Ryanodex

In the U.S.

• Dantrium Intravenous
• Revonto
• Ryanodex

Available Dosage Forms:

• Powder for Suspension
• Powder for Solution

Therapeutic Class: Skeletal Muscle Relaxant, Direct Acting

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.

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.

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.

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.

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.

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 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.

Administer intravenous fluids in fairly large quantities to avert the possibility of crystalluria. Maintain an adequate airway and keep artificial resuscitation equipment available. Institute electrocardiographic monitoring and carefully observe the patient. The value of dialysis in Ryanodex overdosage is not known.

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.

Ryanodex® (NDC 42367-540-32) is available in 20 mL vials containing a sterile lyophilized mixture of 250 mg dantrolene sodium for reconstitution with 5 mL sterile water for injection USP (without a bacteriostatic agent) to yield an orange colored injectable suspension.

Store unreconstituted product at 20 °C to 25 °C (68 ºF to 77 ºF) [see USP Controlled Room Temperature], with excursions permitted to 15 ºC to 30 ºC (59 ºF to 86 ºF) and avoid prolonged exposure to light.

Applies to dantrolene: oral capsule

Other dosage forms:

• intravenous powder for solution, intravenous powder for suspension

Along with its needed effects, dantrolene (the active ingredient contained in Ryanodex) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention. Serious side effects are very rare when dantrolene is taken for a short time, for example, when it is used for a few days before, during, or after surgery or anesthesia to prevent or treat malignant hyperthermia. However, serious side effects may occur, especially when the medicine is taken for a long time.

Check with your doctor immediately if any of the following side effects occur while taking dantrolene:

• Bloody or black, tarry stools
• bloody or dark urine
• bluish color changes in skin color
• changes in speech
• chest pain
• confusion
• constipation
• convulsions (seizures)
• decrease in frequency of urination
• decrease in urine volume
• difficult urination
• difficulty in moving
• difficulty in passing urine (dribbling)
• difficulty in swallowing
• fast, pounding, or irregular heartbeat or pulse
• increased frequency of urination
• increased urge to urinate during the night
• joint pain
• light-colored stools
• lightheadedness
• loss of bladder control
• mental depression
• muscle aching or cramping
• muscle pains or stiffness
• muscle spasm or jerking of all extremities
• nausea and vomiting
• pain in lower back
• pain or burning while urinating
• pain, tenderness, or changes in skin color
• painful urination
• severe stomach pain
• shortness of breath
• skin rash, hives, or itching
• slow or troubled breathing
• sudden decrease in amount of urine
• sudden loss of consciousness
• swelling of foot or leg
• swollen joints
• unusual tiredness or weakness
• upper right abdominal pain
• vomiting of blood or material that looks like coffee grounds
• waking to urinate at night
• yellow eyes or skin

Some side effects of dantrolene may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Diarrhea
• dizziness
• drowsiness
• general feeling of discomfort or illness
• muscle weakness

• Abdominal or stomach cramps or discomfort
• abnormal hair growth
• acne-like rash
• blurred or double vision or any change in vision
• change in taste
• chills and fever
• disturbed color perception
• excessive tearing
• halos around lights
• headache
• itching skin
• loss of appetite
• night blindness
• overbright appearance of lights
• redness of skin
• seeing double
• skin rash, encrusted, scaly and oozing
• sleeplessness
• slurring of speech or other speech problems
• sudden decrease in amount of urine
• sweating
• trouble in sleeping
• tunnel vision
• unable to sleep
• unusual nervousness
• weight loss

Applies to dantrolene: intravenous powder for injection, oral capsule

Nervous system

Nervous system side effects have commonly included drowsiness (30%), dizziness (14%), and malaise. Speech disturbances, headache, seizures and hallucinations have been reported less frequently.[Ref]

Gastrointestinal

Several reports of severe constipation and abdominal distention leading to functional obstruction have been reported.[Ref]

Gastrointestinal side effects have frequently included diarrhea which may be severe enough to require discontinuation. Constipation, abdominal cramps, nausea, and vomiting have been reported less frequently.[Ref]

Hematologic

Hematologic side effects have included aplastic anemia, leukopenia, and lymphocytic lymphoma.[Ref]

Musculoskeletal

Musculoskeletal side effects have commonly included weakness which is usually tolerable. Myalgia and backache have also been reported.[Ref]

Hepatic

Risk of hepatic injury is greater in females, patients over 35 years of age, and in patients on concurrent medications. The severity of the reaction appears to increase with increases in dose and duration.[Ref]

Hepatic side effects have included hepatic injury (1.8%), hepatitis (0.6%), and fatal hepatitis (0.3%).[Ref]

Respiratory

Respiratory side effects have infrequently included pulmonary edema with the use of intravenous dantrolene (the active ingredient contained in Ryanodex) Pleural effusion and pneumonitis have also been reported.[Ref]

Cardiovascular

Cardiovascular side effects have infrequently included pericarditis (both with and without pleural effusion) in patients receiving oral dantrolene (the active ingredient contained in Ryanodex) Cardiovascular side effects reported postmarketing have included heart failure.[Ref]

Local

Local side effects have included thrombophlebitis in patients receiving intravenous dantrolene (the active ingredient contained in Ryanodex) [Ref]

Dermatologic

Dermatologic side effects have included rare reports of acne.[Ref]

Ocular

Ocular side effects have included visual disturbances.[Ref]

Other

Other side effects have included one case of bilateral hearing loss which was thought to have been secondary to dantrolene (the active ingredient contained in Ryanodex) treatment.[Ref]

Hypersensitivity

Hypersensitivity side effects reported postmarketing have included anaphylaxis.

Some side effects of Ryanodex may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.