DANTRIUM Capsules Ref.[8167] Active ingredients: Dantrolene

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, generalised 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, it is desirable to do liver function studies (SGOT/AST, SGPT/ALT, alkaline phosphatase, total bilirubin) for a baseline or to establish whether there is pre-existing liver disease. If baseline liver abnormalities exist and are confirmed, there is a clear possibility that the potential for Dantrium hepatotoxicity could be enhanced, although such a possibility has not yet been established.

Liver functions studies (e.g. serum, SGOT/AST, SGPT/ALT) should be performed at appropriate intervals during Dantrium therapy. If such studies reveal abnormal values, therapy should generally be discontinued. Only where benefits of the drug have been of major importance to the patient, should re-introduction or continuation of therapy be considered. Some patients have revealed a return to normal laboratory values in the face of continued therapy while others have not.

If symptoms compatible with hepatitis, accompanied by abnormalities in liver function tests or jaundice appear, Dantrium should be discontinued. If caused by Dantrium and detected early, the abnormalities in liver function have reverted to normal when the drug was discontinued.

Dantrium has been re-introduced in a few patients who have developed clinical signs, or elevated serum enzymes, of hepatocellular injury.

Re-introduction of Dantrium therapy should only be contemplated in patients who clearly need the drug, and only after complete reversal of the signs of hepatotoxicity and liver function tests. Patients being re-challenged with Dantrium should be hospital in-patients, and small, gradually increasing doses should be used. Laboratory test monitoring should be frequent, and the drug should be withdrawn immediately if there is any indication of recurrent liver abnormality. Some patients have reacted with unmistakable signs of liver abnormality upon administration of a challenge dose, whilst others have not.

The use of Dantrium with other potentially hepatotoxic drugs should be avoided.

There are isolated cases of possibly significant effects of Dantrium on the cardiovascular and respiratory systems. These cases also have other features suggesting a pre-disposition to cardiovascular disease, and impaired respiratory function, particularly obstructive pulmonary disease. Dantrium should be used with caution in such patients.

Caution should be exercised in the simultaneous administration of tranquillising agents and alcohol.

This medicine contains lactose.

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

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.

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.

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.

Summary 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

Metabolism and nutrition disorders

Common: Anorexia

Psychiatric disorders

Common: Mental depression, mental confusion, insomnia, nervousness

Nervous system disorders

Common: Seizure, visuale disturbances, speech disturbances, headache

Cardiac disorders

Common: Pericarditis

Uncommon: Exacerbation of pre-existing cardiac insufficiency

Unknown: Bradycardia, tachycardia

Vascular disorders

Unknown: Labile blood pressure

Respiratory, thoracic and mediastinal disorders

Common: Pleural effusion with associated eosinophilia, respiratory depression

Unknown: Dyspnoea

Gastrointestinal disorders

Common: Nausea and/or vomiting, abdominal pain

Uncommon: Dysphagia, constipation (rarely progressing to signs of intestinal obstruction)

Unknown: Gastrointestinal bleeding

Hepatobiliary disorders

Common: Hepatotoxicity (see section 4.4), liver function test disturbances

Unknown: Jaundice, hepatitis

Skin and subcutaneous disorders

Common: Acne-like rash, skin rash

Uncommon: Sweating

Renal and urinary disorders

Uncommon: Incontinence, increased urinary frequency, urinary retention, haematuria, crystalluria

General disorders and administration site conditions

Common: Chills and /or fever

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.

Not applicable.