Dantrium Intravenous 20 mg Powder for Solution for Injection

4.1     Therapeutic indication

For the treatment of malignant hyperthermia.

In combination with adequate support measures, Dantrium Intravenous is indicated in adults and children in the treatment of malignant hyperthermia.

4.2     Posology and method of administration

Posology

As soon as the MH reaction is recognised, all anaesthetic agents should be discontinued; the administration of 100 % oxygen is recommended. Dantrium Intravenous should be administered by continuous rapid intravenous push beginning at a minimum dose of 1 mg/kg, and continuing until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached.

If the physiologic and metabolic abnormalities reappear, the regimen may be repeated. It is important to note that administration of Dantrium Intravenous should be continuous until symptoms subside. The effective dose to reverse the crisis is directly dependent upon the individual's degree of susceptibility to MH, the amount and time of exposure to the triggering agent, and the time elapsed between onset of the crises and administration of treatment.

Dantrium Intravenous should be administered by rapid intravenous injection at least 2.5 mg/kg body weight (8-10 vials in adults). As long as the main clinical symptoms of tachycardia, hypoventilation, sustained hyperacidity (pH and pCO2 monitoring required) and hyperthermia persist, bolus injection should be repeated. In most cases, a total dose of 10 mg/kg body weight per 24h is sufficient. This dose (10 mg/kg) may need to be exceeded in individual cases. Safe uses up to 40 mg/kg have been described. Based on this experience, higher dosages can be administered in isolated cases if required.

Paediatric population

Experience to date indicates that the dose for children is the same as for adults. No dosage adjustment required.

Method of administration

Dantrium 20 mg powder for solution is available f For intravenous administration only.

After reconstitution, the solution must be filtered with the filtration device provided when drawing up the solution into the syringe ( see section 4.4). Remove the single–use filtration device from the syringe prior to attachment to an intravenous cannula or giving set.

Each vial should be prepared by adding 60 mL of sterile water for injection and the vial shaken until the solution is dissolved.

The reconstituted solution should be filtered using the single use filter provided

For instructions on use reconstitution and filtration of the medicinal product before administration, see section 6.6.

4.3     Contraindications

Hypersensitivity to dantrolene sodium or to any of the excipients listed in section 6.1.

4.4     Special warnings and precautions for use

The use of Dantrium Intravenous in the management of MH malignant hyperthermic crisis is not a substitute for other supportive measures. 

These must be individually continued in their various forms. Dantrium Intravenous may only be infused intravenously. Due to the high pH value of the solution (pH 9.5), extravascular injection/infusion must be avoided as it can lead to tissue necrosis. Due to the risk of vascular occlusion, intraarterial injections must be avoided. Spill of the solution on skin should be avoided. If solution gets on the skin, it must be removed with sufficient water.

In addition, due to the potential for undissolved crystals/particles to appear in the re-constituted product and the subsequent potential risk of exacerbation of injection site reactions/tissue necrosis from crystals within affected vials, use of the filtration device when drawing up the solution is required at all times.

Each vial of Dantrium Intravenous contains 3 g mannitol (for adjustment of isotonic solutions). This amount should be considered if mannitol is used to prevent and treat renal complications related to malignant hyperthermia.

Caution should be exercised if hyperkalaemia symptoms occur (muscular paralysis, ECG changes, bradycardic arrhythmias) or in cases of pre-existing hyperkalaemia (renal insufficiency, digitalis intoxication etc.), as an increase in serum potassium has been demonstrated in animal trials as a result of dantrolene.

Liver damage may occur during dantrolene therapy. This is dependent on the dosage and duration of therapy and may run a lethal course.

This medicine contains less than 1mmol sodium (23mg) per vial that is to say essentially “sodium free.

These measures must be individualised, but it will usually be necessary to discontinue the suspect triggering agents, attend to increased oxygen requirements, manage the metabolic acidosis, institute cooling when necessary, monitor urinary output, and monitor for electrolyte imbalance.

Since the effect of disease state and other drugs on dantrolene sodium related skeletal muscle weakness, including possible respiratory depression, cannot be predicted, patients who receive IV dantrolene sodium preoperatively should have vital signs monitored.

If patients judged with MHS are administered intravenous or oral dantrolene sodium preoperatively, anaesthetic preparation must still follow a standard MHS regimen, including the avoidance of known triggering agents. Monitoring for early clinical and metabolic signs of MH is indicated because attenuation of MH, rather than prevention, is possible. These signs usually call for the administration of additional IV dantrolene sodium.

When mannitol is used to prevent or treat the renal complications of malignant hyperthermia, the mannitol content in the Dantrium vial, i.e. 3000 milligrams of mannitol per 20mg of dantrolene sodium, should be taken into consideration.

Because of the high pH of Dantrium Intravenous and potential for tissue necrosis, care must be taken to prevent extravasation of the intravenous solution into the surrounding tissues. In addition, due to the potential for undissolved crystals/particles to appear in the re-constituted product and the subsequent potential risk of exacerbation of injection site reactions/tissue necrosis from crystals within affected vials, use of the filtration device when drawing up the solution is required at all times.

In some subjects as much as 10mg/kg of dantrolene sodium has been needed to reverse the crisis. In a 70 kg man this dose would require approximately 36 vials. Such a volume has been administered in approximately one and a half hours.

Information for Patients

Based upon data in human volunteers, it will sometimes be appropriate to tell patients who receive dantrolene sodium intravenous that decrease in grip strength and weakness of leg muscles, especially walking down stairs, can be expected postoperatively. Caution is also indicated at meals on the day of administration because difficulty in swallowing and choking has been reported. Caution should be exercised in the concomitant administration of tranquilizing agents.

Hepatotoxicity seen with dantrolene sodium capsules

Dantrolene has a potential for hepatotoxicity, and symptomatic hepatitis, sometimes fatal, has been reported. Factors that may be related to a poorer prognosis include higher daily doses, prolonged duration of therapy, female gender, and increasing patient age. Spontaneous reports also suggest a higher proportion of hepatic events with fatal outcome in elderly patients.

Hepatic dysfunction, including fatal hepatic failure, can occur with dantrolene use, and appears to be related to dose and duration of therapy. Fatal and non-fatal liver disorders of idiosyncratic or hypersensitivity type may also occur with dantrolene sodium therapy.

Evaluation of hepatic function should be done before initiating treatment, and hepatic function should be monitored at appropriate intervals throughout treatment. If monitoring reveals abnormal liver function, or if signs or symptoms of hepatotoxicity occur during therapy, dantrolene should be withdrawn. 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

Isolated case reports and animal studies indicate an interaction between dantrolene and calcium channel blockers, such as verapamil and diltiazem, in the form of heart failure. It is recommended that Dantrium Intravenous and calcium channel blockers should not be used at the same time.

Concomitant administration of Dantrium Intravenous with non-depolarising muscle relaxants such as vecuronium can enhance their effect.

Dantrolene is metabolised by the liver, and it is theoretically possible that its metabolism may be enhanced by drugs known to induce hepatic microsomal enzymes. However, neither phenobarbital nor diazepam appears to affect dantrolene's 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.

The combination of therapeutic doses of intravenous dantrolene sodium and verapamil in halothane/alpha-chloralose anaesthetised swine has resulted in ventricular fibrillation and cardiovascular collapse in association with marked hyperkalaemia.

Hyperkalaemia and myocardial depression have also been reported rarely in malignant hyperthermia-susceptible patients receiving intravenous dantrolene sodium and concomitant calcium channel blockers. Hence, the use of Dantrium Intravenous and calcium channel blockers in combination is not recommended, until the relevance of these findings to humans is established.

Administration of dantrolene may potentiate vecuronium-induced neuromuscular block.

Pregnancy

The safety of Dantrium Intravenous in pregnant women has not been established: There are no or limited data from the use of dantrolene in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3).  Dantrolene crosses the placenta, and should be given only when the potential benefits have been weighed against the possible risk to mother and child.

Breast feeding

No information is available on use of dantrolene during breastfeeding. According to its safety profile, a risk to a breastfed infant cannot be excluded as dantrolene is excreted in breastmilk. Therefore, breastfeeding should be discontinued during administration of Dantrium Intravenous. Based on elimination half-life of dantrolene, breastfeeding can be restarted 60 hours after the last dose.

Dantrolene has been detected in human milk at low concentrations (less than 2 micrograms per milliliter) during repeat intravenous administration over 3 days. Dantrium Intravenous should be used by nursing mothers only if the potential benefit justifies the potential risk to the infant.

Fertility

Data on the effects of dantrolene on fertility in humans are not available.          

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

4.7     Effects on ability to drive and use machines

Dantrium Intravenous has major influence on the ability to drive and use machines, as it can lead to weakness, dizziness and light-headedness. This applies particularly in combination with alcohol or other medicines that depress the central nervous system.

A decrease in grip strength and weakness of leg muscles, especially walking down stairs, can be expected postoperatively. In addition, symptoms such as "light headedness" may be noted. Since some of these symptoms may persist for up to 48 hours, patients must not operate an automobile or engage in other hazardous activity during this time.

4.8        Undesirable effects

Summary of the safety profile

There have been occasional reports of death following MH crisis even when treated with intravenous dantrolene. Incidence figures are not available (the pre-dantrolene mortality of MH crisis was approximately 50 %). Most of these deaths can be accounted for by late recognition, delayed treatment, inadequate dosage, lack of supportive therapy, intercurrent disease and/or the development of delayed complications such as renal failure or disseminated intravascular coagulopathy. In some cases there are insufficient data to completely rule out therapeutic failure of dantrolene.

There are rare reports of fatality in MH crisis, despite initial satisfactory response to Dantrium Intravenous, which involve patients who could not be weaned from dantrolene after initial treatment. The administration of intravenous dantrolene to human volunteers is associated with loss of grip strength and weakness in the legs, as well as subjective CNS complaints.

The following adverse reactions are in approximate order of severity:

Tabulated list of adverse reactions.

Adverse Drug Reactions related to dantrolene sodium are presented below according to system organ class and frequency.

Frequencies are defined according to:

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1000 to < 1/100)

Rare (≥ 1/10000 to < 1/1000)

Very rare (< 1/10000)

Not known: frequency could not be estimated due to the present data

System Organ Class

Frequency

Adverse Drug Reaction

Blood and lymphatic disorders

Unknown

Thrombophlebitis

Immune system disorder

Unknown rare

Allergic reactions, Aanaphylaxis

Metabolism  and  nutrition disorders

Unknown

Hyperkalaemia

Nervous system disorders

Unknown

Drowsiness, dizziness, general weakness, somnolence,

convulsion, speech disorder, headache

Cardiac disorders

Unknown

Cardiac failure, bradycardia, tachycardia

Vascular disorders

Unknown

Thrombophlebitis

Respiratory, thoracic and mediastinal disorders

Unknown

Rare

Pulmonary oedema,

Pleural effusion, respiratory failure, respiratory depression

Gastrointestinal disorders

  Unknown

Abdominal pain/cramps, nausea, vomiting, gastrointestinal bleeding, diarrhoea

Hepatobiliary disorders

Unknown

Jaundice, hepatitis,  hepatic dysfunction including fatal hepatic failure, idiosyncratic or hypertensive liver diseases

Skin and subcutaneous disorders

Rare

Unknown

Urticaria, erythema

Hyperhidrosis

Musculoskeletal and

connective tissue disorders

Unknown

Muscle weakness, muscle fatigue

Renal and urinary disorders

Unknown

Crystalluria

Reproductive  system  and breast disorders

Unknown

Uterine hypotonia

General disorders and administration site conditions

Unknown

common

Fatigue, administration Local injection site reactions

For orally administered dantrolene sodium the unwanted effects associated with the use of Dantrium are as follows:

System Organ Class

Frequency

Adverse Drug Reaction

Metabolism and nutrition disorders

Common

Anorexia

Psychiatric disorders:

Less common

Mental depression, mental confusion

Nervous system disorders:

Common

Seizure, speech disturbance, headache, drowsiness, dizziness

Eye disorders

Common

Visual disturbances

Cardiac disorders

Common

Less common

Pericarditis

Exacerbation of cardiac insufficiency, tachycardia

Vascular disorders

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

Nausea and/or vomiting, abdominal pain, diarrhoea

Swallowing difficulties, constipation (rarely progressing to signs of intestinal obstruction)

Hepato-biliary disorders

Common

Hepatotoxicity (see section 4.4), liver function test disturbances

Skin and subcutaneous tissue 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

Common

weakness, general malaise, fatigue 

Chills and /or fever

5.1 Pharmacodynamic properties

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

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

In anaesthetic-induced malignant hyperthermia, signs indicate a genetic-related anomaly of the muscle cell. It is assumed that the triggering agents cause a sudden rise in myoplasmic calcium, by increasing its release and preventing storage in the sarcoplasmic reticulum. The resulting increase in myoplasmic calcium leads to hypermetabolism, which is the cause of hyperthermia, metabolic acidosis and other symptoms of malignant hyperthermia.

Dantrolene can prevent acute catabolism within the muscle cell by inhibiting the release of calcium from the sarcoplasmic reticulum within the myoplasm. Thus, the physiologic, metabolic and biochemical changes associated with the crisis can be reversed or attenuated. However, dantrolene therapy can only work when calcium has not yet entirely been emptied from the sarcoplasmic reticulum, i.e. dantrolene should be used as early as possible, provided that muscle perfusion is still adequately assured.

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

Mechanism of action

Dantrolene is classified as a direct-acting skeletal muscle relaxant. In isolated nerve-muscle preparation, dantrolene sodium 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, dantrolene 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 dantrolene does not appear to directly affect the CNS, the extent of its indirect effect is unknown.

5.2     Pharmacokinetic properties

Distribution

Dantrolene is reversibly bound to plasma albumin; as an in vitro binding constant, a value of 4.3x104M 1 was established. For the transplacental passage of dantrolene, a factor of 0.4 was found.

Metabolism

Metabolism in the liver takes place through microsomal enzymes both via

5-hydroxylation at the hydantoin ring and via reduction of the nitro group to amine with subsequent acetylation. 5-hydroxydantrolene has similar activity to that of the parent substance, while the acetamino dantrolene does not have any muscle relaxant effect.

Elimination

Excretion is mainly renal and biliary, whereby renal excretion takes place,

even in long-term use, at a ratio of 79% 5-hydroxydantrolene, 17% acetylamino-dantrolene and 1 to 4% unchanged dantrolene. Renal clearance (5-OH-dantrolene) is 1.8 to 7.8 L/h.

Following intravenous administration, the average elimination half-life of dantrolene is variable, generally it is between 4 and 8 hours, in a malignant hyperthermia patient it is 12 hours. Pharmacokinetic studies in children have shown an average elimination half-life of approximately 7.4 to 12.6 hours.

Metabolism

Specific metabolic pathways for the degradation and elimination of dantrolene in humans have been established. Dantrolene is found in measurable amounts in blood and urine. 

Its major metabolites in body fluids are 5-hydroxy dantrolene and an acetylamino metabolite of dantrolene. Another metabolite with an unknown structure appears related to the latter. Dantrolene may also undergo hydrolysis and subsequent oxidation forming nitrophenylfuroic acid.

Elimination

The mean biologic half-life of dantrolene after intravenous administration is variable, between 4 to 8 hours under most experimental conditions. 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.

5.3     Preclinical safety data

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 129 mg/kg) and following oral administration the LD50 is around 3 g/kg in newborn rats (human equivalent dose 484 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 11.1 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. typhyimurium test both in the present 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 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.

Carcinogenicity

Dantrolene sodium showed some evidence of tumourgenicity at high dose levels in Sprague-Dawley female rats. 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.

10.     DATE OF REVISION OF THE TEXT

01 October 2021

10th June 2022

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.

If you get any side effects, talk to your doctor or pharmacist.

This includes any possible side effects not listed in this leaflet. See section 4.

1.What Dantrium Intravenous is and what it is used for

Dantrium is a muscle relaxant. When given by intravenous injection, it is useful in controlling

malignant hyperthermia. This is a rare reaction to anaesthesia in which the body temperature rises

extremely quickly. This serious condition produces a variety of symptoms such as a fast heartbeat and breathing rate, stiff muscles, changes in the acidity of the body and rhythm of the heart as well as high

blood pressure. The reaction requires emergency treatment including oxygen, cooling the body,

controlling its acidity, stopping the anaesthetic and giving Dantrium Intravenous. This injection is

given to you by a doctor immediately when malignant hyperthermia is recognised.

Dantrium Intravenous belongs to the pharmacotherapeutic group of direct-acting muscle relaxants. It is used for the treatment of malignant hyperthermia. The ATC code is M03CA01.

Dantrium Intravenous is a medicine which will be administered to you by a doctor or nurse.

2. What you need to know before you are given Dantrium Intravenous

You will probably have been given Dantrium Intravenous before you see this leaflet. The urgent

need for treatment will have been more important than anything else at the time. Before you are given this injection, your doctor will try to find out if you have had a serious reaction to  Dantrium Intravenous in the past.

Do not take Do not use Dantrium Intravenous-i

If you are allergic (hypersensitive) to dantrolene sodium the active ingredient or any of the other ingredients of Dantrium Intravenous this medicine (listed in see section 6).

Warning and precautions

Take special care with Dantrium Intravenous. You will probably have been given Dantrium Intravenous before you read this leaflet. The urgent need for treatment will have been more important than anything else at the time. Before you are given this injection, your doctor will try to find out if you have had a serious reaction to dantrolene sodium or any of the other ingredients of Dantrium Intravenous in the past.

Other medicines and Dantrium Intravenous

Tell your doctor if you are taking, have recently taken or might use any other medicines, including medicines obtained without a prescription.

Your doctor will also exercise caution if you are taking tranquilizing medicines.

Dantrium Intravenous contains sodium

This medicine contains less than 1 mmol sodium (23mg) per vial that is to say essentially “sodium free”.

3. How Dantrium Intravenous is given

This injection is given to you by a doctor into a vein. The dose of Dantrium Intravenous is based on

body weight; in most cases a total dose of up to 10 mg may be given for each kilogram of your body weight is sufficient however a total dose of up to 40mg for each kilogram of your body weight may be required in rare cases.

Based on experience to date, the dose for children is the same as for adults. Care should be taken that Dantrium Intravenous is not mixed with other intravenous infusion fluids.

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

If you are given more Dantrium Intravenous than you should

Malignant hyperthermia is an emergency situation where rapid infusion of a high Dantrium Intravenous dose is necessary. There are no known specific symptoms of dantrolene overdose. Caution is required if there are any signs of hyperkalaemia.

             If you stop using Dantrium Intravenous

If it should appear necessary to discontinue Dantrium Intravenous therapy, intensive care and supportive therapeutic measures which have been initiated should be continued on an individual basis.

4. Possible side effects

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

The following side effects were observed:

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

muscle weakness, tiredness, dizziness, headache, gastrointestinal complaints such as nausea, vomiting, diarrhoea, anaphylaxis, allergic reactions, mostly of the skin, as well as thrombophlebitis or reactions at the application site, somnolence, convulsion, speech disorder, bradycardia (slowed heartbeat), tachycardia (accelerated heartbeat), pleural effusion (fluid collection in the chest), respiratory failure, abdominal pain, gastrointestinal bleeding, jaundice, hepatitis, hyperhidrosis (increased sweat secretion), crystalluria (accumulation of crystals in urine sediment), heart failure.

You may suffer an allergic reaction, symptoms of which include rash, itching, difficulty in

breathing or swelling of the face, lips, throat or tongue (anaphylaxis).

Reactions at site of injection may occur.

Immediately inform your health care provider if you have liver problems, which may be serious (signs may include, yellowing of skin and eyes, feeling sick or abnormal blood tests)

Rare side effect reported include:

-Weakness of hand and leg muscles and light headedness in the first 48 hours following injection.

-red, swollen, irritated skin and tissue around the area

-extreme shortness of breath

-hives

-red painful lesions

Side effects of unknown frequency which cannot be estimated from the available data:

-dizziness

-drowsiness

-convulsions

-speech disorder

-decreased heart rate

-increased heart rate

-shortness of breath when you exert yourself or when lying down

-chest pain

-wheezing, bluish tint to the skin

-abnormal breathing

-abdominal pain

-nausea, vomiting

-blood in the stool

-yellowing of the skin, fever, loss of appetite

-increased sweating

-cloudy urine

-inflammation and/or redness, sometimes formation of a blood clot in the vein where Dantrium Intravenous was injected

6. Contents of the pack and other information

This leaflet was last revised in 0210/20212.

4.8 Undesirable effects

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, Earlsfor Terrace, IRL – Dublin 2; Tel:+353 1 6764971: FAX: +353 1 6762517.  Website: www.hpra.ie.: Email:medsafety@hpra.ie.

6.5        Nature and contents of container

Clear 70 ml vials, glass Type I (Ph .Eur.), with siliconized chlorobutyl lyophilisation bromobutyl rubber stopper Type I (Ph. Eur.) and with an aluminium cap seal with a polypropylene flip-off disk. The vials are sealed with aluminium caps with polypropylene flip off disks. Each vial is provided with a single-use filtration device. Supplied in packs of 12 or 36 vials.

Not all pack sizes may be marketed.

10         DATE OF REVISION OF THE TEXT

May 2019 01 October 2021

4. Possible side effects

If you get any side effects, talk to your doctor, pharmacist or nurse.  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.: Email:medsafety@hpra.ie.

By reporting side effects you can help provide more information on the safety of this medicine.

6. Contents of the pack and other information

This leaflet was last revised in  05/201910/2021.

QRD update throughout the SPC

Section 4.8 updated in a tabulated format and to include unknown ADRs

Revision date

QRD update throughout the SPC

Section 4.8 updated in a tabulated format and to include unknown ADRs

Revision date

4.2      Posology and method of administration

As soon as the malignant hyperthermia  (MH) MH reaction is recognised, all anaesthetic agents should be discontinued; the administration of 100 % oxygen is recommended.  Dantrium IV should be administered by continuous rapid intravenous push beginning at a minimum dose of 1 mg/kg, and continuing until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached.

4.4         Special warnings and precautions for use

The use of Dantrium IV in the management of a MH crisis is not a substitute for previously known supportive measures.  These measures must be individualised, but it will usually be necessary to discontinue the suspect triggering agents, attend to increased oxygen requirements, manage the metabolic acidosis, institute cooling when necessary, monitor urinary output, and monitor for electrolyte imbalance.

Since the effect of disease state and other drugs on dantrolene sodium related skeletal muscle weakness, including possible respiratory depression, cannot be predicted, patients who receive i.v.IV dantrolene sodium preoperatively should have vital signs monitored.

If patients judged MH-susceptible (with MHS) are administered intravenous or oral dantrolene sodium preoperatively, anesthetic preparation must still follow a standard MHS regimen, including the avoidance of known triggering agents.  Monitoring for early clinical and metabolic signs of MH is indicated because attenuation of MH, rather than prevention, is possible.  These signs usually call for the administration of additional i.v.IV dantrolene sodium.

Hepatic dysfunction, including fatal hepatic failure, can occur with dantrolene use, and appears to be related to dose and duration of therapy. Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may also occur with dantrolene sodium therapy.

4.6      Pregnancy Fertility, pregnancy and lactation

4.8 Undesirable effects

Vasular Vascular disorders:

Less common: Labile blood pressure

4.9      Overdose

Symptoms which may occur in case of overdose include, but are not limited to, muscular weakness and alterations in the state of consciousness (e.g., lethargy, coma), vomiting, diarrhea  diarrhoea, and crystalluria.

6.1      List of excipients

Mannitol

Sodium hydroxide (for pH adjustment)

6.3      Shelf life

Unopened: 3 years.

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 6 hours between 15 and at 25°Cc.  From a microbiological point of view, the product should be used immediately.

6.4      Special precautions for storage

Unopened product:  Do not store above 25°C.

Reconstituted solution:  Do not store above 25°C. Do not refrigerate or freeze.  Protect from direct light. Reconstitution should take place in controlled and validated aseptic conditions.

6.5         Nature and contents of container

Clear 70- ml vials, glass type Type I (Ph. Eur.), with siliconised chlorobutyl lyophilisation stoppers Type I (Ph. Eur.). The vials are sealed with aluminium caps with polypropylene flip-off disks.  Supplied in packs of 12 or 36 vials.

6.6      Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

Each vial of Dantrium IV should be reconstituted by adding 60 ml of waterWater for injection Injection Ph. Eur. and shaking until the solution is clear.  Any unused portion of the reconstituted solution should be discarded.  There are no special requirements relating to the disposal of the container or contents.

7.        MARKETING AUTHORISATION HOLDER

SpePharm Holding Norgine B.V.

Kingsfordweg 151

1043 GR Hogehilweg 7

1101CA  Amsterdam ZO

The Netherlands

8.        MARKETING AUTHORISATION NUMBER(S)

PA 1556/1/3 1336/004/003

9.        DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 022^nd December 1980

Date of last renewal: 022^nd December 20052010

10.      DATE OF REVISION OF THE TEXT

December 2011 September 2014 

4.2      Posology and method of administration

As soon as the malignant hyperthermia  (MH) MH reaction is recognised, all anaesthetic agents should be discontinued; the administration of 100 % oxygen is recommended.  Dantrium IV should be administered by continuous rapid intravenous push beginning at a minimum dose of 1 mg/kg, and continuing until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached.

4.4         Special warnings and precautions for use

The use of Dantrium IV in the management of a MH crisis is not a substitute for previously known supportive measures.  These measures must be individualised, but it will usually be necessary to discontinue the suspect triggering agents, attend to increased oxygen requirements, manage the metabolic acidosis, institute cooling when necessary, monitor urinary output, and monitor for electrolyte imbalance.

Since the effect of disease state and other drugs on dantrolene sodium related skeletal muscle weakness, including possible respiratory depression, cannot be predicted, patients who receive i.v.IV dantrolene sodium preoperatively should have vital signs monitored.

If patients judged MH-susceptible (with MHS) are administered intravenous or oral dantrolene sodium preoperatively, anesthetic preparation must still follow a standard MHS regimen, including the avoidance of known triggering agents.  Monitoring for early clinical and metabolic signs of MH is indicated because attenuation of MH, rather than prevention, is possible.  These signs usually call for the administration of additional i.v.IV dantrolene sodium.

Hepatic dysfunction, including fatal hepatic failure, can occur with dantrolene use, and appears to be related to dose and duration of therapy. Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may also occur with dantrolene sodium therapy.

4.6      Pregnancy Fertility, pregnancy and lactation

4.8 Undesirable effects

Vasular Vascular disorders:

Less common: Labile blood pressure

4.9      Overdose

Symptoms which may occur in case of overdose include, but are not limited to, muscular weakness and alterations in the state of consciousness (e.g., lethargy, coma), vomiting, diarrhea  diarrhoea, and crystalluria.

6.1      List of excipients

Mannitol

Sodium hydroxide (for pH adjustment)

6.3      Shelf life

Unopened: 3 years.

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 6 hours between 15 and at 25°Cc.  From a microbiological point of view, the product should be used immediately.

6.4      Special precautions for storage

Unopened product:  Do not store above 25°C.

Reconstituted solution:  Do not store above 25°C. Do not refrigerate or freeze.  Protect from direct light. Reconstitution should take place in controlled and validated aseptic conditions.

6.5         Nature and contents of container

Clear 70- ml vials, glass type Type I (Ph. Eur.), with siliconised chlorobutyl lyophilisation stoppers Type I (Ph. Eur.). The vials are sealed with aluminium caps with polypropylene flip-off disks.  Supplied in packs of 12 or 36 vials.

6.6      Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

Each vial of Dantrium IV should be reconstituted by adding 60 ml of waterWater for injection Injection Ph. Eur. and shaking until the solution is clear.  Any unused portion of the reconstituted solution should be discarded.  There are no special requirements relating to the disposal of the container or contents.

7.        MARKETING AUTHORISATION HOLDER

SpePharm Holding Norgine B.V.

Kingsfordweg 151

1043 GR Hogehilweg 7

1101CA  Amsterdam ZO

The Netherlands

8.        MARKETING AUTHORISATION NUMBER(S)

PA 1556/1/3 1336/004/003

9.        DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 022^nd December 1980

Date of last renewal: 022^nd December 20052010

10.      DATE OF REVISION OF THE TEXT

December 2011 September 2014 

4.4     Special warnings and precautions for use

The use of Dantrium IV in the management of a MH crisis is not a substitute for previously known supportive measures.  These measures must be individualised, but it will usually be necessary to discontinue the suspect triggering agents, attend to increased oxygen requirements, manage the metabolic acidosis, institute cooling when necessary, monitor urinary output, and monitor for electrolyte imbalance.

Since the effect of disease state and other drugs on dantrolene sodium related skeletal muscle weakness, including possible respiratory depression, cannot be predicted, patients who receive i.v. dantrolene sodium preoperatively should have vital signs monitored.

If patients judged MH-susceptible (MHS) are administered intravenous or oral dantrolene sodium preoperatively, anesthetic preparation must still follow a standard MHS regimen, including the avoidance of known triggering agents.  Monitoring for early clinical and metabolic signs of MH is indicated because attenuation of MH, rather than prevention, is possible.  These signs usually call for the administration of additional i.v. dantrolene sodium.

When mannitol is used to prevent or treat the renal complications of malignant hyperthermia, the mannitol content in the Dantrium vial, i.e. 3000 milligrams of mannitol per 20mg of dantrolene sodium, should be taken into consideration.

Because of the high pH of Dantrium IV and potential for tissue necrosis, care must be taken to prevent extravasation of the intravenous solution into the surrounding tissues.

In some subjects as much as 10mg/kg of dantrolene sodium has been needed to reverse the crisis.  In a 70-kg man this dose would require approximately 36 vials.  Such a volume has been administered in approximately one and a half hours.

Information for Patients

Based upon data in human volunteers, it will sometimes be appropriate to tell patients who receive dantrolene sodium intravenous that decrease in grip strength and weakness of leg muscles, especially walking down stairs, can be expected postoperatively.  In addition, symptoms such as "lightheadedness" may be noted.  Since some of these symptoms may persist for up to 48 hours, patients must not operate an automobile or engage in other hazardous activity during this time.  Caution is also indicated at meals on the day of administration because difficulty in swallowing and choking has been reported. Caution should be exercised in the concomitant administration of tranquilizing agents.

Hepatotoxicity seen with dantrolene sodium capsules

Dantrolene has a potential for hepatotoxicity, and symptomatic hepatitis, sometimes fatal, has been reported. Factors that may be related to a poorer prognosis include higher daily doses, female gender, and increasing patient age. Spontaneous reports also suggest a higher proportion of hepatic events with fatal outcome in elderly patients.

Hepatic dysfunction, including fatal hepatic failure, can occur with dantrolene use, and appears to be related to dose and duration of therapy. Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may also occur with dantrolene sodium therapy.

 Evaluation of hepatic function should be done before initiating treatment, and hepatic function should be monitored at appropriate intervals throughout treatment. If monitoring reveals abnormal liver function, or if signs or symptoms of hepatotoxicity occur during therapy, dantrolene should be withdrawn. 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.

6.3     Shelf life

Unopened: 3 years.

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 6 hours between 15 and 25°C.  From a microbiological point of view, the product should be used immediately.

6.4     Special precautions for storage

Unopened product:  Do not store above 25°C.

Reconstituted solution:  Do not store above 25°C. Do not refrigerate or freeze.  Protect from direct light. Reconstitution should take place in controlled and validated aseptic conditions.

6.5         Nature and contents of container

4.4     Special warnings and precautions for use

The use of Dantrium IV in the management of a MH crisis is not a substitute for previously known supportive measures.  These measures must be individualised, but it will usually be necessary to discontinue the suspect triggering agents, attend to increased oxygen requirements, manage the metabolic acidosis, institute cooling when necessary, monitor urinary output, and monitor for electrolyte imbalance.

Since the effect of disease state and other drugs on dantrolene sodium related skeletal muscle weakness, including possible respiratory depression, cannot be predicted, patients who receive i.v. dantrolene sodium preoperatively should have vital signs monitored.

If patients judged MH-susceptible (MHS) are administered intravenous or oral dantrolene sodium preoperatively, anesthetic preparation must still follow a standard MHS regimen, including the avoidance of known triggering agents.  Monitoring for early clinical and metabolic signs of MH is indicated because attenuation of MH, rather than prevention, is possible.  These signs usually call for the administration of additional i.v. dantrolene sodium.

When mannitol is used to prevent or treat the renal complications of malignant hyperthermia, the mannitol content in the Dantrium vial, i.e. 3000 milligrams of mannitol per 20mg of dantrolene sodium, should be taken into consideration.

Because of the high pH of Dantrium IV and potential for tissue necrosis, care must be taken to prevent extravasation of the intravenous solution into the surrounding tissues.

In some subjects as much as 10mg/kg of dantrolene sodium has been needed to reverse the crisis.  In a 70-kg man this dose would require approximately 36 vials.  Such a volume has been administered in approximately one and a half hours.

Information for Patients

Based upon data in human volunteers, it will sometimes be appropriate to tell patients who receive dantrolene sodium intravenous that decrease in grip strength and weakness of leg muscles, especially walking down stairs, can be expected postoperatively.  In addition, symptoms such as "lightheadedness" may be noted.  Since some of these symptoms may persist for up to 48 hours, patients must not operate an automobile or engage in other hazardous activity during this time.  Caution is also indicated at meals on the day of administration because difficulty in swallowing and choking has been reported. Caution should be exercised in the concomitant administration of tranquilizing agents.

Hepatotoxicity seen with dantrolene sodium capsules

Dantrolene has a potential for hepatotoxicity, and symptomatic hepatitis, sometimes fatal, has been reported. Factors that may be related to a poorer prognosis include higher daily doses, female gender, and increasing patient age. Spontaneous reports also suggest a higher proportion of hepatic events with fatal outcome in elderly patients.

Hepatic dysfunction, including fatal hepatic failure, can occur with dantrolene use, and appears to be related to dose and duration of therapy. Fatal and non-fatal liver disorders of an idiosyncratic or hypersensitivity type may also occur with dantrolene sodium therapy.

 Evaluation of hepatic function should be done before initiating treatment, and hepatic function should be monitored at appropriate intervals throughout treatment. If monitoring reveals abnormal liver function, or if signs or symptoms of hepatotoxicity occur during therapy, dantrolene should be withdrawn. 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.

6.3     Shelf life

Unopened: 3 years.

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for 6 hours between 15 and 25°C.  From a microbiological point of view, the product should be used immediately.

6.4     Special precautions for storage

Unopened product:  Do not store above 25°C.

Reconstituted solution:  Do not store above 25°C. Do not refrigerate or freeze.  Protect from direct light. Reconstitution should take place in controlled and validated aseptic conditions.

6.5         Nature and contents of container