PRO-SIMBIOFLOR

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT COVIFOR (COVIFOR)

Composition

active substance: remdesivir; 1 vial contains remdesivir 100 mg; 1 ml of the prepared (reconstituted) solution contains remdesivir 5 mg; excipients: sodium salt of sulfobutyl ether beta-cyclodextrin, hydrochloric acid, sodium hydroxide.

Pharmaceutical Form

Lyoiphilized powder for concentrate for solution for infusion.

Main Physico-Chemical Properties

White to almost white or yellow lyophilized mass or powder.

Pharmacotherapeutic Group

Antiviral medications for systemic use, direct-acting antiviral medications, other antiviral medications.

ATC Code J05A.

Pharmacological Properties

Pharmacodynamics

Remdesivir is a prodrug of an adenosine nucleotide, which is distributed in cells, where it is metabolized to form a pharmacologically active metabolite, nucleoside triphosphate. The conversion of remdesivir to remdesivir triphosphate has been demonstrated in several cell types. Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and competes with the natural substrate ATP for incorporation into growing RNA chains by the SARS-CoV-2-dependent RNA polymerase, leading to delayed chain termination during viral RNA replication. Remdesivir triphosphate is a weak inhibitor of DNA and RNA polymerases of mammals with low likelihood of mitochondrial toxicity.

Pharmacokinetics

The pharmacokinetics of remdesivir were evaluated in adults in several phase 1 studies. After a single intravenous infusion of the remdesivir solution over 2 hours at doses ranging from 3 to 225 mg, remdesivir demonstrated a linear pharmacokinetic profile. After a single intravenous infusion of remdesivir over 2 hours at doses of 75 and 150 mg, both lyophilized and solution forms of the drug provided similar pharmacokinetic parameters (AUCinf, AUClast, and Cmax), indicating similar efficacy of the formulation. Remdesivir 75 mg - lyophilized drug administered intravenously over 30 minutes provided a similar effect of active metabolite triphosphate GS-443902 on peripheral blood mononuclear cells (PBMC) as remdesivir 150 mg - lyophilized drug administered intravenously over 2 hours. After a single intravenous infusion of 150 mg of [14C]-remdesivir, the mean total percentage of the dose excreted was more than 92%, which accounted for approximately 74% and 18% excreted in urine and feces, respectively. Most of the remdesivir dose excreted in the urine was the metabolite GS-441524 (49%), while 10% was excreted as remdesivir.

Clinical Characteristics

Indications

Treatment of coronavirus disease (COVID-19) in adults who have pneumonia and require additional oxygen therapy (oxygen with low or high flow or other non-invasive ventilation at the start of treatment).

Contraindications

Increased sensitivity to the active substance or to any of the excipients of the drug.

Interaction with Other Medicinal Products and Other Types of Interactions

Studies of drug interactions of remdesivir and other concomitant medications have not been conducted. The general potential for interactions is currently unknown. During the day after taking remdesivir, patients should remain under close supervision. Due to the antagonism observed in vitro, concomitant use of remdesivir with chloroquine phosphate or hydroxychloroquine sulfate is not recommended.

Influence of Other Concomitant Medications on Remdesivir

In vitro, remdesivir is a substrate for enzymes that metabolize medications CYP2C8, CYP2D6, and CYP3A4, as well as a substrate for organic anion-transporting polypeptides 1B1 (OATP1B1) and P-glycoprotein (P-gp) transporters. The potential for interaction of remdesivir with inhibitors/inducers of esterase or CYP2C8, 2D6, or 3A4 has not been studied. The risk of clinically significant interaction is unknown. Potent inhibitors may cause a decrease in remdesivir exposure.

Dexamethasone is a moderate inducer of CYP3A and P-gp. Induction is dose-dependent and occurs after multiple doses. It is unknown whether dexamethasone will have a clinically significant effect on remdesivir, as remdesivir has a moderately high hepatic extraction ratio and is used for a short period in the treatment of COVID-19. In vitro, remdesivir is an inhibitor of CYP3A4, OATP1B1, OATP1B3, BSEP, MRP4, and NTCP. The clinical significance of these in vitro studies has not been established.

Influence of Remdesivir on Other Medications

In vitro, remdesivir is an inhibitor of CYP3A4, OATP1B1, and OATP1B3. The clinical significance of interactions of these medications in vitro has not been established. Remdesivir may temporarily increase plasma concentrations of medications that are substrates of CYP3A or OATP 1B1/1B3. It can be assumed that medications that are substrates of CYP3A4 or substrates of OATP 1B1/1B3 should be administered at least 2 hours after remdesivir. Remdesivir induced CYP1A2 and potentiated CYP3A in vitro. Concomitant use of remdesivir with substrates of CYP1A2 or CYP3A4 with a narrow therapeutic index may lead to a loss of their effectiveness.

Dexamethasone is a substrate of CYP3A4, and although remdesivir inhibits CYP3A4, due to the rapid clearance of remdesivir after intravenous administration, remdesivir is unlikely to have a significant effect on the action of dexamethasone.

Special Warnings and Precautions for Use

There are limited clinical data on the use of remdesivir. When using remdesivir, serious and unexpected adverse events may occur that have not been reported before.

Reactions Related to Infusion Administration of the Drug

During infusion administration of remdesivir, reactions were observed and/or temporarily associated with it: hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, vomiting, excessive sweating, and tremors. It is believed that a lower infusion rate (up to 120 minutes) allows avoiding these signs and symptoms. If signs and symptoms of a clinically significant reaction associated with infusion administration of the drug appear, remdesivir administration should be stopped immediately, and appropriate treatment should be started. The use of remdesivir is contraindicated in patients with known increased sensitivity to remdesivir.

Increased Risk of Elevated Transaminase Levels

In clinical studies of remdesivir (in healthy volunteers and patients with COVID-19), an increase in transaminase levels was observed. In most healthy volunteers who received the drug at a dose of up to 150 mg per day for 14 days, an increase in alanine aminotransferase (ALT) levels was observed, including a 10-fold increase in initial values in one subject without signs of clinical hepatitis; adverse events ≥3 severity were not observed. An increase in transaminase levels was also reported in patients with COVID-19 who received remdesivir, including one patient with an ALT level 20 times higher than the upper limit of normal (ULN). Since an increase in transaminase levels has been reported as a symptom of COVID-19 in some patients, the impact of remdesivir on the increase in transaminase levels in this patient population is questionable.

In all patients, before starting remdesivir treatment and daily during remdesivir treatment, liver function laboratory tests should be performed. Remdesivir should not be prescribed to patients in whom the ALT level at the start of the study is ≥5 times higher than the ULN.

Remdesivir administration should be stopped in patients who:

• During remdesivir treatment, the ALT level is ≥5 times higher than the ULN. Remdesivir administration can be resumed if the ALT level is <5 times higher than the ULN.
• An increase in ALT is accompanied by signs or symptoms of liver inflammation or an increase in conjugated bilirubin, alkaline phosphatase, or international normalized ratio (INR).

Kidney Function Impairment

In animal studies, kidney toxicity of the drug was observed. The mechanism of kidney toxicity development is not fully understood. The significance of these studies for humans cannot be ruled out. Before prescribing remdesivir, all patients should determine the glomerular filtration rate (GFR). The use of the drug in patients with GFR <30 ml/min is contraindicated.

Excipients

Remdesivir contains sodium salt of sulfobutyl ether beta-cyclodextrin, which is excreted by the kidneys and accumulates in patients with reduced kidney function, potentially negatively affecting their function. Therefore, remdesivir should not be used in patients with GFR <30 ml/min.

Risk of Reduced Antiviral Activity of the Drug when Used Concomitantly with Chloroquine or Hydroxychloroquine

Concomitant use of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on in vitro studies demonstrating an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral action of remdesivir.

Use in Pregnancy or Breastfeeding

Pregnancy

No adequate and well-controlled studies have been conducted on the use of remdesivir in pregnant women. Animal studies are insufficient to analyze reproductive toxicity. Remdesivir should not be used during pregnancy, except in cases where the clinical condition of the woman requires treatment with remdesivir. During treatment with the drug, women should use effective contraception.

Breastfeeding

It is unknown whether remdesivir penetrates into breast milk, as well as its effect on breastfeeding and milk production. In animal studies, the analog of the nucleoside metabolite GS-441524 was detected in the blood of lactating rats that received remdesivir. Therefore, excretion of remdesivir and its metabolites into breast milk is possible. Due to the risk of side effects from the use of remdesivir and the possibility of transmission of the virus to newborns with negative SARS-CoV-2 impact, breastfeeding should be stopped or therapy with remdesivir should be avoided, taking into account the benefits of therapy and breastfeeding.

Fertility

There are no data on the effect of remdesivir on fertility in humans.

Ability to Affect Reaction Rate when Driving or Operating Other Mechanisms

It is predicted that remdesivir will not have or will have a negligible effect on the reaction rate when driving or operating other mechanisms.

Method of Administration and Dosage

Remdesivir should be used in medical institutions where patients are under close supervision (see "Special Warnings and Precautions for Use").

Adult Patients

Day 1: a single loading dose of remdesivir is 200 mg, administered by intravenous infusion.

Day 2 and subsequent days: 100 mg once daily, administered by intravenous infusion.

The total duration of treatment should be at least 5 days but no more than 10 days.

Elderly Patients

No dose adjustment is required for the use of remdesivir in patients aged 65 years and older.

Patients with Kidney Function Impairment

The pharmacokinetics of remdesivir have not been evaluated in patients with renal insufficiency. Patients with GFR ≥30 ml/min do not require dose adjustment of remdesivir for the treatment of COVID-19. Remdesivir should not be used in patients with GFR <30 ml/min.

Patients with Liver Function Impairment

The pharmacokinetics of remdesivir have not been evaluated in patients with liver insufficiency. It is unknown whether dose adjustment is required for patients with liver insufficiency; therefore, remdesivir should be used in patients with liver function impairment only when the expected benefit outweighs the potential risk. Before starting remdesivir treatment and daily during remdesivir treatment, liver function laboratory tests should be performed in all patients.

Method of Administration

Remdesivir is intended for intravenous infusion after reconstitution and subsequent dilution. The drug should not be administered as an intramuscular injection.

The infusion solution should be prepared in aseptic conditions immediately before the procedure. Before administration, the solution should be visually inspected for the presence of particulate matter or color change; if present, the solution should be discarded and a new one prepared.

Remdesivir should be dissolved in 19 ml of sterile water for injection and diluted in a solution of sodium chloride for injection 9 mg/ml (0.9%) for 30-120 minutes before administration by intravenous infusion.

Reconstitution Instructions

Retrieve the required number of single-dose vials from storage. For each vial:

• Reconstitute the lyophilized powder of remdesivir by adding 19 ml of sterile water for injection in aseptic conditions, using a syringe and needle of the appropriate size.
• Discard the vial if the vacuum prevents the introduction of sterile water for injection into the vial.
• Shake the vial immediately for 30 seconds.
• Allow the contents of the vial to stand for 2-3 minutes. As a result, a clear solution should form.
• If the contents of the vial have not dissolved completely, shake the vial again for 30 seconds and allow the contents to stand for 2-3 minutes. If necessary, repeat this procedure until the contents of the vial are completely dissolved.
• After dissolution, one vial contains 100 mg/20 ml (5 mg/ml) of remdesivir solution.
• Parenteral medications should be visually inspected for particulate matter and color change before administration, if possible, given the solution and container.
• Dilute the solution immediately after reconstitution.

Dilution Instructions

When mixing, care should be taken to avoid accidental contamination with microorganisms. Since this product does not contain preservatives or bacteriostatic agents for the preparation of the ready-to-use solution for parenteral administration, it is necessary to follow the aseptic method of preparation of medications.

If possible, it is recommended to always administer medications for intravenous use immediately after preparation.

Using Table 1, determine the volume of 0.9% physiological solution to be withdrawn from the infusion bag.

NOTE: 100 ml should be reserved for patients with severe fluid restriction, such as acute respiratory distress syndrome (ARDS) or renal failure.

Withdraw the required volume of physiological solution from the infusion bag using a syringe and needle of the appropriate size. Discard the withdrawn physiological solution.

Withdraw the required volume of reconstituted remdesivir for injection from the vial using a syringe of the appropriate size (see Table 1). Discard any unused volume remaining in the vial with remdesivir.

Administer the required volume of reconstituted remdesivir for injection into the selected infusion bag.

Gently rotate the bag 20 times to mix the solution in the bag. Do not shake.

The prepared diluted solution remains stable for 4 hours at room temperature (20-25°C) or 24 hours in the refrigerator (2-8°C).

Table 2

Children. Not used in the pediatric population.

Overdose

Experience with acute overdose of remdesivir in humans is absent. Treatment of overdose with remdesivir should consist of general supportive measures, including monitoring of vital signs and observation of the patient's clinical condition. There is no specific antidote for the treatment of overdose with remdesivir.

Adverse Reactions

Classification of adverse reactions by frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10 000); frequency unknown (cannot be determined from available data).

From the immune system:

• rarely - hypersensitivity reactions;
• frequency unknown - anaphylactic reaction.

From the nervous system:

• often - headache.

From the cardiovascular system:

• frequency unknown - sinus bradycardia*.

From the gastrointestinal tract:

• often - nausea.

From the liver and bile ducts:

• very often - elevated transaminases.

From the skin and subcutaneous tissue:

• often - rash.

Laboratory indicators:

• very often - prolongation of prothrombin time.

Procedural complications:

• rarely - infusion reaction.

*Reported in the post-marketing period, usually normalizes within 4 days after the last intake of remdesivir without additional intervention.

Reporting suspected adverse reactions after registration of the medicinal product is of great importance. This allows for continuous monitoring of the ratio of benefit to risk associated with the use of the medicinal product. Healthcare professionals should report any suspected adverse reactions using the national reporting system.

Shelf Life

2 years.

Store the diluted solution for infusion for up to 4 hours at a temperature below 25°C or 24 hours in the refrigerator (2°C - 8°C).

Storage Conditions

Store in the original packaging at a temperature not exceeding 30°C.

Store in a place inaccessible to children.

Packaging

1 vial in a cardboard box, 6 cardboard boxes in a cardboard box.

Release Category

By prescription.

Manufacturer

Aspiro Pharma Limited.

Manufacturer's Location and Address of Business

Sy.No.321, Biotech park, Phase-III, Karkapatla Village, Markook Mandal, Siddipet Dist-502281, Telangana State, India.

Applicant

Hetero Labs Limited.