2.1 Dosage for Treatment of Malignant Hyperthermia

In addition to RYANODEX treatment, institute the following supportive measures:

• Discontinue use of malignant hyperthermia (MH)-triggering anesthetic agents (i.e., volatile anesthetic gases and succinylcholine).
• Manage the metabolic acidosis
• Institute cooling when necessary
• Administer diuretics to prevent late kidney injury due to myoglobinuria (the amount of mannitol in RYANODEX is insufficient to maintain diuresis) [see Description (11)]

Administer RYANODEX by intravenous push at a minimum dose of 1 mg/kg. If the physiologic and metabolic abnormalities of MH continue, administer additional intravenous boluses up to the maximum cumulative dosage of 10 mg/kg.

If the physiologic and metabolic abnormalities reappear, repeat RYANODEX dosing by intravenous push starting with 1 mg/kg.

2.2 Dosage for Prevention of Malignant Hyperthermia

The recommended prophylactic dose of RYANODEX is 2.5 mg/kg administered intravenously over a period of at least 1 minute, starting approximately 75 minutes prior to surgery. Avoid agents that trigger MH.

If surgery is prolonged, administer additional individualized RYANODEX doses during anesthesia and surgery [see Clinical Pharmacology (12.3)].

2.3 Dosage for Pediatric Patients

The recommended weight-based dose of RYANODEX for pediatric patients in the treatment and prevention of MH is the same as for adults for these indications [see Dosage and Administration (2.1, 2.2)].

2.4 Reconstitution and Administration Instructions

The supplied lyophilized powder must be reconstituted prior to administration:

(a)

Reconstitute each vial of RYANODEX lyophilized powder by adding 5 mL of sterile water for injection (without a bacteriostatic agent). Do not reconstitute with any other solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection).

(b)

Shake the vial to ensure an orange-colored uniform suspension. Visually inspect the vial for particulate matter and discoloration prior to administration.

(c)

Must use the contents of the vial within 6 hours after reconstitution. Store reconstituted suspensions at controlled room temperature (68°F to 77°F or 20°C to 25°C).

Do not dilute or transfer the reconstituted RYANODEX suspension to another container to infuse the product.

Administer the reconstituted RYANODEX suspension either:

• Into the intravenous catheter while an intravenous infusion of 0.9% sodium chloride injection, or 5% dextrose injection is freely running; or
• Into the indwelling catheter - after assuring its patency - without a freely running infusion. Flush the line to assure that there is no residual RYANODEX remaining in the catheter [see Warnings and Precautions (5.3)].

5.1 Muscle Weakness

RYANODEX is associated with skeletal muscle weakness. The administration of RYANODEX in human volunteers has been associated with loss of grip strength and weakness in the legs. Patients should not be permitted to ambulate without assistance until they have normal strength and balance.

RYANODEX has been associated with dyspnea, respiratory muscle weakness, and decreased inspiratory capacity. Monitor patients for the adequacy of ventilation.

RYANODEX has been associated with dysphagia. Assess patients for difficulty swallowing and choking.

5.2 Somnolence and Dizziness

Somnolence and dizziness can occur following administration of RYANODEX and may persist up to 48 hours post-dose. Patients should not be permitted to ambulate without assistance until they have normal strength and balance. Patients must not operate an automobile or engage in other hazardous activities for 48 hours post-dose.

The concomitant use of sedative agents with RYANODEX may increase the risk of somnolence and dizziness.

5.3 Potential for Tissue Necrosis with Extravasation

Care must be taken to prevent extravasation of RYANODEX into the surrounding tissues due to the high pH of the reconstituted RYANODEX suspension and potential for tissue necrosis.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a study designed to evaluate the safety and tolerability of RYANODEX, healthy volunteers were randomly assigned to receive treatment with RYANODEX or an active comparator at doses ranging from 1 mg/kg to 2.5 mg/kg.

• The RYANODEX dose was infused over the course of 1 minute for each of the doses evaluated.
• The active comparator was an injectable formulation of dantrolene sodium that differed from RYANODEX in that it contained dantrolene sodium and mannitol at concentrations of 0.33 mg/mL and 50 mg/mL, respectively, when reconstituted according to the product's prescribing information. The active comparator was infused at a rate that administered 20 mg of dantrolene per minute for each of the doses evaluated.

Table 1 displays the most common adverse events in this study. These data are not an adequate basis for comparison of the types or frequencies of adverse event types between RYANODEX and the dantrolene sodium comparator.

Adverse events increased in frequency with increasing doses in the trial, but did not differ in frequency between the two treatment groups. RYANODEX-treated subjects were more likely to report immediate adverse events of flushing, dystonia, and dysphagia than those receiving the active comparator.

In all dose groups, hand grip strength declined after dosing. In general, the decline in hand grip strength was more pronounced and occurred more rapidly in the RYANODEX-treated subjects in the 1.0, 1.75, 2.0 and 2.25 mg/kg treatment groups. In the 2.5 mg/kg treatment group, the decline in hand grip strength both in amount and duration was similar between the two treatment groups.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of another formulation of dantrolene sodium for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7.1 Calcium Channel Blockers

Cardiovascular collapse in association with marked hyperkalemia has been reported in patients receiving dantrolene in combination with calcium channel blockers. The concomitant use of RYANODEX and calcium channel blockers is not recommended during the treatment of malignant hyperthermia.

7.2 Muscle Relaxants

The concomitant administration of RYANODEX with muscle relaxants may potentiate the neuromuscular block.

7.3 Antipsychotics and Antianxiety Agents

The concomitant administration of RYANODEX with antipsychotic and antianxiety agents may potentiate their effects on the central nervous system [see Warnings and Precautions (5.2)].

8.1 Pregnancy

8.2 Lactation

Risk Summary

Dantrolene is reported to be present in human milk following intravenous administration over 3 days. There are no data on the effects on the breastfed infant or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed infant, including respiratory depression and muscle weakness, advise patients that breastfeeding is not recommended during treatment with RYANODEX, and for 3 days after the last dose.

Clinical Considerations

A lactating woman should interrupt breastfeeding and pump and discard breast milk during treatment and for 3 days after RYANODEX administration.

8.4 Pediatric Use

The safety and efficacy of RYANODEX in the treatment and prevention of malignant hyperthermia in pediatric patients is based on clinical experience with other intravenous dantrolene sodium products, which suggests adult weight-based doses are appropriate for pediatric patients.

8.5 Geriatric Use

Clinical studies of RYANODEX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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.

10.1 Overdosage Symptoms

Overdosage symptoms include, but are not limited to, muscular weakness and alterations in the state of consciousness (e.g., lethargy, coma), vomiting, diarrhea, and crystalluria.

10.2 Management of Overdosage

Employ general supportive measures for acute overdosage of RYANODEX.

Administer intravenous fluids in fairly large quantities to avert the possibility of crystalluria. Maintain an adequate airway and keep artificial resuscitation equipment available. Institute electrocardiographic monitoring and carefully observe the patient. The value of dialysis in RYANODEX overdosage is not known.

12.1 Mechanism of Action

In isolated nerve-muscle preparation, dantrolene has been shown to produce relaxation by affecting the contractile response of the muscle at a site beyond the myoneural junction. In skeletal muscle, dantrolene dissociates the excitation-contraction coupling, probably by interfering with the release of Ca++ from the sarcoplasmic reticulum.

In the anesthetic-induced malignant hyperthermia syndrome, evidence points to an intrinsic abnormality of skeletal muscle tissue. In affected humans, it has been postulated that “triggering agents” (e.g., general anesthetics and depolarizing neuromuscular blocking agents) produce a change within the cell which results in an elevated myoplasmic calcium. This elevated myoplasmic calcium activates acute cellular catabolic processes that cascade to the malignant hyperthermia crisis.

The addition of dantrolene to the “triggered” malignant hyperthermic muscle cell may reestablish a normal level of ionized calcium in the myoplasm. Inhibition of calcium release from the sarcoplasmic reticulum by dantrolene reestablishes the myoplasmic calcium equilibrium, increasing the percentage of bound calcium. In this way, physiologic, metabolic, and biochemical changes associated with the malignant hyperthermia crisis may be reversed or attenuated.

12.2 Pharmacodynamics

The administration of intravenous dantrolene to human volunteers was associated with loss of grip strength and weakness in the legs, as well as subjective CNS complaints [see Warnings and Precautions (5.1)].

12.3 Pharmacokinetics

The pharmacokinetics of RYANODEX was investigated in healthy volunteers following single-dose administration as an intravenous push over 60 seconds (dose range of 1 to 2.5 mg/kg), via a peripheral catheter. There was a dose-proportional increase in plasma exposure of dantrolene and its metabolite, 5-hydroxydantrolene. Table 2 presents pharmacokinetic parameters of dantrolene after administration of a single RYANODEX dose of 2.5 mg/kg. Time to peak dantrolene concentration was observed at the first time point collected (i.e., median Tmax is 1 minute post-dose). The mean half-life (t1/2) for dantrolene was independent of the RYANODEX dose administered and ranged from 8.5 hours to 11.4 hours over the 1 to 2.5 mg/kg dose range.

When prophylactic intravenous dantrolene infusion was administered, whole blood dantrolene concentrations remained at a near steady state level for 3 or more hours after the infusion was completed.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility