the action of dantrolene sodium.

Diverse other properties of dantrolene sodium have been observed in-vitro, and in animal studies. Dantrolene sodium may inhibit the release of calcium from the smooth endoplasmic reticulum of smooth muscle, but the significance of this observation is questionable; for example, dantrolene sodium has no effect on isolated human urinary bladder smooth muscle. Calcium dependent, pre-synaptic neurotransmitter release may also be inhibited by dantrolene sodium. Again, the clinical significance of this has not been demonstrated.

Elevation of intracellular, free calcium ion concentration is an obligatory step in excitation-contraction coupling of skeletal muscle. Dantrolene sodium, therefore, acts as a muscle relaxant by a peripheral mechanism which is quite different, and easily distinguishable from neuromuscular junction blocking drugs. In contrast with compounds that relax skeletal muscle by acting principally on the central nervous system, dantrolene sodium acts directly on skeletal muscle cells. In rabbit atria, dantrolene sodium has no effect alone, but it may antagonise inotropic agents which act by increasing intramyocardial cell calcium e.g. the experimental drug anthopleurin-A.

5.2 Pharmacokinetic properties

Absorption

Dantrolene sodium is easily and almost completely absorbed from the gastrointestinal tract. After dosing on an empty stomach, plasma dantrolene sodium levels peak within three hours in most subjects.

Distribution

Dantrolene sodium is a highly lipophobic drug. In addition it lacks hydrophilicity. Dantrolene sodium binds to human serum albumin (HSA) with a molar ratio of 0.95 to 1.68 in-vitro. The association constant in-vitro is higher (2.3 to 5.4 × 10 –5 per mol). In-vitro dantrolene sodium can be displaced from HSA by warfarin, clofibrate and tolbutamide but these interactions have not been confirmed in humans (re. manufacturer's da­tabase). Single intravenous dose studies suggest that the primary volume of distribution is about 15 litres. Single oral doses achieve peak plasma concentration of about a quarter of that for a similarly sized intravenous dose.

Metabolism and Elimination

The biological half life in plasma in most human subjects is between 5 and 9 hours, although half lives as long as 12.1 □ 1.9 hours have been reported after a single intravenous dose. Inactivation is by hepatic metabolism in the first instance. There are two alternative pathways. Most of the drug is hydroxylated to 5-hydroxy-dantrolene. The minor pathway involves nitro-reduction to amino-dantrolene which is then acetylated (compound F-490). The 5-hydroxy metabolite is a muscle relaxant with nearly the same potency as the parent molecule, and may have a longer half life than the parent compound. Compound F-490 is much less potent and is probably inactive at the concentrations achieved in clinical samples. Metabolites are subsequently excreted in the urine in the ratio of 79 5-hydroxy-dantrolene: 17 compound F-490: 4 unaltered dantrolene (salt or free acid). The proportion of drug excreted in the faeces depends upon dose size.

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.

Sprague-Dawley female rats fed dantrolene sodium for 18 months at dosage levels of 15, 30 and 60 mg/kg/day showed an increased incidence of benign and malignant mammary tumours compared with concurrent controls. At the highest dose level, there was an increase in the incidence of benign hepatic lymphatic neoplasms. In a 30-month study at the same dose levels also in Sprague-Dawley rats, dantrolene sodium produced a decrease in the time of onset of mammary neoplasms. Female rats at the highest dose level showed an increased incidence of hepatic lymphangiomas and hepatic angiosarcomas.

The only drug-related effect seen in a 30-month study in Fischer-344 rats was a dose-related reduction in the time of onset of mammary and testicular tumours. A 24-month study in HaM/ICR mice revealed no evidence of carcinogenic activity.

The significance of carcinogenicity data relative to use of dantrolene sodium in humans is unknown.

Mutagenicity

Dantrolene sodium has produced positive results in the Ames S.Typhimurium bacterial mutagenesis assay in the presence and absence of a liver activating system.

Reproductive toxicity

Dantrolene sodium administered to male and female rats at dose levels up to 45 mg/kg/day showed no adverse effects on fertility or general reproductive performance.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose Monohydrate

Wheat starch

Talc

Magnesium stearate

Capsule Shell

Gelatin

Erythrosine (E127)

Iron Oxide

Titanium dioxide (E171)

6.2 Incompatibilities

None.

6.3 Shelf life

Three years.

6.4 Special precautions for storage

Store capsules in the blister and outer packaging away from light and moisture

6.5 Nature and contents of container

PVC/Aluminium Blister. 100 Capsules

6.6 Special precautions for disposal

A patient leaflet is provided for details of use and handling of the product.

7 MARKETING AUTHORISATION HOLDER

Norgine Pharmaceuticals Limited

Norgine House

Widewater Place

Moorhall Road

Harefield

Uxbridge

UB9 6NS UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 20011/0032