For UK Healthcare Professionals

Prescribing information and adverse events reporting information can be found at the bottom of the page

AGILUS: dantrolene sodium hemiheptahydrate Norgine

Dantrolene delivery
for the treatment
of Malignant Hyperthermia

In combination with adequate support measures, AGILUS® (dantrolene sodium hemiheptahydrate) is indicated for the treatment of malignant hyperthermia in adults and children of all ages.

Every minute counts in the management of Malignant Hyperthermia

To reduce the risk of serious complications, the timely treatment of Malignant Hyperthermia is required. These complications include:

  • Cardiac dysfunction
  • Pulmonary oedema
  • Renal dysfunction
  • Cardiac arrest
  • Disseminated intravascular coagulation
Percent Complications vs.
Time of Administration of Dantrolene
12% 30% 32% 65% 100% Complication rates (% of patients) 10 – 19 20 – 29 30 – 39 40 – 49 50 – 79 Time to first dose of dantrolene administration (mins) 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

Adapted from Riazi S, et al. 2014.*

*Relationship between dantrolene administration time (interval between first clinical sign and first dose of dantrolene) measured in minutes and percentage of malignant hyperthermia complications from a series of 16 patients.

AGILUS® lets you give the same dose of dantrolene more rapidly, using smaller fluid volumes, and requiring fewer vials, than with DANTRIUM IV (dantrolene sodium).

What causes malignant hyperthermia?

Ca2+ MH Trigger Sarcoplasmic Reticulum
MH trigger causes uncontrolled calcium release from the sarcoplasmic reticulum

Malignant hyperthermia (MH) is a life-threatening syndrome caused by sudden, uncontrolled skeletal muscle hypermetabolism in response to inhalational anaesthetics and depolarizing muscle relaxants.

During an MH crisis calcium channels are rapidly activated causing the release of substantial amounts of calcium ions, leading to muscle contraction and rigidity.

Complications after MH crisis occur in up to 30% of patients, including cardiac, renal, pulmonary and haematological disorders.

In the UK there are approximately 20 cases of MH every year.

How does dantrolene work in MH?

A key component in the treatment of an MH reaction is dantrolene. This is to be administered as soon as possible after MH is suspected.

Dantrolene is a skeletal muscle relaxant that inhibits calcium release by antagonising the ryanodine receptor (RyR1).

Dantrolene depresses the intrinsic mechanisms of excitation–contraction coupling in skeletal muscle.

Agilus Ca2+ Sarcoplasmic Reticulum
AGILUS® reduces calcium release by action on the ryanodine receptor

The introduction of dantrolene in 1979 contributed to a reduction in MH mortality from approximately 80% to 6-10%, and it remains a key therapy in treating a malignant hyperthermia crisis.

Delays in administration produce an increase in complication rates, with a time to treatment of over 50 minutes leading to 100% of patients experiencing complications in a study with 16 patients.

AGILUS® offers significant advantages over DANTRIUM IV

Compared to DANTRIUM IV, when used to treat MH, AGILUS® may lead to a reduction in:*

  • Preparation
    time

    A laboratory non-clinical simulation study found that on average 120mg of AGILUS® (1 vial) can be reconstituted and administered in approximately 1 min 53s vs approximately 18 minutes for 120mg of DANTRIUM IV (6 vials) (assuming a single operator).*

    AGILUS® allows more rapid treatment vs. DANTRIUM IV treatment in a time-critical MH emergency.

  • Total fluid volume
    administered

    The volume of dantrolene solution administered is greatly reduced with AGILUS®.

    To administer a 2.5 mg/kg dose to a 72kg patient requires a fluid volume of 540ml with DANTRIUM IV, but only 33.9ml with AGILUS®.

  • Healthcare
    resource utilisation

    Less time spent on preparation may free up personnel to help manage other aspects of an MH crisis.

*Performed under simulation conditions, using a single operator in a controlled environment.

This study prepared AGILUS® by shaking until reconstituted, which took an average of 32s. AGILUS® summary of product characteristics states that the product should be shaken for 1 minute before being examined. Please see the summary of product characteristics for full preparation information.

The AGILUS® difference
Dantrolene mg per vial WFI* per vial Time to prepare and administer 120mg** Filter required
DANTRIUM IV 20 60 mL 18 min 00 sec Yes
AGILUS® 120 20 mL 1 min 53 sec No

To treat a 72kg patient with a 2.5mg/kg bolus dose of dantrolene, AGILUS® needs 1.5 vials and takes up to 3min 46sec to prepare and administer, compared to 9 vials and 27 minutes for DANTRIUM IV**

*Water for injections. **Performed under simulation conditions, using a single operator in a controlled environment.

How to dose AGILUS®

AGILUS® should be administered rapidly by intravenous injection at an initial dose of 2.5 mg/kg body weight for adult and paediatric patients.

A bolus injection of 2.5 mg/kg should be repeated every 10 minutes as long as the main clinical symptoms persist.

In the same patient, treatment with AGILUS® requires a lower number of vials compared to DANTRIUM IV.

For all bodyweights, the initial dose and any repeat doses should not exceed 300 mg, equivalent to 2.5 vials, per round of treatment.

HCP preparing dose
Dosing examples by body weight to achieve a loading dose of 2.5 mg/kg for both adults and children
Number of vials of AGILUS® to be prepared1 Body weight range Example dosing recommendation
Body weight Dose to be administered
1 Up to 48 kg 3 kg 7.5 mg
6 kg 15 mg
12 kg 30 mg
24 kg 60 mg
48 kg 120 mg
2 From 49 kg to 96 kg 72 kg 180 mg
96 kg 240 mg
3 From 97 kg 120 kg 300 mg
144 kga 300 mga

aFor all bodyweights, the initial dose and any repeat doses should not exceed 300 mg, equivalent to 2.5 vials.

Dosing calculator

  1. 0
  2. 16
  3. 32
  4. 48
  5. 64
  6. 80
  7. 96
  8. 112
  9. 128
  10. 144
Dose (vials)
2
Dose (mg)
240

Gain valuable extra time with AGILUS®

The European Malignant Hyperthermia Group guidelines

  • Wherever volatile anaesthetics or succinylcholine are used, a minimum of 720 mg of dantrolene (equivalent to 6 vials of AGILUS®) should be immediately available.
6

Dantrolene is on the European Medicine Agency (EMA) list of critical medicines.

0 10 If no further vials of AGILUS® can be obtained within 60 minutes If a further 240 mg (2 vials of AGILUS®) can always be obtained within 60 minutes If a further 480 mg (4 vials of AGILUS®) can always be obtained within 30 minutes Number of vials AGILUS® 120mg 10 8 6

In a Phase 1 study, AGILUS® was generally well-tolerated

The Phase 1 study of AGILUS® demonstrated:*

  • This bioequivalence study conducted in healthy volunteers was performed in two parts. In part 1, subjects (n=16) were administered a 60 mg dose of either DANTRIUM IV or AGILUS®. At least 5 days later subjects were administered a 60 mg dose of whichever of the two drugs they had not previously been given. In part 2, subjects (n=5) were administered a single 120 mg dose of AGILUS®. During both parts of the test, sampling for pharmacokinetic analysis and monitoring of safety signals were undertaken.
  • Similar safety profiles of AGILUS® compared to pre-existing dantrolene IV formulation (DANTRIUM IV).
  • Treatment-emergent adverse events were consistent with the skeletal muscle relaxant action of dantrolene.
  • All events classified as adverse drug reactions resolved without intervention by the end of the study.

Pre-clinical safety assessments for AGILUS® showed:

  • Similar peak and overall dantrolene exposure compared to DANTRIUM IV.
  • No new preclinical safety signals in animal toxicology studies.
Adverse reactions by system
System organ class Frequency Adverse drug reactions
Immune system disorders Not known Hypersensitivity, Anaphylactic reaction
Metabolism and nutrition disordersa Not known Hyperkalaemia
Nervous system disorders Not known Dizziness, Somnolence, Seizure, Dysarthria, Headache
Eye disorders Not known Visual impairment
Cardiac disordersa Not known Cardiac failure, Bradycardia, Tachycardia
Vascular disorders Not known Thrombophlebitis
Respiratory, thoracic and mediastinal disorders Not known Respiratory failure, Respiratory depression
Gastrointestinal disorders Not known Abdominal pain, Nausea, Vomiting, Gastrointestinal haemorrhage, Diarrhoea, Dysphagia
Hepatobiliary disorders Not known Jaundiceb, Hepatitisb, Hepatic function abnormal, Hepatic failure including fatal outcomeb, Idiosyncratic or hypersensitive liver diseases
Skin and subcutaneous tissue disorders Not known Urticaria, Erythema, Hyperhidrosis
Musculoskeletal and connective tissue disorders Not known Muscle weakness, Muscle fatigue
Renal and urinary disordersa Not known Crystalluria
Reproductive system and breast disorders Not known Uterine hypotonus
General disorders and administration site conditions Not known Fatigue, Administration site reaction, Asthenia

Adapted from AGILUS® Summary of product characteristics.

Not known: frequency could not be estimated from the available data.

aThese adverse reactions were observed in nonclinical studies.

bThese adverse reactions have been observed with chronic, oral treatment.

The frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

There may be an advantage to reduced administration volume, as it has been shown that increased fluid load during MH treatment is associated with an increased risk of complications.

*Conducted in healthy adult volunteers. Doses of AGILUS® administered were a single intravenous 60 mg dose during part 1, and a single 120 mg dose during part 2 of the study.

AGILUS® gives you the advantage when treating MH vs. DANTRIUM IV

  • Lower number of vials needed to meet guideline stock levels
    Streamline storage and organisation of MH treatment
  • Fewer vials needed to achieve the required dose
    Minimise the staff/time that have to be diverted to reconstitute the treatment
  • Faster to prepare and administer with a reduced fluid load due to a lower reconstituted volume*,**
     Requires a smaller total fluid volume and provides treatment more quickly than DANTRIUM IV, potentially reducing complications during MH treatment

*Compared to DANTRIUM IV. **Performed under simulation conditions, using a single operator in a controlled environment.

AGILUS®: helps you take control of malignant hyperthermia with rapid dantrolene delivery

Video Gallery

How to prepare AGILUS®

A live demonstration on how to prepare AGILUS® ready for administration.

EMHG Guideline overview

Overviewing the European Malignant Hyperthermia (EMHG) guidelines on administration of dantrolene.

What is Malignant Hyperthermia?

Explaining the how Malignant hyperthermia arises in response to volatile anaesthetic agents.

Materials

Frequently Asked Questions

How does AGILUS® change my treatment of MH?
AGILUS® allows you to administer dantrolene rapidly due to the greater solubility, with fewer vials to reconstitute, and a lower volume of fluid needed.
What is the difference in dosing of AGILUS® compared to DANTRIUM IV?
One vial of AGILUS® contains 120mg of dantrolene, with DANTRIUM IV containing 20mg per vial. The dosing for AGILUS® is the same as DANTRIUM IV and should be administered rapidly by intravenous injection at a dose of 2.5mg/kg of body weight.
Are there differences in how AGILUS® is reconstituted?
AGILUS® requires less water for injection to reconstitute a vial (20ml for AGILUS®, compared to 60ml for DANTRIUM IV) and there is no need to use a filter during preparation.
Are the recommended stock levels the same with AGILUS® as with DANTRIUM IV?
Whilst The European Malignant Hyperthermia Group (EMHG) guidelines are not currently adjusted to account for the higher dose per vial of AGILUS®, the required stock levels can be calculated from the dose needed in mg/kg.

For medical information enquiries only, please contact medinfo@norgine.com

Prescribing Information – Please note that prescribing information links will take you to an external website.

AGILUS® prescribing information DANTRIUM IV prescribing information

Adverse events should be reported. Reporting forms and information can be found at http://www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Norgine Pharmaceuticals Ltd on: Tel: +44 (0)1895 826 606
Email: medinfo@norgine.com

References

  1. AGILUS®. Summary of product characteristics.
  2. Larach MG, et al. Anesth Analg. 2010;110:498–507.
  3. Ng Kwet Shing RH, et al. Eur J Anaesthesiol. 2024;41:1–10.
  4. Riazi S, et al. Anesth Analg. 2014;118:381–7.
  5. Brandom BW, et al. Anesth Analg. 2011;112(5):1115–1123.
  6. Burkman JM, et al. Anesthesiology. 2007;106:901–6.
  7. Cieniewicz A, et al. Anaesthesiol Intensive Ther. 2019;51(3):169–177.
  8. Hopkins PM, et al. Anaesthesia. 2021;76:655-664.
  9. Glahn KPE, et al. British Journal of Anaesthesia. 2020;125(2):133–140.
  10. Krause T, et al. Anaesthesia. 2004;59:364–373.
  11. Dantrium IV 20mg powder for solution for injection. Summary of product characteristics.