Fleretis

INSTRUCTIONS for medical use of the medicinal product FLERTIS (FLERTIS)

Composition:

Active substance: edaravone;

1 ml of solution contains edaravone 0.3 mg;

Excipients: cysteine hydrochloride monohydrate; sodium metabisulfite (E 223); sodium chloride; phosphoric acid concentrated; sodium hydroxide; water for injections.

Pharmaceutical form. Infusion solution.

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. Maximum plasma concentration of edaravone (Cmax) was achieved at the end of the infusion. A more than dose-proportional increase in the area under the plasma concentration–time curve (AUC) and Cmax of edaravone was observed. With repeated administration, edaravone does not accumulate in plasma.

Distribution

Edaravone is bound to human serum proteins (92%), primarily to albumin, independently of concentration within the range of 0.1 to 50 μmol/L.

Metabolism

Edaravone is metabolized to sulfate and glucuronide conjugates, which are not pharmacologically active. Glucuronidation of edaravone involves multiple isoforms of uridine diphosphate-glucuronosyltransferase (UGT) (UGT1A6, UGT1A9, UGT2B7, and UGT2B17) in the liver and kidneys. In human plasma, edaravone is primarily present as the sulfate conjugate, which appears to be formed via sulfotransferases.

Elimination

The mean terminal elimination half-life of edaravone is 4.5–6 hours. The elimination half-life of its metabolites ranges from 2 to 2.8 hours. In studies conducted in healthy volunteers, edaravone was excreted predominantly in urine as the glucuronide conjugate (70–90% of the dose). Approximately 5–10% of the dose was recovered in urine as the sulfate conjugate, and only 1% or less of the dose was excreted unchanged. In vitro studies show that the sulfate conjugate of edaravone is hydrolyzed back to edaravone, which is then converted to the glucuronide conjugate in human kidneys prior to excretion in urine.

Clinical characteristics.

Indications.

Treatment of amyotrophic lateral sclerosis (ALS).

Contraindications.

Hypersensitivity to any component of the medicinal product in the medical history. Hypersensitivity reactions and anaphylactic reactions.

Interaction with other medicinal products and other forms of interaction.

Other drugs should not be added to the infusion vial or mixed with the medicinal product Flerdys.

Clinically significant effects of CYP, UGT enzyme inhibitors or major transporters on the pharmacokinetics of edaravone are not expected.

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 the medicinal product Flerdys.

Special precautions for use.

Hypersensitivity reactions

In spontaneous post-marketing reports for edaravone, hypersensitivity reactions (flushing, blisters, and erythema multiforme) and cases of anaphylaxis (urticaria, hypotension, and dyspnea) have been reported. Patients should be closely monitored for hypersensitivity reactions. If hypersensitivity reactions occur, administration of the medicinal product Flerdys should be discontinued, appropriate treatment initiated, and the patient observed until symptoms resolve.

Use in elderly patients

Among 184 ALS patients who received edaravone in 3 placebo-controlled clinical trials, a total of 53 patients were aged 65 years 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 individuals cannot be ruled out.

Renal function impairment

The effect of renal impairment on the pharmacokinetics of Flerdys has not been studied. However, renal impairment is not expected to significantly alter the effect of edaravone. Dose adjustment in these patients is not required.

Hepatic function impairment

The effect of hepatic impairment on the pharmacokinetics of Flerdys has not been studied. Dose adjustment is not required in patients with mild or moderate hepatic impairment. There are no specific dosage recommendations for patients with severe hepatic impairment.

Allergic reactions to sulfites

The medicinal product Flerdys contains sodium bisulfite, which may rarely cause hypersensitivity reactions and bronchospasm.

This medicinal product contains 14.84 mmol (or 341.339 mg) of sodium per dose. Caution should be exercised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

Pregnancy

There is insufficient data on the safety of Flerdys during pregnancy. In animal studies, administration of edaravone at clinically relevant doses to pregnant rats and rabbits had adverse effects on embryofetal development (increased mortality, reduced growth, delayed sexual maturation, and behavioral changes). Most of these effects occurred at doses 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 Flerdys.

In the general US population, the estimated background risk of major congenital malformations and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. The background risk of major congenital malformations 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 weight at all doses. In dams allowed to deliver naturally, offspring weight was decreased at the highest tested dose. Maternal toxicity was also observed at the highest tested dose. No adverse effects on reproductive function in offspring were observed. A no-toxic dose for embryofetal development was not identified; the lowest dose was less than the recommended human dose of 60 mg when adjusted for body surface area (mg/m²).

In rabbits, intravenous administration of edaravone (0, 3, 20, or 100 mg/kg/day) throughout organogenesis resulted in embryofetal death at the highest studied dose, which was associated with maternal toxicity. The maximum no-toxic dose for embryofetal development was approximately 6 times higher than the recommended human dose (RHD) when adjusted for body surface area (mg/m²).

The effects of edaravone (0, 3, 20, or 200 mg/kg/day) administered intravenously to rats from gestation day 17 through the lactation period were evaluated in two studies. In the first study, offspring mortality was observed at the high dose, and increased activity was observed at medium and high doses. In the second study, increased stillbirths, offspring mortality, and delayed physical development (vaginal opening) were observed at the highest dose. Edaravone did not affect reproductive function in offspring in either study. Maternal toxicity was evident in both studies at all doses except the lowest. The no-effect dose for developmental toxicity (3 mg/kg/day) is lower than the RHD when adjusted for mg/m².

Breastfeeding

There are no data on the presence of edaravone in human milk, the effect of the drug on breastfeeding, or on milk production. In rats, edaravone and its metabolites are excreted in milk. The decision regarding breastfeeding should take into account the benefits of breastfeeding for the child's development and health, the mother's clinical need for Flerdys, any potential adverse effects of Flerdys on the breastfed infant, and the impact of the mother's underlying disease. Patients should be advised to inform their physician if they intend to breastfeed or are currently breastfeeding.

Effects on fertility

Intravenous administration of edaravone (0, 3, 20, or 200 mg/kg) to animals before and during mating in both males and females, and in females up to day 7 of pregnancy, did not affect fertility; however, disturbances in estrus cycle and mating were observed at the highest dose studied. No effects on reproductive function were observed at lower doses, which were 3 times higher than the RHD of 60 mg when adjusted for body surface area (mg/m²).

Ability to affect reaction speed when driving or operating machinery

The medicinal product is intended for use in a hospital setting; therefore, such data are not available.

Method of administration and dosage.

The medicinal product Fertis is intended for intravenous infusion only. Parenteral medicinal products should be visually inspected for the presence of particulate matter and discoloration prior to administration, whenever solution and container permit.

The recommended daily dose is 60 mg administered as an intravenous infusion over 60 minutes.

The following treatment regimen is recommended:

• Initial course — 14 days of drug administration, followed by a 14-day break.
• Subsequent courses — administration of 10 doses of the drug over 14 days, followed by a 14-day break.

Each 60 mg dose of Fertis should be administered sequentially from two 30 mg vials for intravenous infusion over 60 minutes (infusion rate approximately 1 mg per minute [3.33 mL per minute]).

If any signs or symptoms of hypersensitivity reactions occur, the infusion must be stopped immediately (see section "Special precautions").

Other medicinal products should not be added to the infusion bag or mixed with Fertis.

Children.

The safety and efficacy of Fertis in children have not been established.

Overdose.

Cases of overdose have not been reported.

Adverse Reactions

In clinical studies, the most serious adverse effects observed during edaravone treatment included hypersensitivity and allergic reactions to sulfites, including anaphylactic symptoms. Bruising or contusions, gait disturbance, headache, dermatitis, and eczema were the most common adverse reactions observed in at least 7–10% of patients receiving edaravone during the studies. Respiratory failure, glucosuria, infection, or lichen were observed in at least 4–6% of patients.

During the post-marketing period, hypersensitivity reactions and anaphylactic reactions have been reported with edaravone use. Because these events were reported voluntarily and the population size is unknown, it is not possible to reliably estimate their frequency or establish a causal relationship to the drug exposure.

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

No special storage conditions required.

Keep out of reach and sight of children.

Incompatibilities.

Do not mix with other medicinal products except those specified in the section “Dosage and administration”.

Packaging.

100 ml in glass bottles. 1 bottle per carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.