Radicut

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Radicut uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Patient information
• Radicut reviews

1 INDICATIONS AND USAGE

Radicut is indicated for the treatment of amyotrophic lateral sclerosis (ALS).

Radicut is indicated for the treatment of amyotrophic lateral sclerosis (ALS) (1)

2 DOSAGE AND ADMINISTRATION

The recommended dosage is 60 mg administered as an intravenous infusion over 60 minutes as follows:

• - Initial treatment cycle: daily dosing for 14 days followed by a 14-day drug-free period
• - Subsequent treatment cycles: daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods

2.1 Dosage Information

• The recommended dosage of Radicut 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

Radicut 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 Radicut 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 [ see Warnings and Precautions (5.1, 5.2) ].

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

3 DOSAGE FORMS AND STRENGTHS

Radicut is supplied for intravenous infusion in a single-dose polypropylene bag containing 30 mg of Radicut in 100 mL of clear, colorless aqueous solution.

• - Injection: 30 mg/100 mL in a single-dose polypropylene bag (3 )

4 CONTRAINDICATIONS

Radicut is contraindicated in patients with a history of hypersensitivity to Radicut or any of the inactive ingredients of this product. Hypersensitivity reactions and anaphylactic reactions have occurred .

• - Patients with a history of hypersensitivity to Radicut or any of the inactive ingredients in Radicut (4 )

5 WARNINGS AND PRECAUTIONS

• - Hypersensitivity Reactions: Advise patients to seek immediate medical care
• - Sulfite Allergic Reactions: Radicut 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 Radicut.

Patients should be monitored carefully for hypersensitivity reactions. If hypersensitivity reactions occur, discontinue Radicut, treat per standard of care, and monitor until the condition resolves .

5.2 Sulfite Allergic Reactions

Radicut 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 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

• - Hypersensitivity Reactions [see Warnings and Precautions ]
• - Sulfite 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 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 Radicut 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 .

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Radicut 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 USE IN SPECIFIC POPULATIONS

• - Pregnancy: Based on animal data, may cause fetal harm

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of Radicut in pregnant women. In animal studies, administration of Radicut 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 Radicut (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 Radicut (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 Radicut (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 Radicut in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Radicut 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 Radicut and any potential adverse effects on the breastfed infant from Radicut or from the underlying maternal condition.

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 184 patients with ALS who received Radicut 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 Radicut has not been studied. However, renal impairment is not expected to significantly affect the exposure to Radicut. No dose adjustment is needed in these patients.

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of Radicut 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.

11 DESCRIPTION

The active ingredient in Radicut is Radicut, which is a member of the substituted 2-pyrazolin-5-one class. The chemical name of Radicut 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:

Radicut is a white crystalline powder with a melting point of 129.7°C. It is freely soluble in acetic acid, methanol, or ethanol and slightly soluble in water or diethyl ether.

Radicut injection is a clear, colorless liquid provided as a sterile solution.

Radicut injection is supplied for intravenous infusion in a polypropylene bag containing 30 mg Radicut 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.

chem_structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

Radicut is administered by IV infusion. The maximum plasma concentration of Radicut 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 Radicut. With multiple-dose administration, Radicut does not accumulate in plasma.

Distribution

Radicut 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 Radicut is 4.5 to 6 hours. The half-lives of its metabolites are 2 to 2.8 hours.

Metabolism

Radicut is metabolized to a sulfate conjugate and a glucuronide conjugate, which are not pharmacologically active. The glucuronide conjugation of Radicut involves multiple uridine diphosphate glucuronosyltransferase isoforms (UGT1A6, UGT1A9, UGT2B7, and UGT2B17) in the liver and kidney. In human plasma, Radicut is mainly detected as the sulfate conjugate, which is presumed to be formed by sulfotransferases.

Excretion

In Japanese and Caucasian healthy volunteer studies, Radicut 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 Radicut is hydrolyzed back to Radicut, 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 Radicut pharmacokinetics has been found [see Use in Specific Populations ].

Patients with Renal and Hepatic Impairment

No pharmacokinetic data are available in patients with renal impairment or hepatic impairment [see Use in Specific Populations (8.6, 8.7) ].

Male and Female Patients

No gender effect on Radicut pharmacokinetics has been found.

Racial or Ethnic Groups

There were no significant racial differences in Cmax and AUC of Radicut between Japanese and Caucasian subjects.

Drug Interaction Studies

The pharmacokinetics of Radicut is not expected to be significantly affected by inhibitors of CYP enzymes, UGTs, or major transporters.

In vitro studies demonstrated that, at clinical dose, Radicut 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. Radicut and its metabolites are not expected to induce CYP1A2, CYP2B6, or CYP3A4 at the clinical dose level of Radicut.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

The carcinogenic potential of Radicut has not been adequately assessed.

Mutagenesis

Radicut was negative in in vitro and in vivo (mouse micronucleus) assays.

Impairment of Fertility

Intravenous administration of Radicut (0, 3, 20, or 200 mg/kg) prior to and throughout mating in males and females and continuing in females to gestation day 7 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 3 times the RHD of 60 mg, on a body surface area (mg/m²) basis.

14 CLINICAL STUDIES

The efficacy of Radicut for the treatment of ALS was established in a 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:

• Functionality retained most activities of daily living (defined as scores of 2 points or better on each individual item of the ALS Functional Rating Scale – Revised [ALSFRS-R; described below])
• Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] ≥ 80%)
• Definite or Probable ALS based on El Escorial revised criteria
• Disease duration of 2 years or less

The study enrolled 69 patients in the Radicut 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.

Radicut was administered as an intravenous infusion of 60 mg given 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 (Cycle 1)
• Subsequent 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 a 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 item 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. The distribution of change in ALSFRS-R scores from baseline to Week 24 by percent of patients is shown in Figure 1.

Figure 1: Distribution of Change from Baseline to Week 24 in ALSFRS-R Scores

figure-1

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Radicut injection is supplied as a 30 mg/100 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 . 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). 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.

17 PATIENT COUNSELING INFORMATION

Advise the patients to read the FDA-approved patient labeling (Patient Information).

Hypersensitivity Reactions

Advise patients to seek immediate medical care if they experience signs or symptoms of a hypersensitivity reaction .

Sulfite Allergic Reactions

Advise patients about potential for sulfite sensitivity. Inform patients that Radicut 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 .

Pregnancy and Breastfeeding

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during Radicut therapy .

Advise patients to notify their healthcare provider if they intend to breastfeed or are breastfeeding an infant .

Marketed and distributed by:

Mitsubishi Tanabe Pharma America, Inc., a US subsidiary of Mitsubishi Tanabe Pharma Corporation

525 Washington Blvd., Suite 400,

Jersey City, NJ 07310

Radicut is a trademark of Mitsubishi Tanabe Pharma Corporation

© Mitsubishi Tanabe Pharma Corporation [2017]

118839 [08/2017] Iss. 08/17

PATIENT INFORMATION

Radicut (ra di ká vah)

(edaravone injection)

for intravenous infusion

• This Patient Information or Medication Guide has been approved by the U.S. Food and Drug Administration Revised or Issued: 08/2017

Radicut pharmaceutical active ingredients containing related brand and generic drugs:

• Edaravone

Radicut available forms, composition, doses:

• N/A

Radicut destination | category:

• Human:
• Cardiovascular drugs
• Nootropics and neurotonics

Radicut Anatomical Therapeutic Chemical codes:

• N06BX - Other psychostimulants and nootropics

Radicut pharmaceutical companies:

• Mitsubishi-Tokyo Pharmaceuticals

References

1. Dailymed."RADICAVA (EDARAVONE) INJECTION [MITSUBISHI TANABE PHARMA AMERICA, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."EDARAVONE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "edaravone". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Radicut after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Radicut not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology