FDA

Ryanodex

Approved 22 Jul 2014IntravenousFor suspension

Indications

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 )

Contraindications

None None ( 4 )

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 )

5.1Muscle 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.

5.2Somnolence 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.

At a glance

Brand name: Ryanodex
Active substance: dantrolene sodium
Route: Intravenous
Dosage form: For suspension
Applicant: Eagle Pharms
Status: Prescription
FDA approval: 22 Jul 2014
Application: NDA205579-001

Indications

( 1 )

Warnings and precautions

5.1Muscle Weakness

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

5.2Somnolence and Dizziness Somnolence

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Available data from published case reports with RYANODEX use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Dantrolene readily crosses the placenta; however, no serious adverse events have been reported in the neonate following maternal administration of dantrolene prior to delivery. There are risks to the pregnant woman and fetus associated with untreated malignant hyperthermia ( see Clinical Considerations ).

In animal reproduction studies, dantrolene sodium administered to rats and rabbits produced embryolethality (rabbits) and decreased pup survival (rats) at doses seven times the human oral dose ( see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Disease-associated maternal and embryo/fetal risk Malignant hyperthermia is a medical emergency which can be fatal for the pregnant woman and fetus if left untreated. Life-sustaining therapy should not be withheld due to pregnancy. Labor or 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. Data Animal Data 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.

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.

6.1Clinical 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).

Ryanodex

Indications

Contraindications

Warnings and precautions

5.1Muscle Weakness

5.2Somnolence and Dizziness Somnolence

At a glance

Two medicines in one question?

Ryanodex

Indications

Contraindications

Warnings and precautions

5.1Muscle Weakness

5.2Somnolence and Dizziness Somnolence

At a glance

Two medicines in one question?

5.3Potential for Tissue Necrosis with Extravasation

Interactions

7.1Calcium Channel Blockers

7.2Muscle Relaxants

7.3Antipsychotics and Antianxiety Agents

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Official product information