Instructions Flertis solution for infusions 0.3 mg/ml glass bottle 100 ml No. 1
Composition
active ingredient: edaravone;
1 ml of solution contains edaravone 0.3 mg;
Excipients: cysteine hydrochloride, monohydrate; sodium metabisulfite (E 223); sodium chloride; concentrated phosphoric acid; sodium hydroxide; water for injections.
Dosage form
Solution for infusion.
Main physicochemical properties: clear colorless liquid.
Pharmacotherapeutic group
Other drugs for the treatment of diseases of the central nervous system. ATC code N07XX14.
Pharmacological properties
Pharmacodynamics.
The mechanism by which edaravone exerts its therapeutic effect in patients with amyotrophic lateral sclerosis (ALS) is unknown.
Pharmacokinetics.
The drug is administered by intravenous infusion. The maximum concentration of edaravone in the blood plasma (Cmax) was achieved at the end of the infusion. There was a trend of more than dose-proportional increase in the area under the concentration-time curve (AUC) and Cmax of edaravone. With repeated administration, edaravone does not accumulate in plasma.
Distribution
Edaravone binds to human serum proteins (92%), primarily albumin, and is concentration-independent over the range of 0.1 to 50 μmol/L.
Metabolism
Edaravone is metabolized to a sulfate and glucuronide conjugate, which are not pharmacologically active. 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 primarily found as the sulfate conjugate, which is apparently formed by sulfotransferases.
Breeding
The mean terminal elimination half-life of edaravone is 4.5–6 hours. The half-life of its metabolites is 2 to 2.8 hours. In studies in healthy volunteers, edaravone was excreted primarily in the urine as the glucuronide conjugate (70–90% of the dose). Approximately 5–10% of the dose was recovered in the urine as the sulfate conjugate, and only 1% or less of the dose was recovered in the urine as unchanged drug. In vitro studies have demonstrated that the sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in the human kidney before being excreted in the urine.
Indication
Treatment of amyotrophic lateral sclerosis (ALS).
Contraindication
History of hypersensitivity to any component of the medicinal product. Hypersensitivity reactions and anaphylactic reactions.
Interaction with other medicinal products and other types of interactions
Other medications should not be administered into the infusion bottle or mixed with Flertis.
The pharmacokinetics of edaravone are not expected to be significantly affected by inhibitors of CYP enzymes, UGTs, or major transporters.
In vitro studies have demonstrated that at clinical doses, edaravone and its metabolites will not 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 of Flertis.
Application features
Hypersensitivity reactions
Hypersensitivity reactions (redness, blistering and erythema multiforme) and cases of anaphylaxis (urticaria, hypotension and dyspnoea) have been reported in spontaneous post-marketing reports of edaravone. Patients with hypersensitivity reactions should be closely monitored. If hypersensitivity reactions occur, Flertis should be discontinued, appropriate treatment should be given and the patient should be observed until recovery.
Use in elderly patients
Among 184 patients with ALS who received edaravone in 3 placebo-controlled clinical trials, a total of 53 patients were 65 years of age or older, including 2 patients over 75 years of age. No overall differences in safety or efficacy were observed between these patients and younger patients, but greater sensitivity in some elderly subjects cannot be ruled out.
Kidney dysfunction
The effect of renal impairment on the pharmacokinetics of Flertis has not been studied. However, renal impairment is not expected to significantly alter the exposure of edaravone. No dose adjustment is necessary for these patients.
Liver dysfunction
The effect of hepatic impairment on the pharmacokinetics of Flertis has not been studied. No dose adjustment is required in patients with mild or moderate hepatic impairment. There are no specific dosing recommendations for patients with severe hepatic impairment.
Allergic reactions to sulfites
The drug Flertis contains sodium bisulfite, which may rarely cause hypersensitivity reactions and bronchospasm.
This medicinal product contains 14.84 mmol (or 341.339 mg)/dose of sodium. Caution should be exercised when administering this medicinal product to patients on a controlled sodium diet.
Use during pregnancy or breastfeeding
There is insufficient data on the safety of Flertis during pregnancy. In animal studies, edaravone administration to pregnant rats and rabbits at clinically relevant doses caused adverse effects on embryo/fetal development (increased mortality, decreased growth, delayed sexual development, and behavioral changes). Most of these effects occurred at doses that were also associated with maternal toxicity. Patients should be advised to inform their physician if they become pregnant or intend to become pregnant during treatment with Flertis.
In the general US 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 of major birth defects and miscarriage in patients with ALS is unknown.
In rats, intravenous administration of edaravone (0, 3, 30, or 300 mg/kg/day) throughout the period of organogenesis resulted in reduced fetal weights at all doses. In females allowed to give birth naturally, offspring weights were 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 non-toxic dose for embryo-fetal development was identified; the low dose was less than the recommended human dose of 60 mg based on body surface area (mg/m2).
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 that was associated with maternal toxicity. The maximum non-toxic dose for embryofetal development is approximately 6 times the recommended human dose (RHD) based on body surface area (mg/m2).
The effects of edaravone (0, 3, 20, or 200 mg/kg/day) administered intravenously to rats on GD 17 during lactation on the offspring were evaluated 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, increased stillbirths, offspring mortality, and delayed physical development (vaginal opening) were observed at the highest dose. Reproductive function in the offspring was not affected by edaravone in either study. Maternal toxicity was evident in both studies at all doses except the lowest dose. The no-effect dose (3 mg/kg/day) is less than the ADI on a mg/m2 basis.
Breastfeeding period
There are no data on the presence of edaravone in human milk, the effects of the drug on breastfeeding or on milk production. In rats, edaravone and its metabolites are excreted in milk. The benefit of breastfeeding to the development and health of the child should be weighed against the mother's clinical need for Flertis, taking into account any potential adverse effects of Flertis on the breastfed child and the impact of the mother's underlying disease. Patients should be advised to inform their physician if they intend to breastfeed or are breast-feeding an infant.
Impact on fertility
Intravenous administration of edaravone (0, 3, 20, or 200 mg/kg) to animals prior to and during mating in males and females, and in females up to day 7 of gestation, had no effect on fertility; however, disruption of the estrous cycle and mating was observed at the highest dose tested. No effects on reproductive function were observed at lower doses, which were 3 times the RDX of 60 mg based on body surface area (mg/m2).
Ability to influence reaction speed when driving vehicles or other mechanisms
The drug is intended for use in a hospital setting, therefore such data are not available.
Method of administration and doses
Flertis is for intravenous infusion only. Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration, if possible.
The recommended daily dose is 60 mg, administered as an intravenous infusion over 60 minutes.
The following treatment regimen is recommended:
The first course is 14 days of taking the drug, followed by a 14-day break.
The following courses involve administering 10 doses of the drug for 14 days, followed by a 14-day break.
Each 60 mg dose of Flertis is administered sequentially from two 30 mg intravenous infusion vials over 60 minutes (infusion rate approximately 1 mg per minute [3.33 mL per minute]).
If any signs or symptoms of a hypersensitivity reaction occur, the infusion should be discontinued immediately (see section 4.4).
Other medications should not be administered into the infusion bag or mixed with Flertis.
Children.
The safety and efficacy of the drug in children have not been established.
Overdose
Cases of overdose have not been described.
Adverse reactions
In clinical trials, the most serious adverse reactions with edaravone treatment included hypersensitivity and allergic reactions to sulfites, including anaphylactic symptoms. Bruising or bruising, gait disturbance, headache, dermatitis, and eczema were the most common adverse reactions, occurring in at least 7–10% of patients treated with edaravone during the studies. Respiratory failure, glycosuria, infection, or lichen occurred in at least 4–6% of patients.
Hypersensitivity and anaphylactic reactions have been reported in post-marketing experience with edaravone. Because these events were reported voluntarily and the patient population is not known, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Reporting of suspected adverse reactions
Reporting of adverse reactions after registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the link: https//aisf.dec.gov.ua/.
Expiration date
2 years.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
Does not require special storage conditions.
Keep out of reach of children.
Incompatibility.
Do not mix with other medicinal products except those mentioned in the section "Method of administration and dosage".
Packaging
100 ml in glass bottles. 1 bottle in a pack.
Release category: By prescription.
Producer
JSC "Farmak".
Location of the manufacturer and address of its place of business.
Ukraine, 04080, Kyiv, Kyrylivska St., 74.
