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.
6.1Clinical 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
6.2Postmarketing 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).
