Section 4.4 updated with the following text:
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., discolored feces, 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, it is desirable to do liver function studies (SGOT/ALT, SGPT/AST, 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.
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.
Caution should be exercised in the simultaneous administration of tranquillising agents and alcohol.
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The colouring agent E110 can cause allergic-type reactions including asthma. Allergy is more common in those people who are allergic to aspirin.
Section 4.5 updated with the following text:
Hyperkalemia and myocardial depression have been observed in malignant hyperthermia-susceptible patients receiving intravenous dantrolene and concomitant calcium channel blockers
The effects of non-depolarizing muscle relaxants may be potentiated in patients administered Dantrium.
Section 4.6 updated with the following text:
Dantrolene 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.
Section 4.8 updated with the following text:
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.
Other undesirable effects reported by > 1% or < 1% in post-marketing adverse drug reaction reports are:
Metabolism and nutrition disorders:
> 1%: Anorexia
Psychiatric disorders:
< 1%: Mental depression, mental confusion, nervousness, insomnia
Nervous system disorders:
> 1%: Seizure, visual disturbances, speech disturbance, headache
Cardiac disorders:
> 1%: Pericarditis
< 1%: Exacerbation of cardiac insufficiency, tachycardia
Vascular disorders:
< 1%: Labile blood pressure
Respiratory, thoracic and mediastinal disorders:
> 1%: Pleural effusion with associated eosinophilia, respiratory depression
< 1%: Dyspnoea
Gastrointestinal disorders:
> 1%: Nausea and/or vomiting, abdominal pain
<1%: Dysphagia, constipation (rarely progressing to signs of intestinal obstruction)
Hepato-biliary disorders:
> 1%: Hepatotoxicity (see section 4.4), liver function test disturbances
Skin and subcutaneous tissue disorders:
> 1%: Acne-like rash, skin rash
< 1%: Sweating
Renal and urinary disorders:
<1%: Incontinence, increased urinary frequency, urinary retention, haematuria, crystalluria
General disorders and administration site conditions:
> 1%: Chills and /or fever
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.
Section 4.9 updated with the following text:
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.
Section 10 updated with the following text:
30/09/2008
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