RYANODEX DANTROLENE SODIUM

RYANODEX ® (dantrolene sodium) for injectable suspension is a sterile lyophilized powder. RYANODEX is supplied in 20 mL vials containing 250 mg dantrolene sodium and the following inactive ingredients: 125 mg mannitol, 25 mg polysorbate 80, 4 mg povidone K12 and sufficient sodium hydroxide or hydrochloric acid for pH adjustment. When reconstituted with 5 mL sterile water for injection USP (without a bacteriostatic agent), this yields a suspension with a pH of approximately 10.3. RYANODEX is a skeletal muscle relaxant. Chemically, RYANODEX is a hydrate of 1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione sodium salt. The structural formula for the hydrated salt is: The hydrated salt contains approximately 15% water (3-1/2 moles) and has a molecular weight of 399. The anhydrous salt (dantrolene) has a molecular weight of 336. Structural Formula

RYANODEX ® is indicated for the: Treatment of malignant hyperthermia in conjunction with appropriate supportive measures [see Dosage and Administration ( 2.1 )] Prevention of malignant hyperthermia in patients at high risk. RYANODEX is a skeletal muscle relaxant drug indicated for: Treatment of malignant hyperthermia in conjunction with appropriate supportive measures. ( 1 ) Prevention of malignant hyperthermia in patients at high risk. ( 1 )

Treatment of Malignant Hyperthermia (MH) ( 2.1 ) Administer by intravenous push at a minimum of 1 mg/kg. If signs continue, administer additional intravenous boluses up to maximum cumulative dosage of 10 mg/kg. Institute supportive measures (e.g., discontinue MH-triggering agents, manage metabolic acidosis, cooling if necessary, administer diuretics) Prevention of MH in Patients at High Risk ( 2.2 ) Administer 2.5 mg/kg intravenously over a period of at least 1 minute, starting approximately 75 minutes prior to surgery. Avoid agents that trigger MH. Administer additional individualized doses during anesthesia and surgery if surgery is prolonged. Pediatric Patients : recommended weight-based dose is the same as for adults ( 2.3 ) Reconstitution : With 5 mL of sterile water for injection (without a bacteriostatic agent) prior to administration ( 2.4 ) 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 )].

None None ( 4 )

Administration to conscious subjects is associated with loss of grip strength and weakness in the legs, drowsiness and dizziness. Other common adverse reactions are: nausea, thrombophlebitis, tissue necrosis secondary to extravasation, urticaria and erythema, and injection site reactions (pain, erythema, swelling) ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eagle at 1-855-318-2170 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Table 1: Adverse Events in Healthy Volunteers Number of subjects (%) RYANODEX [N=30] n (%) Dantrolene Sodium Comparator [N=31] n (%) Flushing 8 (27) 1 (3) Somnolence 5 (17) 4 (13) Dysphonia 4 (13) 1 (3) Dysphagia 3 (10) 4 (13) Nausea 3 (10) 3 (10) Feeling abnormal 3 (10) 3 (10) Headache 1 (3) 4 (13) Vomiting 1 (3) 2 (6) Vision blurred 1 (3) 1 (3) Pain in extremity 1 (3) 1 (3) Muscular weakness/Asthenia 1 (3) 1 (3) Atrioventricular block 1 (3) 0 Tachycardia 1 (3) 0 Infusion site pain 1 (3) 0 Dizziness 1 (3) 0 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. 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 ( 5.3 )]. 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. Hepatotoxicity Cases of hepatotoxicity following the use of intravenous dantrolene products have been reported. Elevated liver enzymes have occurred hours to days following use of intravenous dantrolene, though many of these cases were observed in patients with comorbidities (e.g., critical illness).

Calcium Channel Blockers : Concomitant use can cause cardiovascular collapse in association with marked hyperkalemia ( 7.1 ) Muscle Relaxants : Concomitant use with muscle relaxants may potentiate their effects ( 7.2 ) Sedatives : Concomitant use with sedative agents may potentiate their effects ( 7.3 ) 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 )] .