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warnings and cautions
5 WARNINGS AND PRECAUTIONS Skeletal Muscle Weakness : Ambulate patients with assistance until they have normal strength and balance ( 5.1 ) Dyspnea, Respiratory Muscle Weakness, and Decreased Inspiratory Capacity : Monitor patients for the adequacy of ventilation ( 5.1 ) Dysphagia : Assess patients for difficulty swallowing and choking ( 5.1 ) Somnolence and Dizziness : Can occur following RYANODEX administration; may persist up to 48 hours post-dose. Ambulate patients with assistance until they have normal strength and balance ( 5.2 ) Tissue Necrosis with Extravasation : Due to high pH of reconstituted RYANODEX for injectable suspension, care must be taken to prevent extravasation into surrounding tissues ( 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 ADVERSE REACTIONS 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).