Dantrium

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Dantrolene sodium hemiheptahydrate 50 mg
Available from:
Pfizer New Zealand Limited
INN (International Name):
Dantrolene sodium hemiheptahydrate 50 mg
Dosage:
50 mg
Pharmaceutical form:
Capsule
Composition:
Active: Dantrolene sodium hemiheptahydrate 50 mg
Units in package:
Unknown,
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Procter & Gamble Pharmaceuticals Inc
Product summary:
Package - Contents - Shelf Life: Unknown, -   - 36 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-2558a
Authorization date:
1976-09-08

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NEW ZEALAND DATA SHEET

PRODUCT NAME

DANTRIUM

Capsule, 25 mg

DANTRIUM

Capsule, 50 mg

QUALITATIVE AND QUANTITATIVE COMPOSITION

DANTRIUM Capsule 25 mg contains 25 mg dantrolene sodium hemiheptahydrate

DANTRIUM Capsule 50 mg contains 50 mg dantrolene sodium hemiheptahydrate

Dantrolene sodium is1-{[5-(p-nitrophenyl) furfurylidene]amino} hydantoin sodium hydrate.

The anhydrous salt has a molecular weight of 336. The hydrated salt contains approximately

15% water (3 1/2 moles) and has a molecular weight of 399.

Excipient(s) with known effect

Lactose monohydrate

Sodium lauril sulfate

Sunset yellow FCF.

For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Capsules

It is an orange powder, slightly soluble in water, but due to its slightly acidic nature the

solubility increases somewhat in alkaline solution.

CLINICAL PARTICULARS

4.1 Therapeutic indications

DANTRIUM is indicated in controlling the manifestations of clinical spasticity resulting

from serious chronic disorders such as spinal cord injury, stroke, cerebral palsy, or multiple

sclerosis. It is of particular benefit to the patient whose functional rehabilitation has been

retarded by the sequelae of spasticity. Such patients must have presumably reversible

spasticity where relief of spasticity will aid in restoring residual function. There is no

evidence that patients with contractures will benefit. DANTRIUM is not indicated in the

treatment of skeletal muscle spasm resulting from rheumatic disorders or electroconvulsive

therapy.

If improvement occurs, it will ordinarily occur within the dosage titration schedule (see

section 4.2), as manifested by a decrease in the severity of spasticity and the ability to resume

a daily function not quite attainable without DANTRIUM.

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Occasionally, subtle but meaningful improvements in spasticity may occur with DANTRIUM

therapy. In such instances information regarding improvement should be solicited from the

patient directly and from those who are in constant daily contact and attendance with the

patient. Brief withdrawal of DANTRIUM for a period of 2 to 4 days will frequently

demonstrate exacerbation of the manifestation of spasticity and may serve to confirm a

clinical impression.

A decision to continue the administration of DANTRIUM on a long term basis is justified if

introduction of the drug into the patient's regimen produces a significant reduction in painful

and/or disabling spasticity such as clonus, or permits a significant reduction in the intensity

and/or degree of nursing care required, or rids the patient of an annoying manifestation of

spasticity considered important by the patient themselves.

4.2 Dose and method of administration

Dose

Prior to the administration of DANTRIUM consideration should be given to the potential

response to treatment. A decrease in spasticity sufficient to allow a daily function not

otherwise attainable should be the therapeutic goal of treatment with DANTRIUM. Refer to

section 4.1 for a description of the response to be anticipated.

It is important to establish a therapeutic goal (regain and maintain a specific function such as

therapeutic

exercise

program,

utilisation

braces,

transfer

manoeuvres,

etc.)

before

beginning

DANTRIUM

therapy.

Dosage

should

increased

until

maximum

performance compatible with the dysfunction due to underlying disease is achieved. No

further increase in dosage is then indicated.

Usual dosage

It is important that the dosage be titrated and individualised for maximum effect. The lowest

dose compatible with optimal response is recommended.

In view of the potential for liver damage in long-term DANTRIUM use, therapy should be

stopped if benefits are not evident within 45 days.

Adults

Begin therapy with 25 mg once daily; increase to 25 mg two, three, or four times daily and

then by increments of 25 mg up to as high as 50 mg two, three or four times daily if

necessary. The maximum recommended dose is 200 mg/day. As most patients will respond

to this or a lower dose, and hepatotoxicity appears to be dose-related above 200 mg/day,

higher doses should be used only rarely and with close monitoring (see section 4.4). Doses

higher than 400 mg/day should not be used.

Each dosage level should be maintained for four to seven days to determine the patient's

response. The dose should not be increased beyond, and may even have to be reduced to, the

amount at which the patient received maximal benefit without adverse effects.

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Special populations

Paediatric population

A similar approach should be utilised starting with 0.5 mg/kg of body weight twice daily; this

is increased to 0.5 mg/kg three or four times daily and then by increments to a maximum of

2 mg/kg three times a day. Doses higher than 50 mg four times daily should not be used in

children.

4.3 Contraindications

Active hepatic disease, such as acute hepatitis and active cirrhosis, is a contraindication for

use of DANTRIUM. DANTRIUM is contraindicated where spasticity is utilised to sustain

upright posture and balance in locomotion or whenever spasticity is utilised to obtain or

maintain increased function.

4.4 Special warnings and precautions for use

If no observable benefit is derived from the administration of DANTRIUM after a total of

45 days,

therapy

should

discontinued.

lowest

possible

effective

dose

individual patient should be prescribed.

Hepatotoxicity

DANTRIUM should be used with caution in patients with a history of previous liver disease

or dysfunction.

It is important to recognise that DANTRIUM has a potential for hepatotoxicity, and should

not be used in conditions other than those recommended. Symptomatic hepatitis (fatal and

non-fatal) has been reported at various dose levels of the drug. Hepatotoxicity appears to be

dose-related above 200 mg/day and this is the maximum recommended dose. Patients

receiving higher doses should be closely monitored. Even sporadic short courses of doses

above 400 mg/day within a treatment regimen markedly increased the risk of serious hepatic

injury. Liver dysfunction as evidenced by blood chemical abnormalities alone (liver enzyme

elevations) 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 been

most frequently observed between the third and twelfth month of therapy. At the start of

DANTRIUM therapy, it is essential to do liver function studies (SGOT, SGPT, 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.

DANTRIUM should be used only in conjunction with appropriate monitoring of hepatic

function. Liver function studies (e.g. SGOT or SGPT) 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 reinitiation 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.

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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 characteristically have reverted to normal

when the drug was discontinued. DANTRIUM therapy has been reinstituted in a few patients

who have developed clinical and/or laboratory evidence of hepatocellular injury. If such

reinstitution of therapy is done, it should be attempted only in patients who clearly need

DANTRIUM and only after previous symptoms and laboratory abnormalities have cleared.

The patient should be hospitalised and the drug should be restarted in very small and

gradually increasing doses. Laboratory monitoring should be frequent and the drug should be

withdrawn immediately if there is any indication of recurrent liver involvement. Some

patients have reacted with unmistakable signs of liver abnormality upon administration of a

challenge dose, while others have not.

DANTRIUM should be used with particular caution in females and in patients over 35 years

view

of the

apparently

greater

likelihood

of drug-induced,

potentially fatal,

hepatocellular disease in these groups. Careful consideration should be given to the possible

risks involved in the concurrent use of hormonal oral contraceptives with DANTRIUM (see

section 4.5).

Renal Impairment

In patients with impaired renal function, dosage may have to be significantly reduced and the

possibility of a drug related further impairment borne in mind (see section 4.8).

Pulmonary Impairment

DANTRIUM should be used with caution in patients with impaired pulmonary function,

particularly those with obstructive pulmonary disease, and in patients with severely impaired

cardiac function due to myocardial disease. DANTRIUM is associated with pleural effusion

with associated eosinophilia.

Photosensitivity

DANTRIUM might possibly evoke a photosensitivity reaction; patients should be cautioned

about exposure to sunlight while on therapy.

Neuroleptic Malignant Syndrome

The published literature has included some reports of DANTRIUM use in patients with

Neuroleptic Malignant Syndrome (NMS). DANTRIUM capsules are not indicated for the

treatment of NMS and patients may expire despite treatment with DANTRIUM capsules.

Use in the Elderly

Spontaneous reports suggest a higher proportion of hepatic events with fatal outcome in

elderly patients receiving DANTRIUM. In general dose selection for an elderly patient

should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac

function, and of concomitant disease or other drug therapy. As with all patients receiving

DANTRIUM, it is recommended that elderly patients receive the lowest dose compatible

with the optimal response (see section 4.2).

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Long-term Safety

Long-term safety of DANTRIUM in humans has not been established. Chronic studies in

rats, dogs and monkeys at dosages greater than 30 mg/kg/day showed growth or weight

depression and signs of hepatopathy and possible occlusion nephropathy, all of which were

reversible upon cessation of treatment. 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 and, at the

highest

dosage

increase

incidence

hepatic

lymphangiomas

hepatic

angiosarcomas. These effects were not seen in 2 1/2-year studies in Sprague-Dawley or

Fischer 344 rats or in 2-year studies in mice of the HaM/ICR strain.

Paediatric population

The long-term safety of DANTRIUM in children under the age of 5 years has not been

established. Because of the possibility that adverse effects of the drug could become

apparent

only

after

many

years,

benefit-risk

consideration

long-term

DANTRIUM is particularly important in paediatric patients.

4.5 Interaction with other medicines and other forms of interaction

While a definite drug interaction with oestrogen therapy has not yet been established, caution

should be observed if the two drugs are to be given concomitantly. Hepatotoxicity has

occurred more often in women over 35 years of age receiving concomitant oestrogen therapy.

There are very rare reports of cardiovascular collapse in patients treated simultaneously with

verapamil and dantrolene sodium. The combination of therapeutic doses of intravenous

dantrolene sodium and verapamil in halothane/-chloralose anaesthetised swine has resulted

ventricular

fibrillation

cardiovascular

collapse

association

with

marked

hyperkalaemia.

Until

relevance

these

findings

humans

established,

combination of dantrolene sodium and calcium channel blockers, such as verapamil, is not

recommended.

The effects of non-depolarising muscle relaxants may be potentiated in patients administered

dantrolene.

Administration of DANTRIUM may potentiate vecuronium-induced neuromuscular block.

Dantrolene causes dizziness, drowsiness, and weakness; alcohol and other CNS depressants

such as sedatives and tranquilising agents may intensify this effect.

4.6 Fertility, pregnancy and lactation

Fertility

No data available.

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Pregnancy - Category B2

The safety of DANTRIUM for use in women who are or who may become pregnant has not

been established; hence it should be given only when the potential benefits have been

weighed against possible hazard to mother and child. Dantrolene crosses the placenta.

Lactation

DANTRIUM should not be used by nursing mothers. Dantrolene has been detected in human

breast milk.

4.7 Effects on ability to drive and use machinery

Patients should be cautioned against driving a motor vehicle or participating in hazardous

occupations

while

taking

DANTRIUM.

Dantrolene

causes

dizziness,

drowsiness

weakness; alcohol and other CNS depressants may intensify this effect.

4.8 Undesirable effects

most

frequently

occurring

adverse

effects

DANTRIUM

have

been

drowsiness,

dizziness, weakness, general malaise, fatigue, and diarrhoea. These effects have been

experienced by approximately 20% of patients. They are generally transient, occurring early

in treatment, and can often be obviated by beginning with a low dose and increasing dosage

gradually until an optimal regimen is established. Diarrhoea may be severe and may

necessitate

temporary

withdrawal

DANTRIUM

therapy.

diarrhoea

recurs

upon

readministration of DANTRIUM, therapy should probably be withdrawn permanently.

Other less frequent adverse effects, listed according to system, are:

Gastrointestinal

Constipation, rarely progressing to signs of intestinal obstruction, GI

bleeding,

anorexia,

gastric

irritation,

abdominal

cramps,

vomiting,

nausea, dry mouth, saliva hypertension, dyspepsia, dysphagia.

Haematologic

Aplastic

anaemia,

anaemia,

leukopenia,

lymphocytic

lymphoma,

thrombocytopenia.

Hepatobiliary

Liver function test disturbances, hepatitis (see section 4.4).

Neurologic

Speech

disturbance,

seizure,

headache,

light-headedness,

visual

disturbance, diplopia, alteration of taste.

Cardiovascular

Tachycardia,

erratic

blood

pressure,

heart

failure,

phlebitis,

exacerbation of cardiac insufficiency.

Psychiatric

Mental depression, mental confusion, increased nervousness, insomnia.

Urogenital

Increased urinary frequency, crystalluria, haematuria, difficult erection,

urinary incontinence and/or nocturia, difficult urination, chromaturia

and/or urinary retention. A transient lowering of G.F.R. and renal

plasma flow after 8 weeks' therapy has been reported.

Integumentary

Abnormal hair growth, acne-like rash, pruritus, urticaria, eczematoid

eruption, sweating.

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Musculoskeletal

Myalgia, backache.

Respiratory

Feeling of suffocation, respiratory depression, respiratory failure.

Special Senses

Excessive tearing.

Hypersensitivity

Pleural effusion with associated eosinophilia, pericarditis, anaphylaxis.

Other

Chills and fever.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows

continued

monitoring

benefit/risk

balance

medicine.

Healthcare

professionals

asked

report

suspected

adverse

reactions

https://nzphvc.otago.ac.nz/reporting/.

4.9 Overdose

Signs and symptoms are likely to be an extension of those under ADVERSE EFFECTS.

Unconsciousness may supervene. Total skeletal paralysis is unlikely in conscious patients.

For acute overdosage general supportive measures should be employed. Intravenous fluids

should be administered in fairly large quantities to avert the possibility of crystalluria. An

adequate airway should be maintained and artificial resuscitation equipment should be at

hand.

Electrocardiographic

monitoring

should

instituted,

patient

carefully

observed. To date, no experience has been reported with dialysis; its value in DANTRIUM

overdosage is not known.

For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766).

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

The structural formula for the hydrated salt is:

Mechanism of action and pharmacodynamic effects

In isolated nerve-muscle preparations, DANTRIUM has been shown to produce relaxation of

the contractile state of the skeletal muscle by an effect beyond the myoneural junction and

directly on the muscle itself. In these preparations DANTRIUM uncouples the excitation and

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contraction of the skeletal muscle, probably by interfering with the release of calcium ions

from the sarcoplasmic reticulum. This effect appears to be more pronounced in fast muscle

fibres as compared to slow ones, but generally affects both. A central nervous system effect

occurs with drowsiness, dizziness and generalised weakness in some 20% of cases. The

extent

involvement

DANTRIUM-induced

muscle

relaxation

unknown.

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

Based on assays of whole blood and plasma, slightly greater amounts of dantrolene are

associated with red blood cells than with the plasma fraction of blood. Significant amounts

of dantrolene are bound to plasma proteins, mostly albumin, and this binding is readily

reversible.

Binding

plasma

protein

significantly

altered

diazepam,

diphenylhydantoin, or phenylbutazone. Binding to plasma proteins is reduced by warfarin

and clofibrate and increased by tolbutamide.

Biotransformation and Elimination

The mean biological 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. 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.

Approximately 20 to 25% of an oral dose appears in the urine in the metabolised form and

1% or less is excreted unchanged. About 45 to 50% of the same oral dose appears in the bile.

5.3 Preclinical safety data

Genotoxicity

No data available.

Carcinogenicity

Carcinogenicity

humans

cannot

fully

excluded,

this

possible

risk

chronic

administration must be weighed against the benefits of the drug (i.e. after a brief trial) for the

individual patient.

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Reproductive and developmental toxicity

No data available.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Gelatin

Iron oxide red

Iron oxide yellow

Lactose monohydrate

Magnesium stearate

Maize starch

Purified talc

Sodium lauril sulfate

Sunset yellow FCF

Titanium dioxide.

6.2 Incompatibilities

No data available.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Store at or below 30°C.

6.5 Nature and contents of container

DANTRIUM capsules are available as:

25 mg capsules: Orange and tan, opaque, coded "DANTRIUM 25 mg", "0149" and "0030"

with a single line all in black.

50 mg capsules: Orange and tan, opaque, coded "DANTRIUM 50 mg", "0149" and "0031"

with a double line all in black.

DANTRIUM capsules are available in plastic bottles of 100.

Note: DANTRIUM is available for the continuing management of patients whose treatment

was initiated in a hospital or other institution recognised as a special centre for rehabilitation.

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6.6 Special precautions for disposal

Any unused medicine or waste material should be disposed of in accordance with local

requirements.

MEDICINE SCHEDULE

Prescription medicine.

SPONSOR

Pfizer New Zealand Limited

PO Box 3998

Auckland, New Zealand

Toll Free Number: 0800 736 363

DATE OF FIRST APPROVAL

07 September 2006

10. DATE OF REVISION OF THE TEXT

4 February 2019

Registered Trademark

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Reformat to MedSafe Data Sheet guidance

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