ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: oHypersensitivity Reactions [see Warnings and Precautions (5.1) oSulfite Allergic Reactions [see Warnings and Precautions (5.2) . oHypersensitivity Reactions [see Warnings and Precautions (5.1) . oSulfite Allergic Reactions [see Warnings and Precautions (5.2) . Most common adverse reactions (at least 10% and greater than placebo) are contusion, gait disturbance, and headache, (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Mitsubishi Tanabe Pharma America, Inc. at 1-888-292-0058 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 months. The population consisted of Japanese patients who had 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 StudiesTable 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.Table 1: Adverse Reactions from Pooled Placebo-Controlled Trialsa that Occurred in >= 2% of RADICAVA-Treated Patients and >= 2% More Frequently than in Placebo PatientsAdverse ReactionRADICAVA(N=184)%Placebo(N=184)%Contusion159Gait disturbance139Headache106Dermatitis85Eczema74Respiratory failure, respiratory disorder, hypoxia64Glycosuria42Tinea infection42 Pooled placebo-controlled studies include two additional studies with 231 additional patients, all using the same treatment regimen [see Clinical Studies (14)].. 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Skin and subcutaneous tissue disorders: Hypersensitivity reactions and anaphylaxis.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis. The carcinogenic potential of edaravone has not been adequately assessed. Mutagenesis. Edaravone was negative in in vitro (bacterial reverse mutation and Chinese hamster lung chromosomal aberration) and in vivo (mouse micronucleus) assays. Impairment of Fertility Intravenous administration of edaravone (0, 3, 20, or 200 mg/kg) prior to and throughout mating in males and females and continuing in females to gestation day had no effect on fertility; however, disruption of the estrus cycle and mating behavior was observed at the highest dose tested. No effects on reproductive function were observed at the lower doses, which are up to times the RHD of 60 mg, on body surface area (mg/m2) basis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism by which RADICAVA exerts its therapeutic effect in patients with ALS is unknown. 12.2 Pharmacodynamics Cardiac ElectrophysiologyAt dose times the recommended dose, RADICAVA does not prolong the QT interval to any clinically relevant extent.. 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 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.. Distribution. Edaravone is bound to human serum proteins (92%), mainly to albumin, with no concentration dependence in the range of 0.1 to 50 micromol/L.. Elimination. The mean terminal elimination half-life of edaravone is 4.5 to hours. The half-lives of its metabolites are to 2.8 hours.. Metabolism Edaravone is metabolized to sulfate conjugate and glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A6, UGT1A9, UGT2B7, and UGT2B17) in the liver and kidney. In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases.. Excretion In Japanese and Caucasian healthy volunteer studies, edaravone was excreted mainly in the urine as its glucuronide conjugate form (70-90% of the dose). Approximately 5-10% of the dose was recovered in the urine as sulfate conjugate, and only 1% of the dose or less was recovered in the urine as unchanged form. In vitro studies suggest that sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the human kidney before excretion into the urine. Specific Populations. Geriatric Patients No age effect on edaravone pharmacokinetics has been found [see Use in Specific Populations (8.5) ].. Patients with Renal Impairment Following single IV infusion of 30 mg edaravone (half the recommended dosage) over 60 minutes, mean Cmax and AUC0- of unchanged edaravone were 1.15 and 1.20-fold greater in the subjects with mild renal impairment (eGFR 60-89 mL/min/1.73m2), and were 1.25 and 1.29-fold greater in the subjects with moderate renal impairment (eGFR 30-59 mL/min/1.73m2) when compared to subjects with normal renal function, respectively. These changes in exposures are not considered to be clinically significant and therefore no dosage adjustments are necessary in patients with mild to moderate renal impairment. The effects of severe renal impairment on the pharmacokinetics of edaravone have not been studied.. Patients with Hepatic Impairment Following single IV infusion of 30 mg edaravone (half the recommended dosage) over 60 minutes, mean Cmax and AUC0- of unchanged edaravone were 1.20 and 1.07-fold greater in the subjects with mild hepatic impairment (Child-Pugh score or 6), were 1.24 and 1.14-fold greater in the subjects with moderate hepatic impairment (Child-Pugh score to 9), and were 1.20 and 1.19-fold greater in subjects with severe hepatic impairment (Child-Pugh score 10 to 14) when compared to subjects with normal hepatic function, respectively. These changes in exposures are not considered to be clinically significant and therefore no dosage adjustments are necessary in patients with hepatic impairment.. Male and Female Patients No gender effect on edaravone pharmacokinetics has been found.. Racial or Ethnic Groups There were no significant racial differences in Cmax and AUC of edaravone between Japanese and Caucasian subjects.. Drug Interaction Studies The pharmacokinetics of edaravone is not expected to be significantly affected by inhibitors of CYP enzymes, UGTs, or major transporters. In vitro studies demonstrated that, at clinical dose, edaravone and its metabolites are not expected to significantly inhibit cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4), UGT1A1, UGT2B7, or transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2) in humans. Edaravone and its metabolites are not expected to induce CYP1A2, CYP2B6, or CYP3A4 at the clinical dose level of RADICAVA.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The efficacy of RADICAVA for the treatment of ALS was established in 6-month, randomized, placebo-controlled, double-blind study conducted in Japanese patients with ALS who were living independently and met the following criteria at screening: 1.Functionality retained most activities of daily living (defined as scores of points or better on each individual text of the ALS Functional Rating Scale Revised [ALSFRS-R; described below])2.Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] >= 80%)3.Definite or Probable ALS based on El Escorial revised criteria4.Disease duration of years or less The study enrolled 69 patients in the RADICAVA arm and 68 in the placebo arm. Baseline characteristics were similar between these groups, with over 90% of patients in each group being treated with riluzole. RADICAVA was administered as an intravenous infusion of 60 mg given over 60 minute period according to the following schedule: oAn initial treatment cycle with daily dosing for 14 days, followed by 14-day drug-free period (Cycle 1)oSubsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods (Cycles 2-6). The primary efficacy endpoint was comparison of the change between treatment arms in the ALSFRS-R total scores from baseline to Week 24. The ALSFRS-R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS (speech, salivation, swallowing, handwriting, cutting food, dressing/hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency). Each text is scored from 0-4, with higher scores representing greater functional ability. The decline in ALSFRS-R scores from baseline was significantly less in the RADICAVA-treated patients as compared to placebo (see Table 2). The distribution of change in ALSFRS-R scores from baseline to Week 24 by percent of patients is shown in Figure 1.Table 2: Analysis of Change from Baseline to Week 24 in ALSFRS-R ScoresTreatmentChange from BaselineLS Mean +- SE (95% CI)Treatment Difference (RADICAVA placebo [95% CI])p-valueRADICAVA 60mg-5.01+-0.642.49 (0.99, 3.98)0.0013Placebo-7.50+-0.66Figure 1: Distribution of Change from Baseline to Week 24 in ALSFRS-R Scores. 1.Functionality retained most activities of daily living (defined as scores of points or better on each individual text of the ALS Functional Rating Scale Revised [ALSFRS-R; described below]). 2.Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] >= 80%). 3.Definite or Probable ALS based on El Escorial revised criteria. 4.Disease duration of years or less oAn initial treatment cycle with daily dosing for 14 days, followed by 14-day drug-free period (Cycle 1). oSubsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods (Cycles 2-6). figure-1.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS RADICAVA is contraindicated in patients with history of hypersensitivity to edaravone or any of the inactive ingredients of this product. Hypersensitivity reactions and anaphylactic reactions have occurred [see Warnings and Precautions (5.1, 5.2)].. oPatients with history of hypersensitivity to edaravone or any of the inactive ingredients in RADICAVA (4). oPatients with history of hypersensitivity to edaravone or any of the inactive ingredients in RADICAVA (4).

DESCRIPTION SECTION.

11 DESCRIPTION The active ingredient in RADICAVA is edaravone, which is member of the substituted 2-pyrazolin-5-one class. The chemical name of edaravone is [3-methyl-1-phenyl-2-pyrazolin-5-one]. The molecular formula is C10H10N2O and the molecular weight is 174.20.The chemical structure is:Edaravone is white crystalline powder with melting point of 129.7C. It is freely soluble in acetic acid, methanol, or ethanol and slightly soluble in water or diethyl ether. RADICAVA injection is clear, colorless liquid provided as sterile solution. RADICAVA injection is supplied for intravenous infusion in polypropylene bag containing 30 mg edaravone in 100 mL isotonic, sterile, aqueous solution, which is further overwrapped with polyvinyl alcohol (PVA) secondary packaging. The overwrapped package also contains an oxygen absorber and oxygen indicator to minimize oxidation. Each bag contains the following inactive ingredients: L-cysteine hydrochloride hydrate (10 mg), sodium bisulfite (20 mg). Sodium chloride is added for isotonicity and phosphoric acid and sodium hydroxide are added to adjust to pH 4.. chemstructure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION The recommended dosage is 60 mg administered as an intravenous infusion over 60 minutes as follows: oInitial treatment cycle: daily dosing for 14 days followed by 14-day drug-free period oSubsequent treatment cycles: daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods (2). oInitial treatment cycle: daily dosing for 14 days followed by 14-day drug-free period. oSubsequent treatment cycles: daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods (2). 2.1 Dosage Information The recommended dosage of RADICAVA is an intravenous infusion of 60 mg administered over 60-minute period according to the following schedule: oAn initial treatment cycle with daily dosing for 14 days, followed by 14-day drug-free periodoSubsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods. The recommended dosage of RADICAVA is an intravenous infusion of 60 mg administered over 60-minute period according to the following schedule: oAn initial treatment cycle with daily dosing for 14 days, followed by 14-day drug-free period. oSubsequent 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.PreparationDo 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.AdministrationAdminister each 60 mg dose of RADICAVA injection as two consecutive 30 mg intravenous infusion bags over total of 60 minutes (infusion rate approximately mg per minute [3.33 mL per minute]).Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with hypersensitivity reaction [see Warnings and Precautions (5.1, 5.2) ]. Other medications should not be injected into the infusion bag or mixed with RADICAVA.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS RADICAVA is supplied for intravenous infusion in single-dose polypropylene bag containing 30 mg of edaravone in 100 mL of clear, colorless aqueous solution.. oInjection: 30 mg/100 mL in single-dose polypropylene bag (3). oInjection: 30 mg/100 mL in single-dose polypropylene bag (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use Of the 184 patients with ALS who received RADICAVA in placebo-controlled clinical trials, total of 53 patients were 65 years of age and older, including 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied RADICAVA injection is supplied as 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 70510-2171-130 mg/100 mL (0.3 mg/mL) single-dose bag NDC 70510-2171-22 bags per carton. NDC 70510-2171-130 mg/100 mL (0.3 mg/mL) single-dose bag. NDC 70510-2171-22 bags per carton. 16.2 Storage and Handling Store at up to 25C (77F). Excursions permitted from 15C to 30C (59F to 86F) [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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE RADICAVA is indicated for the treatment of amyotrophic lateral sclerosis (ALS).. RADICAVA is indicated for the treatment of amyotrophic lateral sclerosis (ALS) (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patients to read the FDA-approved patient labeling (Patient Information).Hypersensitivity ReactionsAdvise patients to seek immediate medical care if they experience signs or symptoms of hypersensitivity reaction [see Warnings and Precautions (5.1)]. Sulfite Allergic ReactionsAdvise patients about potential for sulfite sensitivity. Inform patients that RADICAVA contains sodium bisulfite, which may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, and to seek immediate medical care if they experience these signs or symptoms [see Warnings and Precautions (5.2)]. Pregnancy and BreastfeedingAdvise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during RADICAVA therapy [see Use in Specific Populations (8.1)].Advise patients to notify their healthcare provider if they intend to breastfeed or are breastfeeding an infant [see Use in Specific Populations (8.2)].Marketed and distributed by:Mitsubishi Tanabe Pharma America, Inc., US subsidiary of Mitsubishi Tanabe Pharma Corporation 525 Washington Blvd., Suite 400, Jersey City, NJ 07310 RADICAVA is registered trademark of Mitsubishi Tanabe Pharma Corporation(C) Mitsubishi Tanabe Pharma Corporation 65002655 Iss. 03/2021.

LACTATION SECTION.

8.2 Lactation Risk SummaryThere 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 mothers clinical need for RADICAVA and any potential adverse effects on the breastfed infant from RADICAVA or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis. The carcinogenic potential of edaravone has not been adequately assessed. Mutagenesis. Edaravone was negative in in vitro (bacterial reverse mutation and Chinese hamster lung chromosomal aberration) and in vivo (mouse micronucleus) assays. Impairment of Fertility Intravenous administration of edaravone (0, 3, 20, or 200 mg/kg) prior to and throughout mating in males and females and continuing in females to gestation day had no effect on fertility; however, disruption of the estrus cycle and mating behavior was observed at the highest dose tested. No effects on reproductive function were observed at the lower doses, which are up to times the RHD of 60 mg, on body surface area (mg/m2) basis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL . radicava-soft-bag-sawai. radicava-soft-bag-terumo.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Cardiac ElectrophysiologyAt dose times the recommended dose, RADICAVA does not prolong the QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.

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 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.. Distribution. Edaravone is bound to human serum proteins (92%), mainly to albumin, with no concentration dependence in the range of 0.1 to 50 micromol/L.. Elimination. The mean terminal elimination half-life of edaravone is 4.5 to hours. The half-lives of its metabolites are to 2.8 hours.. Metabolism Edaravone is metabolized to sulfate conjugate and glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of edaravone involves multiple uridine diphosphate glucuronosyltransferase (UGT) isoforms (UGT1A6, UGT1A9, UGT2B7, and UGT2B17) in the liver and kidney. In human plasma, edaravone is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases.. Excretion In Japanese and Caucasian healthy volunteer studies, edaravone was excreted mainly in the urine as its glucuronide conjugate form (70-90% of the dose). Approximately 5-10% of the dose was recovered in the urine as sulfate conjugate, and only 1% of the dose or less was recovered in the urine as unchanged form. In vitro studies suggest that sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the human kidney before excretion into the urine. Specific Populations. Geriatric Patients No age effect on edaravone pharmacokinetics has been found [see Use in Specific Populations (8.5) ].. Patients with Renal Impairment Following single IV infusion of 30 mg edaravone (half the recommended dosage) over 60 minutes, mean Cmax and AUC0- of unchanged edaravone were 1.15 and 1.20-fold greater in the subjects with mild renal impairment (eGFR 60-89 mL/min/1.73m2), and were 1.25 and 1.29-fold greater in the subjects with moderate renal impairment (eGFR 30-59 mL/min/1.73m2) when compared to subjects with normal renal function, respectively. These changes in exposures are not considered to be clinically significant and therefore no dosage adjustments are necessary in patients with mild to moderate renal impairment. The effects of severe renal impairment on the pharmacokinetics of edaravone have not been studied.. Patients with Hepatic Impairment Following single IV infusion of 30 mg edaravone (half the recommended dosage) over 60 minutes, mean Cmax and AUC0- of unchanged edaravone were 1.20 and 1.07-fold greater in the subjects with mild hepatic impairment (Child-Pugh score or 6), were 1.24 and 1.14-fold greater in the subjects with moderate hepatic impairment (Child-Pugh score to 9), and were 1.20 and 1.19-fold greater in subjects with severe hepatic impairment (Child-Pugh score 10 to 14) when compared to subjects with normal hepatic function, respectively. These changes in exposures are not considered to be clinically significant and therefore no dosage adjustments are necessary in patients with hepatic impairment.. Male and Female Patients No gender effect on edaravone pharmacokinetics has been found.. Racial or Ethnic Groups There were no significant racial differences in Cmax and AUC of edaravone between Japanese and Caucasian subjects.. Drug Interaction Studies The pharmacokinetics of edaravone is not expected to be significantly affected by inhibitors of CYP enzymes, UGTs, or major transporters. In vitro studies demonstrated that, at clinical dose, edaravone and its metabolites are not expected to significantly inhibit cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4), UGT1A1, UGT2B7, or transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2) in humans. Edaravone and its metabolites are not expected to induce CYP1A2, CYP2B6, or CYP3A4 at the clinical dose level of RADICAVA.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryThere 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. DataAnimal 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. no-effect dose for embryofetal developmental toxicity was not identified; the low dose is less than the recommended human dose of 60 mg, on 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 times the recommended human dose (RHD) on 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 mg/m2 basis.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. RADICAVA (ra di ka vah)(edaravone injection)for intravenous infusionWhat is RADICAVARADICAVA is prescription medicine used to treat people with Amyotrophic Lateral Sclerosis (ALS).It is not known if RADICAVA is safe and effective in children.Do not receive RADICAVA if you are allergic to edaravone or any of the ingredients in RADICAVA. See the end of this leaflet for complete list of ingredients in RADICAVA. Before you receive RADICAVA, tell your healthcare provider about all of your medical conditions, including if you:ohave asthma.oare allergic to other medicines.oare pregnant or plan to become pregnant. It is not known if RADICAVA will harm your unborn baby. oare breastfeeding or plan to breastfeed. It is not known if RADICAVA passes into your breastmilk. You and your healthcare provider should decide if you will receive RADICAVA or breastfeed. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive RADICAVAoYou will be prescribed RADICAVA by healthcare provider. RADICAVA will be given by intravenous (IV) infusion into your vein.oIt takes about hour to receive the full dose of RADICAVA.oYour healthcare provider will tell you how often you will receive RADICAVA. oYour healthcare provider will monitor you closely during your treatment with RADICAVA.What are the possible side effects of RADICAVARADICAVA may cause serious side effects including:1.Hypersensitivity (allergic) reactions. Hypersensitivity reactions have happened in people receiving RADICAVA and can happen after your infusion is finished. Tell your healthcare provider right away or go to the nearest emergency room if you have any of the following symptoms:ohivesobreathing problemoitchingoswelling of the lips, tongue, faceodizzinessowheezingofainting2.Sulfite allergic reactions. RADICAVA contains sodium bisulfite, sulfite that may cause type of allergic reaction that can be serious and life-threatening. Sodium bisulfite can also cause less severe allergic reactions, for example, asthma episodes, in certain people. Sulfite sensitivity can happen more often in people who have asthma than in people who do not have asthma. Tell your healthcare provider right away or go to the nearest emergency room if you have any of the following symptoms:ohivesotrouble breathing or swallowingoitchingoswelling of the lips, tongue, faceodizzinessoasthma attack (in people with asthma)owheezingofaintingYour healthcare provider will monitor you during treatment to watch for signs and symptoms of all the serious side effects.The most common side effects of RADICAVA include bruising (contusion), problems walking (gait disturbance), and headache.These are not all the possible side effects of RADICAVA. Call your healthcare provider for medical advice about side effects. You may report side effects to Mitsubishi Tanabe Pharma America, Inc. at 1-888-292-0058 orFDA at 1-800-FDA-1088 or www.fda.gov/medwatch.What are the ingredients in RADICAVAActive ingredient: edaravoneInactive ingredients: L-cysteine hydrochloride hydrate, sodium bisulfite, sodium chloride, phosphoric acid, and sodium hydroxide.Marketed and distributed by: Mitsubishi Tanabe Pharma America, Inc., US subsidiary of Mitsubishi Tanabe Pharma Corporation, 525 Washington Blvd., Suite 400, Jersey City, NJ 07310 For more information, go to www.Radicava.com or call 1-888-292-0058. This Patient Information or Medication Guide has been approved by the U.S. Food and Drug Administration Revised or Issued 11/2018. ohave asthma.. oare allergic to other medicines.. oare pregnant or plan to become pregnant. It is not known if RADICAVA will harm your unborn baby. oare breastfeeding or plan to breastfeed. It is not known if RADICAVA passes into your breastmilk. You and your healthcare provider should decide if you will receive RADICAVA or breastfeed. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.. oYou will be prescribed RADICAVA by healthcare provider. RADICAVA will be given by intravenous (IV) infusion into your vein.. oIt takes about hour to receive the full dose of RADICAVA.. oYour healthcare provider will tell you how often you will receive RADICAVA. oYour healthcare provider will monitor you closely during your treatment with RADICAVA.. ohives. obreathing problem. oitching. oswelling of the lips, tongue, face. odizziness. owheezing. ofainting. ohives. otrouble breathing or swallowing. oitching. oswelling of the lips, tongue, face. odizziness. oasthma attack (in people with asthma). owheezing. ofainting. This Patient Information or Medication Guide has been approved by the U.S. Food and Drug Administration Revised or Issued 11/2018.

SPL UNCLASSIFIED SECTION.

2.1 Dosage Information The recommended dosage of RADICAVA is an intravenous infusion of 60 mg administered over 60-minute period according to the following schedule: oAn initial treatment cycle with daily dosing for 14 days, followed by 14-day drug-free periodoSubsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods. The recommended dosage of RADICAVA is an intravenous infusion of 60 mg administered over 60-minute period according to the following schedule: oAn initial treatment cycle with daily dosing for 14 days, followed by 14-day drug-free period. oSubsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oPregnancy: Based on animal data, may cause fetal harm (8.1). oPregnancy: Based on animal data, may cause fetal harm (8.1). 8.1 Pregnancy Risk SummaryThere 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. DataAnimal 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. no-effect dose for embryofetal developmental toxicity was not identified; the low dose is less than the recommended human dose of 60 mg, on 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 times the recommended human dose (RHD) on 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 mg/m2 basis.. 8.2 Lactation Risk SummaryThere 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 mothers 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 placebo-controlled clinical trials, total of 53 patients were 65 years of age and older, including 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHypersensitivity Reactions: Advise patients to seek immediate medical care (5.1) oSulfite Allergic Reactions: RADICAVA contains sodium bisulfite, which may cause allergic type reactions (5.2). oHypersensitivity Reactions: Advise patients to seek immediate medical care (5.1). oSulfite Allergic Reactions: RADICAVA contains sodium bisulfite, which may cause allergic type reactions (5.2). 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, 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.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology Oral administration of edaravone (0, 10, 30, 100, or 300 mg/kg/day) in dogs for 39 weeks resulted in neurotoxicity, characterized by white matter vacuolation in the spinal cord and vacuolation and nerve fiber atrophy in the sciatic nerve, at the two highest doses tested. The microscopic findings were accompanied by gait abnormalities, loss of patellar reflex, and inability to rise. Plasma edaravone exposures (Cmax and AUC) at the higher no-effect dose for neurotoxicity (30 mg/kg/day) were approximately times more than those in humans at the recommended human dose of RADICAVA ORS (105 mg).

INSTRUCTIONS FOR USE SECTION.

Instructions for Use INSTRUCTIONS FOR USERADICAVA (ra di ka vah) ORS(edaravone)oral suspension Read this Instructions for Use before you take RADICAVA ORS for the first time and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Important information about measuring RADICAVA ORS: Always measure your prescribed dose of RADICAVA ORS using the oral syringe provided. Ask your healthcare provider or pharmacist who provided the medicine any questions you have about how to measure your prescribed dose. If you miss dose, do not take doses of RADICAVA ORS the next day. Do not take dose of RADICAVA ORS on days 15 through 28. How to prepare RADICAVA ORS: Keep this Instructions for Use handy when preparing the treatment.oIf your healthcare provider prescribes Starter Kit, you will receive bottles of RADICAVA ORS. Each bottle will contain 35 mL of RADICAVA ORS for total of 70 mL to be used for your first treatment cycle of 14 days. Only open the second bottle when you have finished the first bottle.oIf you were not prescribed the Starter Kit, for each treatment cycle you will receive bottle of RADICAVA ORS that contains total of 50 mL of RADICAVA ORS. After the first treatment cycle, RADICAVA ORS is to be used for 10 days out of 14 day periods.oOnly use the bottle adapter and the reusable mL oral syringes provided with the bottle. Do not use household teaspoon to measure your medicine. How to store RADICAVA ORS:oStore RADICAVA ORS upright at room temperature between 68F to 77F (20C to 25C). Protect from light.oOpening the bottle:oWhen you open the bottle of RADICAVA ORS for the first use, write the date you open the bottle on the bottle label.oAfter opening the bottle of RADICAVA ORS, use within 15 days.oAfter bottle of RADICAVA ORS has been opened and used, white crust may form on the neck or on the side of the bottle. This is due to normal use and RADICAVA ORS can continue to be uses as prescribed. oKeep bottle tightly closed between each use. oThrow away (discard) any RADICAVA ORS that is not used within 15 days after opening the bottle or within 30 days from the date of shipment shown on the carton pharmacy label, whichever happens first. Ask your pharmacist how to properly throw away (discard) RADICAVA ORS you are no longer able to use.oKeep RADICAVA ORS and all medicines out of the reach of children.Each RADICAVA ORS carton contains:o1 RADICAVA ORS bottleo1 bottle adaptero2 (5 mL) reusable oral syringesUse new mL oral syringe and bottle adapter when using new bottle of RADICAVA ORS (see Figure A)Figure AImportant information:oKeep these instructions for future use.oDo not share RADICAVA ORS with anyone else.oCall your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.oPeople who have problems using their hands may need assistance to draw up and give the correct dose of RADICAVA ORS.How to take RADICAVA ORS: Take RADICAVA ORS as prescribed by your healthcare provider. Dosing Information: RADICAVA ORS has different dosing schedules:oFor the first treatment cycle, you will take RADICAVA ORS every day for 14 days, followed by 14 days without the medicine. oFor the cycles after the first treatment cycle, you will take RADICAVA ORS daily for 10 out of 14 days, followed by 14 days without the medicine. How RADICAVA ORS will be provided:oIf your healthcare provider prescribes the Starter Kit, you will receive bottles of RADICAVA ORS. Each bottle contains 35 mL of RADICAVA ORS for total of 70 mL to deliver 14 doses. oThere may be some medicine that remains in each bottle after the dose on day and day 14 of the first treatment cycle. Throw away (discard) any medicine that remains.oIf you were not prescribed the starter kit, for each treatment cycle, you will receive bottle of RADICAVA ORS that contains total of 50 mL of RADICAVA ORS to deliver 10 doses. oThere may be some medicine that remains in each bottle after 10 doses. Throw away (discard) any medicine that remains. Fasting Information: oDo not eat or drink anything hours before each dose of RADICAVA ORS if you eat high-fat meal. oDo not eat or drink anything hours before each dose of RADICAVA ORS if you eat low-fat meal.oDo not eat or drink anything hours before each dose of RADICAVA ORS if you take calorie supplement.oYou should wait at least hour after taking your medicine before eating or drinking anything except water.Step 1: Before each use of RADICAVA ORS: Before opening the bottle, turn it upside down (invert) and shake vigorously up and down for at least 30 seconds (see Figure B). Look at the liquid medicine to make sure it is mixed well. If you see any small pieces at the bottom of the bottle, invert the bottle and shake it up and down for another 30 seconds or until you can no longer see the pieces at the bottom of the bottle (see Figure B). If the liquid medicine all looks the same, you can proceed to Step 2.Shake up and down for at least 30 secondsFigure BStep 2: Open the bottle by firmly pressing down on the bottle cap and turning it counterclockwise (to the left). Place the open bottle upright on flat surface. Do not throw away the bottle cap; you will need to replace it after taking each dose.First time use of bottle only. This must only be done time for each bottle. Insert the ribbed end of the bottle adapter into the bottle by firmly pressing it in as far as it will go (see Figure C). Do not remove the bottle adapter. Figure CStep 3: Remove the oral syringe from plastic wrap and make sure the plunger is inserted all the way into the barrel. Push the oral syringe plunger toward its tip to remove excess air (see Figure D). Insert the oral syringe into the opening of the bottle adapter until it is firmly in place (see Figure E). Turn the bottle upside down and slowly pull the plunger to remove small amount of liquid (see Figure F). Figure Figure EFigure FStep 4: Keep the bottle upside down and pull the plunger until it goes up to the last line (5 mL) (see Figure G). While keeping the plunger in the same position, turn the bottle upright, and place it carefully on flat surface. Remove the oral syringe by gently twisting or pulling it out from the bottle (see Figure H). Check the amount of medicine again before moving on to the next step (see Figure I).Note: Do not remove the oral syringe while the bottle is upside down (medicine may leak out through the adapter).Note: If the dose is not correct, insert the oral syringe tip firmly into the bottle adapter. Push the plunger all the way in so that the medicine flows back into the bottle. Turn the bottle upside down. Repeat Step 4. Figure GFigure HFigure IStep 5: Place the tip of the oral syringe in the mouth and aim towards the inside of the cheek. Slowly press down on the plunger until the oral syringe is empty. Swallow all of the medicine (see Figure J). If needed, you can use up to ounces or cup of water to help swallow the medicine. Note: It is normal for small amount of medicine to remain in the tip of the syringe after taking.Figure JStep 6: Leave the bottle adapter inside the bottle. Place the bottle cap on the bottle and turn the cap clockwise (to the right). Keep bottle tightly closed between each use (see Figure K). Figure KStep 7: Remove the plunger from the oral syringe barrel by pulling the plunger and the barrel away from each other. Rinse the oral syringe (plunger and barrel) with water only. Allow it to air dry. Figure LStep 8: When the oral syringe (plunger and barrel) is dry, put the plunger back into the oral syringe barrel. Do not throw away the oral syringe. Store the syringe in clean, dry place.You must complete Steps through under How to take RADICAVA ORS before starting Step under How to take dose of RADICAVA ORS oral suspension through feeding tube.How to take dose of RADICAVA ORS oral suspension through feeding tube: Step 9: Using catheter-tip syringe, flush the feeding tube with ounce (30 mL) of water (see Figure M).Figure MStep 10: Place the oral syringe provided (containing the mL of RADICAVA ORS) into the feeding tube. Slowly push down the plunger until the oral syringe is empty (see Figure N).Figure NStep 11: Using catheter-tip syringe, flush the feeding tube with ounce (30 mL) of water after taking dose of RADICAVA ORS (see Figure O).Figure OStep 12: Leave the adapter in the bottle. Place the bottle cap on the bottle and turn it clockwise (to the right) to close the bottle. Keep the bottle tightly closed between each use (see Figure P).Figure PStep 13: Remove the plunger from the oral syringe barrel by pulling the plunger and barrel away from each other. Rinse the oral syringe (plunger and barrel) with water only (see Figure Q). Allow it to air dry. Figure QStep 14: When the oral syringe (plunger and barrel) are dry, put the plunger back into the oral syringe barrel. Do not throw away the oral syringe. Store the oral syringe in clean, dry place.Marketed and distributed by:Mitsubishi Tanabe Pharma America, Inc., US subsidiary of Mitsubishi Tanabe Pharma Corporation Jersey City, NJ 07310 For more information, go to www.Radicava.com or call 1- 888-292-0058.RADICAVA ORS(R)is registered trademark of Mitsubishi Tanabe Pharma Corporation(C) 2021 Mitsubishi Tanabe Pharma Corporation. All rights reserved.This Instructions for Use has been approved by the U.S. Food and Drug Administration. 22022-1Issued: 05/2022. Read this Instructions for Use before you take RADICAVA ORS for the first time and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.. Important information about measuring RADICAVA ORS: Always measure your prescribed dose of RADICAVA ORS using the oral syringe provided. Ask your healthcare provider or pharmacist who provided the medicine any questions you have about how to measure your prescribed dose. If you miss dose, do not take doses of RADICAVA ORS the next day. Do not take dose of RADICAVA ORS on days 15 through 28.. How to prepare RADICAVA ORS: Keep this Instructions for Use handy when preparing the treatment.. oIf your healthcare provider prescribes Starter Kit, you will receive bottles of RADICAVA ORS. Each bottle will contain 35 mL of RADICAVA ORS for total of 70 mL to be used for your first treatment cycle of 14 days. Only open the second bottle when you have finished the first bottle.. oIf you were not prescribed the Starter Kit, for each treatment cycle you will receive bottle of RADICAVA ORS that contains total of 50 mL of RADICAVA ORS. After the first treatment cycle, RADICAVA ORS is to be used for 10 days out of 14 day periods.. oOnly use the bottle adapter and the reusable mL oral syringes provided with the bottle. Do not use household teaspoon to measure your medicine.. How to store RADICAVA ORS:. oStore RADICAVA ORS upright at room temperature between 68F to 77F (20C to 25C). Protect from light.. oOpening the bottle:oWhen you open the bottle of RADICAVA ORS for the first use, write the date you open the bottle on the bottle label.oAfter opening the bottle of RADICAVA ORS, use within 15 days.. oWhen you open the bottle of RADICAVA ORS for the first use, write the date you open the bottle on the bottle label.. oAfter opening the bottle of RADICAVA ORS, use within 15 days.. oAfter bottle of RADICAVA ORS has been opened and used, white crust may form on the neck or on the side of the bottle. This is due to normal use and RADICAVA ORS can continue to be uses as prescribed. oKeep bottle tightly closed between each use. oThrow away (discard) any RADICAVA ORS that is not used within 15 days after opening the bottle or within 30 days from the date of shipment shown on the carton pharmacy label, whichever happens first. Ask your pharmacist how to properly throw away (discard) RADICAVA ORS you are no longer able to use.. oKeep RADICAVA ORS and all medicines out of the reach of children.. o1 RADICAVA ORS bottle. o1 bottle adapter. o2 (5 mL) reusable oral syringes. oKeep these instructions for future use.. oDo not share RADICAVA ORS with anyone else.. oCall your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.. oPeople who have problems using their hands may need assistance to draw up and give the correct dose of RADICAVA ORS.. Dosing Information:. RADICAVA ORS has different dosing schedules:. oFor the first treatment cycle, you will take RADICAVA ORS every day for 14 days, followed by 14 days without the medicine. oFor the cycles after the first treatment cycle, you will take RADICAVA ORS daily for 10 out of 14 days, followed by 14 days without the medicine.. How RADICAVA ORS will be provided:. oIf your healthcare provider prescribes the Starter Kit, you will receive bottles of RADICAVA ORS. Each bottle contains 35 mL of RADICAVA ORS for total of 70 mL to deliver 14 doses. oThere may be some medicine that remains in each bottle after the dose on day and day 14 of the first treatment cycle. Throw away (discard) any medicine that remains.. oIf you were not prescribed the starter kit, for each treatment cycle, you will receive bottle of RADICAVA ORS that contains total of 50 mL of RADICAVA ORS to deliver 10 doses. oThere may be some medicine that remains in each bottle after 10 doses. Throw away (discard) any medicine that remains. Fasting Information: oDo not eat or drink anything hours before each dose of RADICAVA ORS if you eat high-fat meal. oDo not eat or drink anything hours before each dose of RADICAVA ORS if you eat low-fat meal.. oDo not eat or drink anything hours before each dose of RADICAVA ORS if you take calorie supplement.. oYou should wait at least hour after taking your medicine before eating or drinking anything except water.. Figure Figure EFigure F. Figure GFigure HFigure I. ifu-figure-a. ifu-figure-b. ifu-figure-c. ifu-figure-d. ifu-figure-e. ifu-figure-f. ifu-figure-g. ife-figure-h. ifu-figure-i. ifu-figure-j. ifg-figure-k. ifu-figure-l. ifu-figure-m. ifu-figure-n. ifu-figure-o. ifu-figure-p. ifu-figure-q.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)05/2022 Dosage and Administration (2.1, 2.3, 2.4)05/2022 Contraindications (4)05/2022 Warnings and Precautions (5.1, 5.2)05/2022. Indications and Usage (1)05/2022. Dosage and Administration (2.1, 2.3, 2.4)05/2022. Contraindications (4)05/2022. Warnings and Precautions (5.1, 5.2)05/2022.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling RADICAVAStore RADICAVA at up to 25C (77F). Excursions permitted from 15C to 30C (59F to 86F) [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.RADICAVA ORSPharmacyStore RADICAVA ORS refrigerated between 2oC to 8oC (36F to 46F) and protect from light. Do not freeze. Store upright.PatientStore RADICAVA ORS upright at room temperature between 20C to 25C (68F to 77F). Protect from light.Discard 15 days after opening bottle or if unopened 30 days from date of shipment indicated on the carton pharmacy label.