RYANODEX®


(dantrolene sodium) for injectable suspension, for intravenous use.


Brief Summary of Prescribing Information. See Package Insert For Full Prescribing Information


INDICATIONS AND USAGE RYANODEX®


is indicated for the:


• Treatment of malignant hyperthermia in conjunction with appropriate supportive measures (see Dosage and Administration)


• Prevention of malignant hyperthermia in patients at high risk.


DOSAGE AND ADMINISTRATION (Selected Information) 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)


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.


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.


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).


Reconstitution and


Administration Instructions The supplied lyophilized powder must be reconstituted prior to administration:


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).


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


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).


(For complete Dosage and Administration Section, see full Prescribing Information)


CONTRAINDICATIONS None.


WARNINGS AND PRECAUTIONS 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.


Flushing


Somnolence Dysphonia Dysphagia Nausea


Feeling abnormal


Headache Vomiting


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


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.


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.


ADVERSE REACTIONS 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.


Table 1: Adverse Events in Healthy Volunteers


Number(%) of subjects


RYANODEX [N=30]


8 (27) 5 (17) 4 (13) 3 (10) 3 (10) 3 (10)


1 (3) 1 (3)


DANTROLENE SODIUM COMPARATOR [N=31]


1 (3)


4 (13) 1 (3)


4 (13) 3 (10) 3 (10)


4 (13) 2 (6)


Vision blurred


Pain in extremity


Muscular Weakness/ Asthenia


Atrioventricular block


Tachycardia


Infusion site pain


Dizziness


1 (3) 1 (3)


1 (3) 1 (3)


1 (3) 1 (3)


1 (3)


1 (3) 1 (3)


1 (3) 0


0 0


0


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.


Pulmonary Edema There have been reports of pulmonary edema developing during the treatment of malignant hyperthermia crises with another dantrolene sodium dosage form. The contributory effect of the diluent volume and mannitol in these cases is not known.


Thrombophlebitis and Tissue Necrosis There have been reports of thrombophlebitis following administration of intravenous dantrolene. Tissue necrosis secondary to extravasation has been reported (see Warnings and Precautions).


Hypersensitivity/Anaphylactic Reactions There have been reports of urticaria and erythema possibly associated with the administration of dantrolene sodium for injection. Anaphylaxis has been reported.


Injection Site Reactions Injection site reactions including pain, erythema, and swelling, commonly due to extravasation, have been reported.


DRUG INTERACTIONS 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.


Muscle Relaxants


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


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).


USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C


Adequate and well controlled studies have not been conducted with RYANODEX in pregnant women. However, animal reproduction studies have been conducted with dantrolene sodium. In these studies, dantrolene sodium administered to rats and rabbits produced embryolethality (rabbits) and decreased pup survival (rats) at doses seven times the human oral dose. RYANODEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.


Labor and Delivery In one uncontrolled study, 100 mg per day of prophylactic oral dantrolene sodium was administered to term pregnant patients awaiting labor and delivery. Dantrolene readily crossed the placenta, with maternal and fetal whole blood levels approximately equal at delivery; neonatal levels then fell approximately 50% per day for 2 days before declining sharply. No neonatal respiratory and neuromuscular side effects were observed in this study.


Nursing Mothers


Dantrolene is present in human milk. In one case report, low dantrolene concentrations (less than 2 micrograms per milliliter) were measured in the breast milk of a lactating woman during repeat intravenous dantrolene administration over 3 days. Because of the potential for serious adverse reactions of respiratory depression and muscle weakness in nursing infants from dantrolene, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.


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.


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.


OVERDOSAGE


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.


Management of Overdosage Employ general supportive measures for acute overdosage of RYANODEX.


PATIENT COUNSELING INFORMATION Inform patients, their families, or their caregivers of the following:


Muscle Weakness Muscle weakness (i.e. decrease in grip strength and weakness of leg muscles, especially walking down stairs) is likely to occur with the use of RYANODEX. Patients should be provided assistance with standing and walking until their strength has returned to normal (see Warnings and Precautions).


Difficulty Swallowing Caution is indicated at meals on the day of administration because difficulty swallowing and choking have occurred with the use of dantrolene sodium products in general; dysphagia has been reported with the use of RYANODEX (see Warnings and Precautions).


Dizziness and Somnolence The use of RYANODEX has been associated with dizziness and somnolence. (see Warnings and Precautions).


Driving or Operating Machinery Symptoms such as “lightheadedness” may occur. 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 (see Warnings and Precautions).


Revised: 7/2014


Marketed by: Eagle Pharmaceuticals, Inc. Woodcliff Lake, NJ 07677


© 2014 Eagle Pharmaceuticals, Inc. All rights reserved. 50 Tice Blvd, Suite 315 Woodcliff Lake, NJ 07677 (201) 326-5300 8/2014


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