2.1 Dosage Information

 

The recommended dosage of RADICAVA is an intravenous infusion of 60 mg administered over a 60-minute period according to the following schedule:

•

An initial treatment cycle with daily dosing for 14 days, followed by a 14-day drug-free period

•

Subsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods.

2.2 Preparation and Administration Information

RADICAVA is for intravenous infusion only.

Preparation

Do not use if the oxygen indicator has turned blue or purple before opening the package [see How Supplied/Storage and Handling (16.1,16.2)]. Once the overwrap package is opened, use within 24 hours [see Storage and Handling (16.2)].

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Administration

Administer each 60 mg dose of RADICAVA injection as two consecutive 30 mg intravenous infusion bags over a total of 60 minutes (infusion rate approximately 1 mg per minute [3.33 mL per minute]).

Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity reaction [seeWarnings and Precautions (5.1,5.2)].

Other medications should not be injected into the infusion bag or mixed with RADICAVA.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions (redness, wheals, and erythema multiforme) and cases of anaphylaxis (urticaria, decreased blood pressure, and dyspnea) have been reported in spontaneous postmarketing reports with RADICAVA.

Patients should be monitored carefully for hypersensitivity reactions. If hypersensitivity reactions occur, discontinue RADICAVA, treat per standard of care, and monitor until the condition resolves [see Contraindications (4)].

5.2 Sulfite Allergic Reactions

RADICAVA contains sodium bisulfite, a sulfite that may cause allergic type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity occurs more frequently in asthmatic people.

6.1 Clinical Trial 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 randomized, placebo-controlled trials, 184 ALS patients were administered RADICAVA 60 mg in treatment cycles for 6 months. The population consisted of Japanese patients who had a median age of 60 years (range 29-75) and were 59% male. Most (93%) of these patients were living independently at the time of screening.

Most Common Adverse Reactions Observed During Clinical Studies

Table 1 lists the adverse reactions that occurred in ≥ 2% of patients in the RADICAVA-treated group and that occurred at least 2% more frequently than in the placebo-treated group in randomized placebo-controlled ALS trials. The most common adverse reactions that occurred in ≥10% of RADICAVA-treated patients were contusion, gait disturbance, and headache.

 

a Pooled placebo-controlled studies include two additional studies with 231 additional patients, all using the same treatment regimen [see Clinical Studies (14)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of RADICAVA outside of the United States. 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.

Skin and subcutaneous tissue disorders: Hypersensitivity reactions and anaphylaxis.

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of RADICAVA in pregnant women. In animal studies, administration of edaravone to pregnant rats and rabbits resulted in adverse developmental effects (increased mortality, decreased growth, delayed sexual development, and altered behavior) at clinically relevant doses. Most of these effects occurred at doses that were also associated with maternal toxicity (see Animal Data).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk for major birth defects and miscarriage in patients with ALS is unknown.

Data

Animal Data

In rats, intravenous administration of edaravone (0, 3, 30, or 300 mg/kg/day) throughout the period of organogenesis resulted in reduced fetal weight at all doses. In dams allowed to deliver naturally, offspring weight was reduced at the highest dose tested. Maternal toxicity was also observed at the highest dose tested. There were no adverse effects on reproductive function in the offspring. A no-effect dose for embryofetal developmental toxicity was not identified; the low dose is less than the recommended human dose of 60 mg, on a body surface area (mg/m2) basis.

In rabbits, intravenous administration of edaravone (0, 3, 20, or 100 mg/kg/day) throughout the period of organogenesis resulted in embryofetal death at the highest dose tested, which was associated with maternal toxicity. The higher no-effect dose for embryofetal developmental toxicity is approximately 6 times the recommended human dose (RHD) on a body surface area (mg/m2) basis.

The effects on offspring of edaravone (0, 3, 20, or 200 mg/kg/day), administered by intravenous injection to rats from GD 17 throughout lactation, were assessed in two studies. In the first study, offspring mortality was observed at the high dose and increased activity was observed at the mid and high doses. In the second study, there was an increase in stillbirths, offspring mortality, and delayed physical development (vaginal opening) at the highest dose tested. Reproduction function in offspring was not affected in either study. Maternal toxicity was evident in both studies at all but the lowest dose tested. The no-effect dose for developmental toxicity (3 mg/kg/day) is less than the RHD on a mg/m2 basis.

8.2 Lactation

Risk Summary

There are no data on the presence of edaravone in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Edaravone and its metabolites are excreted in the milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for RADICAVA and any potential adverse effects on the breastfed infant from RADICAVA or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of RADICAVA in pediatric patients have not been established.

8.5 Geriatric Use

Of the 184 patients with ALS who received RADICAVA in 3 placebo-controlled clinical trials, a total of 53 patients were 65 years of age and older, including 2 patients 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

The effect of renal impairment on the pharmacokinetics of RADICAVA has not been studied. However, renal impairment is not expected to significantly affect the exposure to edaravone. No dose adjustment is needed in these patients.

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of RADICAVA has not been studied. No dose adjustment is needed for patients with mild or moderate hepatic impairment. No specific dosing recommendation can be provided for patients with severe hepatic impairment.

12.1 Mechanism of Action

The mechanism by which RADICAVA exerts its therapeutic effect in patients with ALS is unknown.

12.3 Pharmacokinetics

RADICAVA is administered by IV infusion. The maximum plasma concentration (Cmax) of edaravone was reached by the end of infusion. There was a trend of more than dose-proportional increase in area under the concentration-time curve (AUC) and Cmax of edaravone. With multiple-dose administration, edaravone does not accumulate in plasma.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

RADICAVA injection is supplied as a 30 mg/100 mL (0.3 mg/mL) clear, colorless, sterile solution for intravenous infusion in single-dose polypropylene bags, each overwrapped with polyvinyl alcohol (PVA) secondary packaging containing an oxygen absorber and oxygen indicator, which should be pink to reflect appropriate oxygen levels [see Dosage and Administration (2.2) and How Supplied/Storage and Handling(16.2)]. These are supplied in cartons as listed below.

 

NDC 70510-2171-1 30 mg/100 mL (0.3 mg/mL) single-dose bag

 

NDC 70510-2171-2 2 bags per carton

16.2 Storage and Handling

Store at up to 25°C (77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light. Store in overwrapped package to protect from oxygen degradation until time of use. The oxygen indicator will turn blue or purple if the oxygen has exceeded acceptable levels. Once the overwrap package is opened, use within 24 hours.