Agilus 120 mg powder for solution for injection

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

Treatment with Agilus should be started as soon as a malignant hyperthermia crisis is suspected.

Posology

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

As long as the main clinical symptoms of tachycardia, hypoventilation, sustained hyperacidity (pH and partial pressure of carbon dioxide (pCO2) monitoring required) and hyperthermia persist, a bolus injection of 2.5 mg/kg should be repeated every 10 minutes.

If a cumulative dose of 10 mg/kg or above is considered, the diagnosis of malignant hyperthermia should be re-examined.

The volume of Agilus to be administered (in mL) for a 2.5 mg/kg dose is calculated as follows:

The following table provides examples of dosing based on the number of vials needed for the initial 2.5 mg/kg dose, required immediately by rapid injection:

Table 1. Dosing examples

^aTotal volume of one reconstituted vial is 22.6 mL.

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

Treatment of recrudescence (recurrence)

It should be noted that the hypermetabolic features of malignant hyperthermia recur within the first 24 hours after initial resolution. If a recrudescence occurs, Agilus should be re-administered at a dose of 2.5 mg/kg every 10 minutes until the signs of malignant hyperthermia regress once more.

Paediatric population

No dose adjustment required.

Method of administration

For intravenous use.

Each vial should be prepared by adding 20 mL of water for injections and the vial shaken until the solution is dissolved. Reconstituted Agilus is a yellow-orange solution with a final volume of 22.6 mL.

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

The use of Agilus in the management of malignant hyperthermic crisis is not a substitute for other supportive measures. These must be individually continued in their various forms.

Caution should be exercised if hyperkalaemia symptoms occur (muscular paralysis, electrocardiogram 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 studies as a result of the co-administration of dantrolene with verapamil. Concomitant use of Agilus and calcium channel blockers is not recommended (see section 4.5).

Agilus is only for intravenous use. Due to the high pH value of the solution (pH 9.5), extravascular injection must be avoided as it can lead to tissue necrosis. Due to the risk of vascular occlusion, intraarterial injections must be avoided.

Spill of solution on skin should be avoided. If solution gets on the skin, it must be removed with sufficient water (see section 6.6).

Liver damage may occur during dantrolene therapy. This has been observed during longer term, oral administration and may run a lethal course.

Excipients

Hydroxypropylbetadex

Agilus contains 3530 mg hydroxypropylbetadex (a cyclodextrin) in each vial, which is equivalent to 156.2 mg/mL in the reconstituted solution. Hydroxypropylbetadex increases solubility of dantrolene and thereby reduces preparation time and fluid volume.

Hydroxypropylbetadex has been associated with ototoxicity in animal studies (see section 5.3); and cases of hearing impairment (identified by audiometric assessment) have been observed in studies in other clinical settings. Cases of hearing impairment have been observed at hydroxypropylbetadex exposure levels comparable to the higher range of recommended Agilus doses. In most cases the hearing impairment has been transient and of slight to mild severity. For patients requiring high Agilus doses (above 10 mg/kg) the diagnosis should be re-evaluated (see section 4.2).

The potential risk for hearing impairment may be of particular concern in patients with increased risk for hearing loss, e.g. recurring/chronic ear infections. Exposure to hydroxypropylbetadex from Agilus is expected to be higher in patients with renal impairment. The potential risks associated with hydroxypropylbetadex may be higher in these patients.

Sodium

This medicinal product contains 6.9 mg sodium per vial, equivalent to 0.345% of the World Health Organisation recommended maximum daily intake of 2 g sodium for an adult.

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. Concomitant use of Agilus and calcium channel blockers is not recommended (see section 4.4).

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

Pregnancy

There are no or limited data for the use of dantrolene in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Postpartum uterine atony has been reported after intravenous dantrolene therapy. The risk of floppy child syndrome in neonates has also been described when intravenous dantrolene was administered to the mother during caesarean section. Dantrolene crosses the placenta and should only be used during pregnancy when the potential benefits have been weighed against the possible risk to mother and child.

Breastfeeding

No information is available on the 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 Agilus. Based on elimination half-life of dantrolene, breastfeeding can be restarted 60 hours after the last dose.

Fertility

Data on the effects of dantrolene on fertility in humans are not available. In animal studies, no adverse effects on fertility were observed (see section 5.3).

Agilus has a major influence on the ability to drive and use machines, as it can lead to skeletal muscle weakness, dizziness and light-headedness. Since some of these symptoms may persist for up to 48 hours, patients must not drive or use machines.

Agilus is a skeletal muscle relaxant. The most commonly reported adverse event of intravenous dantrolene administration, skeletal muscle weakness, is related to this mode of action.

The adverse reactions observed are linked to dantrolene and its formulations for acute, intravenous use and for chronic, oral use. Some of the adverse reactions listed may also be observed as a result of the underlying malignant hyperthermia crisis. Adverse reactions 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.

Table 2: List of adverse drug reactions

^aThese adverse reactions were observed in nonclinical studies

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

Paediatric population

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

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

Malignant hyperthermia is an emergency situation where rapid injection of a high dose of Agilus may be necessary (see section 4.2).

Dantrolene acts as a muscle relaxant. Severe muscle weakness with resultant respiratory depression can occur. Therefore, in cases of accidental overdose, symptomatic and general supportive measures should be employed.

The value of dialysis in dantrolene overdose is not known. There is no specific antidote for dantrolene.

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

Mechanism of action and pharmacodynamic effects

Dantrolene is a skeletal muscle relaxant that binds to the ryanodine receptor-1 (RYR1) suppressing release of calcium from the sarcoplasmic reticulum (SR). Dantrolene has little or no effect on the contraction of the cardiac muscle, except possibly at higher doses.

Dantrolene therapy can only work when Ca2+has not yet entirely been emptied from the SR, i.e. dantrolene should be used as early as possible, provided that muscle perfusion is still adequately assured.

Clinical efficacy and safety

The efficacy of dantrolene is well established. The assessment of known and potential risks of intravenous dantrolene is also based on post-marketing exposure data. Published studies in healthy volunteers provide supportive safety data.

In conscious healthy subjects (n = 12), depression of muscle twitch tension was found to stabilise within 2-3 minutes following repeat intravenous bolus doses of 0.1 mg/kg dantrolene every 5 minutes. There was no recovery before the next dose. A dose of 2.5 mg/kg has been shown to produce a maximum dose response in muscle.

Clinical efficacy and safety studies of Agilus have not been performed. A 2-part, part-randomised, open-label, single dose, relative bioavailability study of Agilus versus 20 mg intravenous dantrolene was performed in healthy adult volunteers (n = 21). Adverse events reported in the study for both products were consistent with the known mechanism of action of dantrolene as a skeletal muscle relaxant and with previous literature.

In published case series quicker administration of dantrolene is correlated with improved outcomes. In the relative bioavailability study, the mean time taken to reconstitute 1 vial of Agilus (120 mg) and 1 vial of 20 mg intravenous dantrolene was 50 seconds, and 90 seconds, respectively.

In a laboratory simulation study of the overall vial preparation/administration process, the mean times taken to prepare and administer 1 vial of Agilus (120 mg) and 1 vial of 20 mg intravenous dantrolene were as follows:

• Adult cannula: 1 minute and 53 seconds, and 3 minutes, respectively

• Paediatric cannula: 1 minute and 57 seconds, and 4 minutes and 2 seconds, respectively

Recrudescence is estimated to occur in 10-15% of malignant hyperthermia patients and is more likely to occur in severe cases in which higher doses of dantrolene are required to control the initial reaction.

In a retrospective review and analysis of case studies containing adequate data between 1979 and 2020, 116 adult patients (18 years and older) received dantrolene as treatment for malignant hyperthermia. Among these patients, 112 (97%) were reported to have survived. The median therapeutic dose administered was 2.4 mg/kg and in the majority of patients (58%) a therapeutic dose of 2.5 mg/kg was sufficient to resolve an episode of MH. In 87% of patients, therapeutic doses did not exceed 5 mg/kg and in 95% of patients, doses did not exceed 10 mg/kg.

Paediatric population

In a retrospective review and analysis of case studies containing adequate data between 1979 and 2020, 91 paediatric patients (aged <1 month up to 18 years old) received dantrolene as treatment for malignant hyperthermia. Amongst these patients, 87 (96%) were reported to have survived. The median therapeutic dose administered was similar for all paediatric age groups, ranging from 2 to 3 mg/kg, and in the majority of patients (59%) a therapeutic dose of 2.5 mg/kg was sufficient to resolve an episode of MH. In 89% of patients, therapeutic doses did not exceed 5 mg/kg and in 98% of patients, doses did not exceed 10 mg/kg.

Absorption

In conscious healthy subjects (n=12), a whole blood maximum concentration (Cmax) of 4.2 µg/mL was reported after 2.4 mg/kg intravenously dantrolene, blocking up to 75% of skeletal muscle contraction (dose response plateau). In patients with suspected or proven malignant hyperthermia (n=6) who received prophylactic treatment with dantrolene 2.5 mg/kg intravenously, reported Cmax values ranged between 4.3 and 6.5 µg/mL.

Distribution

Dantrolene is reversibly bound to plasma albumin. In human plasma in vitro at the concentration of 6 µg/mL of Agilus, dantrolene was 94.9% protein bound. Following a 120 mg single intravenous dose of Agilus to healthy volunteers the volume of distribution was 49.2 L.

Biotransformation

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

A clinical study conducted in healthy volunteers demonstrated the relative bioavailability of Agilus with 20 mg intravenous dantrolene. The elimination half-life (t_1/2) for dantrolene was between 9-11 hours for both products.

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.

Paediatric population

The pharmacokinetic profile of dantrolene reported in one clinical study in children dosed at 2.4 mg/kg was similar to that observed in adults. The t_1/2 was about 10 hours in children (n=10) between 2 and 7 years of age scheduled for minor elective surgery. No paediatric specific (any age group) safety issues have been identified compared to the adult population.

Hydroxypropylbetadex

Hydroxypropylbetadex, an ingredient of Agilus, is cleared unchanged by renal filtration, with a short half-life, of 1 to 2 hours, reported in patients with normal renal function.

Subacute and chronic toxicity

A 14-day repeat dose intravenous study with Agilus was conducted in the rat at doses of 2.5 mg/kg/day (73.5 mg/kg/day hydroxypropylbetadex and 8.3 mg/kg/day PEG 3350) and 10 mg/kg/day (294.2 mg/kg/day hydroxypropylbetadex and 33 mg/kg/day PEG 3350. The no adverse effect level (NOAEL) dose was 2.5 mg/kg/day for Agilus (human equivalent dose for dantrolene 0.4 mg/kg/day). Kidney effects were observed on repeated administration in the 10 mg/kg/day treatment group (human equivalent dose for dantrolene 1.6 mg/kg/day) as well as in the control group receiving the same volume of excipients. Thus, the kidney effects were linked to hydroxypropylbetadex's known toxicity of vacuolated renal tubular epithelial cells in both male and female rats and increased incidence of vacuolated alveolar macrophages in male rats, but were of low grade. These effects are consistent with a well-established reversible class effect associated with the use of hydroxypropylbetadex when given chronically to rodents. No auditory functions/ototoxicity were investigated in this study.

In chronic toxicity studies with rats, dogs and monkeys oral administration of dantrolene at greater than 30 mg/kg/day (human equivalent dose 4.8 , 16.7 and 9.7 mg/kg/day, 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. The relevance of these findings to the acute intravenous use of dantrolene in the treatment of malignant hyperthermia in humans has not been determined.

Mutagenicity

Dantrolene yielded positive results in the Ames S. typhimurium test both in the presence and absence of a liver metabolising system.

Carcinogenicity

Dietary doses of dantrolene sodium in rats at doses of 15, 30 and 60 mg/kg/day (human equivalent dose 2.4, 4.8, and 9.7 mg/kg/day, respectively) for up to 18 months resulted in increases in benign hepatic lymphatic neoplasms at the highest dose level, and in females only, an increase in mammary tumours.

In a 30-month study in Sprague-Dawley rats fed dantrolene, the highest dose level produced a decrease in the time of onset of mammary neoplasms. Female rats at the highest dose level showed an increased incidence of hepatic lymphangiomas and hepatic angiosarcomas.

In a 30-month study in Fischer-344 rats a dose-related reduction in the time of onset of mammary and testicular tumours was observed.

The relevance of these data for short term use of intravenous dantrolene for the treatment of malignant hyperthermia in humans is not known.

Reproductive toxicology

In male and female adult rats and female pregnant rabbits, oral formulations of dantrolene up to an achieved oral dose of 45 mg/kg/day (human equivalent dose 7.3 and 14.5 mg/kg/day respectively) did not have any adverse effects on rat fertility or general reproductive capability but in pregnant rabbits 45 mg/kg/day on gestational days 6-18 led to increased formation of unilateral or bilateral supernumerary ribs in the pups.

Hydroxypropylbetadex

There is evidence of hydroxypropylbetadex-induced ototoxicity in several nonclinical species following single and repeat sub-cutaneous (SC) dosing. In rats (the most sensitive species to hydroxypropylbetadex ototoxicity), a dose of 2000 mg/kg is close to the critical dose for inducing significant hearing loss and cochlear damage following SC administration. Doses greater than 2000 mg/kg cause significant hair cell damage and completely abolish distortion product otoacoustic emissions, whereas lower doses have relatively little effect on functional and structural measures. In literature studies, no ototoxicity from 500 to 1000 mg/kg has been reported in rats. The relevance of these findings for human exposure to hydroxypropylbetadex is not clear.

Hydroxypropylbetadex

Macrogol 3350 (E1521)

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Unopened vial: 36 months. After reconstitution: reconstituted solution should be used within 6 hours. Reconstituted solution must be protected from light. Do not store above 25ºC and do not refrigerate.

Chemical and physical in-use stability after reconstitution has been demonstrated for 6 hours at 25ºC.

From a microbiological point of view, unless the method of opening/reconstitution precludes the risk of microbial contamination, the reconstituted product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and should not exceed 6 hours at 25ºC.

The unopened vial does not require any special temperature storage conditions. Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution, see section 6.3.

Type I glass vial with a rubber stopper and a seal.

Packs of 6 or 10 vials.

Not all pack sizes may be marketed.

Each vial should be reconstituted by adding 20 mL water for injections and shaking for approximately 1 minute, before inspecting for particulates. Further shaking may be necessary. The reconstituted solution should be a yellow-orange colour and free from particulates. The volume of solution in a reconstituted vial is 22.6 mL.

Reconstituted Agilus solution must not be mixed with other solutions or given via the same venous access (see section 6.2).

Spill of solution on skin should be avoided. If solution gets on the skin, it must be removed with sufficient water (see section 4.4).

This medicinal product is for single use only and any residual reconstituted solution should be discarded. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.