Remidia

Remdesivir.

Each vial contains Remdesivir lyophilized powder injection 100 mg (a sterile, preservative-free lyophilized solid that is to be reconstituted with 19 mL of sterile water for injection and diluted into 0.9% saline prior to intravenous (IV) administration).

Pharmacology: Pharmacodynamics: Mechanism of action: Remdesivir is an adenosine nucleotide prodrug that is metabolized within host cells to form the pharmacologically active nucleoside triphosphate metabolite. Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain termination during replication of the viral RNA.
Antiviral activity: Remdesivir exhibited in vitro activity against a clinical isolate of SARS-CoV-2 in primary human airway epithelial cells with a 50% effective concentration (EC50) of 9.9 nM after 48 hours of treatment. The EC50 values of Remdesivir against SARS-CoV-2 in Vero cells were 137 nM at 24 hours and 750 nM at 48 hours post-treatment. The antiviral activity of Remdesivir was antagonised by chloroquine phosphate in a dose-dependent manner when the two drugs were co-incubated at clinically relevant concentrations in HEp-2 cells infected with respiratory syncytial virus (RSV). Higher Remdesivir EC50 values were observed with increasing concentrations of chloroquine phosphate. Increasing concentrations of chloroquine phosphate reduced formation of Remdesivir triphosphate in normal human bronchial epithelial cells.
Resistance: Cell culture resistance profiling of Remdesivir using the rodent CoV murine hepatitis virus identified 2 substitutions (F476L and V553L) in the viral RNA-dependent RNA polymerase at residues conserved across CoVs that conferred 5.6-fold reduced susceptibility to Remdesivir. Introduction of the corresponding substitutions (F480L and V557L) into SARS-CoV resulted in 6-fold reduced susceptibility to Remdesivir cell culture and attenuated SARS-CoV pathogenesis in a mouse model.
The cell culture development of SARS-CoV-2 resistance to Remdesivir has not been assessed to date. No clinical data are available on the development of SARS-CoV-2 resistance to Remdesivir.
Clinical Studies: NIAID ACTT-1 Trial in Subjects with Mild/Moderate and Severe COVID-19: A randomized, double-blind, placebo-controlled clinical trial evaluated Remdesivir 200 mg once daily for 1 day followed by Remdesivir 100 mg once daily for 9 days (for a total of up to 10 days of intravenously administered therapy) in hospitalized adult subjects with COVID-19 with evidence of lower respiratory tract involvement. Treatment with Remdesivir was stopped in subjects who were discharged from the hospital prior to the completion of 10 days of treatment.
The trial enrolled 1,062 subjects: 105 (9.9%) subjects with mild/moderate disease and 957 (90.1%) subjects with severe disease. A total of 285 subjects (26.8%) (n=131 received Remdesivir) were on invasive mechanical ventilation/ECMO. Subjects were randomized in a 1:1 manner, stratified by disease severity at enrollment, to receive Remdesivir (n=541) or placebo (n=521), plus standard of care.
The primary clinical endpoint was time to recovery within 29 days after randomization, defined as either discharged from the hospital or hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care. The median time to recovery was 10 days in the Remdesivir group compared to 15 days in the placebo group recovery rate ratio, 1.29; [95% CI 1.12 to 1.49]; p<0.001). Overall, the odds of improvement in the ordinal scale were higher in the Remdesivir group at Day 15 when compared to the placebo group (odds ratio, 1.6; [95% CI, 1.3 to 1.9]; p<0.001). In a preliminary analysis conducted after 607 recoveries, 14-day mortality was 7.1% for the Remdesivir group versus 11.9% for the placebo group (hazard ratio, 0. 70 [95% CI 0.47, 1.04]; p=0.07).
Among subjects with mild/moderate disease at enrollment (n=105), the median time to recovery was 5 days in both the Remdesivir and placebo groups (recovery rate ratio, 1.22; [95% CI 0.82 to 1.81]); the odds of improvement in the ordinal scale in the Remdesivir group at Day 15 when compared to the placebo group wereas follows: odds ratio, 1.46; [95% CI, 0.71 to 2.97].
Among subjects with severe disease at enrollment (n=957), the median time to recovery was 11 days in the Remdesivir group compared to 18 days in the placebo group (recovery rate ratio, 1.31; [95% CI, 1.12 to 1.52]; p<0.001); the odds of improvement in the ordinal scale in the Remdesivir group at Day 15 when compared to the placebo group were as follows: odds ratio, 1.56; [95% CI, 1.24 to 1.95].
Study GS-US-540-5773 in Subjects with Severe COVID-19: A randomized, open-label multi-center clinical trial (Study GS-US-540-5773) of hospitalized subjects at least 12 years of age with confirmed SARS-CoV-2 infection, oxygen saturation of ≤94% on room air, and radiological evidence of pneumonia compared 200 subjects who received IV Remdesivir for 5 days with 197 subjects who received IV Remdesivir for 10 days. Patients on mechanical ventilation at screening were excluded. All subjects received 200 mg of Remdesivir on Day 1 and 100 mg once daily on subsequent days, plus standard of care. Treatment with Remdesivir was stopped in subjects who were discharged from the hospital prior to completion of their protocol-defined duration of treatment.
The primary endpoint was clinical status on Day 14 assessed on a 7-point ordinal scale consisting of the following categories: 1, death; 2, hospitalized, receiving invasive mechanical ventilation or ECMO; 3, hospitalized, receiving noninvasive ventilation or high-flow oxygen devices; 4, hospitalized, requiring low-flow supplemental oxygen; 5, hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or not related to COVID-19); 6, hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol for Remdesivir administration); and 7, not hospitalized. After adjusting for between-group differences at baseline, patients receiving a 10-day course of Remdesivir had similar clinical status at Day 14 as those receiving a 5-day course (odds ratio for improvement, 0.75; [95% CI 0.51 to 1.12]). 28-day mortality was 11.5% and 14.2% in the 5- and 10-day treatment groups, respectively.
Study GS-US-540-5774 in Subjects with Moderate COVID-19: A randomized, open-label multi-center clinical trial (Study GS-US-540-5774) of hospitalized subjects at least 12 years of age with confirmed SARS-CoV-2 infection and radiological evidence of pneumonia without an oxygen requirement during screening compared treatment with Remdesivir for 5 days (n=191) and treatment with Remdesivir for 10 days (n=193) with standard of care (SOC) (n=200). Subjects treated with Remdesivir received 200 mg on Day 1 and 100 mg once daily on subsequent days. Treatment with Remdesivir was stopped in subjects who were discharged from the hospital prior to completion of their protocol-defined duration of treatment.
The primary endpoint was clinical status on Day 11 assessed on a 7-point ordinal scale consisting of the following categories: 1, death; 2, hospitalized, receiving invasive mechanical ventilation or ECMO; 3, hospitalized, receiving noninvasive ventilation or high-flow oxygen devices; 4, hospitalized, requiring low-flow supplemental oxygen; 5, hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or not related to COVID-19); 6, hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol for Remdesivir administration); and 7, not hospitalized. Baseline clinical status, oxygen support status, and median duration of symptoms and hospitalization prior to first dose of Remdesivir were similar across treatment groups. Overall, the odds of improvement in clinical status were higher in the 5-day Remdesivir group at Day 11 when compared to those receiving only SOC (odds ratio, 1.65; [95% CI, 1.09 to 2.48]; p=0.017). The odds of improvement in clinical status with the 10-day treatment group when compared to those receiving only SOC were not statistically significantly different (odds ratio, 1.31; [95% CI 0.88 to 1.95]; p=0.183). At Day 28, mortality was ≤ 2% in all treatment groups.
Study GS-US-540-5758 in Hospitalized China Subjects with Severe COVID-19: A randomized, double-blind, placebo control, and multi center clinical trial in China (Study GSUS-540-5758) of hospitalized adult subjects who confirmed SARS-CoV-2 infection with Pneumonia confirmed by chest imaging or had oxygen saturation of 94% or lower on room air, OR, ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mmHg or less.
One hundred and fifty-eight subjects received Remdesivir for 10 days (200 mg on the first day and continued with 100 mg Day 10) compared with seventy eight subject received placebo.
The primary endpoint was time to clinical improvement within 28 days after randomization, which defined as a two-point reduction in patients' admission status on a six-point ordinal scale (1, Discharged or having reached discharge criteria (defined as clinical recovery-ie, normalization of pyrexia, respiratory rate <24 breaths per minute, saturation of peripheral oxygen >94% on room air, and relief of cough, all maintained for at least 72 h); 2, Hospital admission but no requiring oxygen therapy; 3, Hospital admission for oxygen therapy (but not requiring high-flow oxygen therapy); 4, Hospital admission for noninvasive ventilation or high-flow oxygen therapy; 5, Hospital admission for extracorporeal membrane oxygenation or mechanical ventilation; and 6, Death), or live discharge from the hospital, whichever came first. The secondary endpoint was 28-day all-cause mortality. The time to clinical improvement in Remdesivir group were not statistically significant different (21 vs 23 days; 95% CI: 0.87 to 1.75). The mortality were also not statistically significant different between Remdesivir and placebo group (14% vs 13%; 95% CI: -8.1 to 10.3). The main outcomes of this trial are presented in the table as follows: (See Table 1.)


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Pharmacokinetics: The pharmacokinetic properties of Remdesivir has been investigated in healthy volunteers.
No pharmacokinetic data is available from patients with COVID-19.
Absorption: The pharmacokinetic properties of Remdesivir and the predominant circulating metabolite GS-441524 have been evaluated in healthy adult subjects. Following intravenous administration of Remdesivir adult dosage regimen, peak plasma concentration was observed at end of infusion, regardless of dose level, and declined rapidly thereafter with a half-life of approximately 1 hour. Peak plasma concentrations of GS-441524 were observed at 1.5 to 2.0 hours post start of a 30 minutes infusion.
Distribution: Remdesivir is approximately 88% bound to human plasma proteins. Protein binding of GS-441524 was low (2% bound) in human plasma. After a single 150 mg dose of [₁₄C]-Remdesivir in healthy subjects, the blood to plasma ratio of ₁₄C-radioactivity was approximately 0.68 at 15 minutes from start of infusion, increased over time reaching ratio of 1.0 at 5 hours, indicating differential distribution of Remdesivir and its metabolites to plasma or cellular components of blood.
Biotransformation: Remdesivir is extensively metabolized to the pharmacologically active nucleoside analog triphosphate GS-443902 (formed intracellularly). The metabolic activation pathway involves hydrolysis by esterases, which leads to the formation of the intermediate metabolite, GS-704277. Phosphoramidate cleavage followed by phosphorylation forms the active triphosphate, GS-443902. Dephosphorylation of all phosphorylated metabolites can result in the formation of nucleoside metabolite GS-441524 that itself is not efficiently re-phosphorylated. The human mass balance study also indicates presence of a currently unidentified major metabolite (M27) in plasma.
Elimination: Following a single 150 mg IV dose of [₁₄C]-Remdesivir, mean total recovery of the dose was 92%, consisting of approximately 74% and 18% recovered in urine and feces, respectively. The majority of the Remdesivir dose recovered in urine was GS-441524 (49%), while 10% was recovered as Remdesivir. These data indicate that renal clearance is the major elimination pathway for GS-441524. The median terminal half-lives of Remdesivir and GS-441524 were approximately 1 and 27 hours, respectively.
Other special populations: Gender, race and age: Pharmacokinetic differences for gender, race, and age have not been evaluated.
Paediatric patients: The pharmacokinetics in paediatric patients have not been evaluated.
Renal impairment: The pharmacokinetics of Remdesivir and GS-441524 in renal impairment has not been evaluated. Remdesivir is not cleared unchanged in urine to any substantial extent, but its main metabolite GS-441524 is renally cleared and the metabolite levels in plasma may theoretically increase in patients with impaired renal function. The excipient betadex sulfobutyl ether sodium is renally cleared and accumulates in patients with decreased renal function. Remdesivir should not be used in patients with eGFR <30 mL/min.
Hepatic impairment: The pharmacokinetics of Remdesivir and GS-441524 in hepatic impairment has not been evaluated. The role of the liver in the metabolism of Remdesivir is unknown.
Preclinical Studies: Toxicology: Following intravenous administration (slow bolus) of Remdesivir to rhesus monkeys and rats, severe renal toxicity occurred after short treatment durations. In male rhesus monkeys at dosage levels of 5, 10, and 20 mg/kg/day for 7 days resulted, at all dose levels, in increased mean urea nitrogen and increased mean creatinine, renal tubular atrophy, and basophilia and casts, and an unscheduled death of one animal at the 20 mg/kg/day dose level. In rats, dosage levels of >3 mg/kg/day for up to 4 weeks resulted in findings indicative of kidney injury and/or dysfunction.
Systemic exposures (AUC) of the predominant circulating metabolite of Remdesivir (GS-441524) were 0.1 times (monkeys at 5 mg/kg/day) and 0.3 times (rat at 3 mg/kg/day) the exposure in humans at the RHD. An unidentified major metabolite (M27) was shown to be present in human plasma. The exposure of M27 in rhesus monkeys and rats is unknown. Animal studies may therefore not be informative of potential risks associated with this metabolite.
Carcinogenesis: Long-term animal studies to evaluate the carcinogenic potential of Remdesivir have not been performed.
Mutagenesis: Remdesivir was not genotoxic in a battery of assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes, and in vivo rat micronucleus assays.
Reproductive toxicity: In female rats, decreases in corpora lutea, numbers of implantation sites, and viable embryos, were seen when Remdesivir was administered intravenously daily at a systemically toxic dose (10 mg/kg/day) 14 days prior to mating and during conception; exposures of the predominant circulating metabolite (GS-441524) were 1.3 times the exposure in humans at the RHD. There were no effects on female reproductive performance (mating, fertility, and conception) at this dose level.
In rats and rabbits, Remdesivir demonstrated no adverse effect on embryofoetal development when administered to pregnant animals at systemic exposures (AUC) of the predominant circulating metabolite of Remdesivir (GS-441524) that were up to 4 times the exposure in humans at the recommended human dose (RHD).
In rats, there were no adverse effects on pre- and post-natal development at systemic exposures (AUC) of the predominant circulating metabolite of Remdesivir (GS-441524) that were similar to the exposure in humans at the recommended human dose (RHD).
It is unknown if the active nucleoside analog triphosphate GS-443902 and the unidentified major human metabolite M27 are formed in rats and rabbits. The reproductive toxicity studies may therefore not be informative of potential risks associated with these metabolites.

Badan POM, the Indonesia Food and Drug Administration, has issued an Emergency Use Authorization (EUA) to permit the emergency use of Remdesivir is for treatment or laboratory confirmed coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) patients hospitalized with severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO).
The Emergency Use Authorization of Remdesivir is for treatment or laboratory confirmed coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) patients hospitalized with severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2); ≤94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO).

This section provides essential information on the use of Remdesivir for the treatment of laboratory confirmed coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) patients hospitalized with severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤ 94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO).
Please refer to this fact sheet for information on use of Remdesivir under the EUA.
DOSING: Use of Remdesivir is confined to healthcare facilities in which patients can be monitored closely.
The recommended dosage of Remdesivir in patients 12 years of age and older and weighing at least 40 kg is: Day 1 - single loading dose of Remdesivir 200 mg given by intravenous infusion; Day 2 onwards - 100 mg given once daily by intravenous infusion.
The total duration of treatment should be at least 5 days and not more than 10 days.
Special populations: Elderly: No dose adjustment of Remdesivir is required in patients over the age of 65 years.
Renal impairment: The pharmacokinetics of Remdesivir have not been evaluated in patients with renal impairment. Patients with eGFR ≥30 mL/min have received Remdesivir for treatment of COVID-19 with no dose adjustment. Remdesivir should not be used in patients with eGFR <30 mL/minute.
Hepatic impairment: The pharmacokinetics of Remdesivir have not been evaluated in patients with hepatic impairment. It is not known if dosage adjustment is appropriate in patients with hepatic impairment.
Pediatric population: The safety and efficacy of Remdesivir in children under the age of 12 years and weighing < 40 kg have not yet been established. No data are available.
Method of administration: For intravenous use.
Remdesivir is for administration by intravenous infusion after reconstitution and further dilution. It must not be given as an intramuscular (IM) injection.
For instructions on reconstitution and dilution of the medicinal product before administration, see as follows: (See Table 2.)


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Prepare solution for infusion under aseptic conditions and on the same day as administration. Remdesivir should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Should either be observed, the solution should be discarded and fresh solution prepared.
Remdesivir must be reconstituted with 19 mL sterile water for injections and diluted in sodium chloride 9 mg/mL (0.9%) solution for injection before being administered via intravenous infusion over 30 to 120 minutes.
Preparation of Remdesivir solution for infusion: Reconstitution: Remove the required number of single-use vial(s) from storage. For each vial: Aseptically reconstitute Remdesivir lyophilized powder injection by addition of 19 mL of sterile water for injections using a suitably sized syringe and needle per vial.
Discard the vial if a vacuum does not pull the sterile water for injections into the vial.
Immediately shake the vial for 30 seconds.
Allow the contents of the vial to settle for 2 to 3 minutes. A clear solution should result.
If the contents of the vial are not completely dissolved, shake the vial again for 30 seconds and allow the contents to settle for 2 to 3 minutes. Repeat this procedure as necessary until the contents of the vial are completely dissolved.
Inspect the vial to ensure the container closure is free from defects and the solution is free of particulate matter.
Dilute immediately after reconstitution.
Dilution: Care should be taken to prevent inadvertent microbial contamination. As there is no preservative or bacteriostatic agent present in this product, aseptic technique must be used in preparation of the final parenteral solution. It is always recommended to administer IV medicines immediately after preparation when possible.
Using Table 3 as follows, determine the volume of sodium chloride 9 mg/mL (0.9%) solution for injection to withdraw from the infusion bag. (See Table 3.)


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Note: 100 mL should be reserved for patients with severe fluid restriction, e.g. with ARDS or renal failure.
Withdraw and discard the required volume of sodium chloride 9 mg/mL from the bag using an appropriately sized syringe and needle per Table 3.
Withdraw the required volume of reconstituted Remdesivir lyophilized powder injection using an appropriately sized syringe per Table 3. Discard any unused portion remaining in the Remdesivir vial.
Transfer the required volume of reconstituted Remdesivir lyophilized powder injection to the selected infusion bag.
Gently invert the bag 20 times to mix the solution in the bag. Do not shake.
The prepared solution is stable for 4 hours at room temperature (20°C to 25°C) or 24 hours in the refrigerator (2°C to 8°C) (including any time before dilution into intravenous infusion fluid).
After infusion is complete, flush with at least 30 mL of sodium chloride 9 mg/mL.
Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
IMPORTANT: This product contains no preservative. Any unused portion of a single-dose Remdesivir vial should be discarded after a diluted solution is prepared.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Should either be observed, the solution should be discarded and fresh solution prepared.
The prepared diluted solution should not be administered simultaneously with any other medication. The compatibility of Remdesivir injection with IV solutions and medications other than 0.9% saline is not known.

Treatment of overdose with Remdesivir should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with Remdesivir.

Remdesivir is contraindicated in patients with known hypersensitivity to any ingredient of Remdesivir.

There are limited clinical data available for Remdesivir. Serious and unexpected adverse events may occur that have not been previously reported with Remdesivir use.
Hypersensitivity including infusion-related and anaphylactic reactions: Hypersensitivity reactions including infusion-related and anaphylactic reactions have been observed during and following administration of Remdesivir. Signs and symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, vomiting, diaphoresis, and shivering. Slower infusion rates, with a maximum infusion time of up to 120 minutes, can be considered to potentially prevent these signs and symptoms. If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue administration of Remdesivir and initiate appropriate treatment.
Increased Risk of Transaminase Elevations: Transaminase elevations have been observed in the Remdesivir clinical trials, including in healthy volunteers and patients with COVID-19. Liver function should be determined in all patients prior to starting Remdesivir and should be monitored while receiving it as clinically appropriate. No clinical studies with Remdesivir have been conducted in patients with hepatic impairment. Remdesivir should only be used in patients with hepatic impairment if the potential benefit outweighs the potential risk.
Remdesivir should not be initiated in patients with Alanine Aminotransferase (ALT) ≥5 times the upper limit of normal at baseline.
Remdesivir should be discontinued in patients who develop: ALT ≥5 times the upper limit of normal during treatment with Remdesivir. It may be restarted when ALT is <5 times the upper limit of normal. OR; ALT elevation accompanied by signs or symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or international normalised ratio (INR).
Renal impairment: In animal studies on rats and monkeys, severe renal toxicity was observed. The mechanism of this renal toxicity is not fully understood. A relevance for humans cannot be excluded. All patients should have eGFR determined prior to starting Remdesivir and while receiving it as clinically appropriate. Remdesivir should not be used in patients with eGFR <30 mL/min.
Excipients: Remdesivir contains betadex sulfobutyl ether sodium, which is renally cleared and accumulates in patients with decreased renal function, which may potentially adversely affect renal function. Therefore Remdesivir should not be used in patients with eGFR <30 mL/min.
Risk of reduced antiviral activity when coadministered with chloroquine or hydroxychloroquine: Coadministration of Remdesivir and chloroquine phosphate or hydroxychloroquine sulphate is not recommended based on in vitro data demonstrating an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of Remdesivir.

Pregnancy: There are no or limited amount of data from the use of Remdesivir in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see Pharmacology: Preclinical Studies under Actions). Remdesivir should not be used during pregnancy unless the clinical condition of the women requires treatment with it.
Women of child-bearing potential have to use effective contraception during treatment.
Breast-feeding: It is unknown whether Remdesivir is excreted in human milk or the effects on the breast-fed infant, or the effects on milk production.
In animal studies, the nucleoside analog metabolite GS-441524 has been detected in the blood of nursing rat pups of mothers given Remdesivir. Therefore, excretion of Remdesivir and/or metabolites into the milk of lactating animals can be assumed.
Because of the potential for viral transmission to SARS-CoV-2-negative infants and adverse reactions from the drug in breast-feeding infants, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Remdesivir therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: No human data on the effect of Remdesivir on fertility are available. In male rats, there was no effect on mating or fertility with Remdesivir treatment. In female rats, however, an impairment of fertility was observed. The relevance for humans is unknown.

The most common adverse reaction in healthy volunteers is increased transaminases (14%). The most common adverse reaction in patients with COVID-19 is nausea (4%).
The adverse reactions in Table 4 are listed as follows by system organ class and frequency. Frequencies are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000). (See Table 4.)


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No clinical interaction studies have been performed with Remdesivir. The overall potential for interactions is currently unknown; patients should remain under close observation during the days of Remdesivir administration. Due to antagonism observed in vitro, concomitant use of Remdesivir with chloroquine phosphate or hydroxychloroquine sulphate is not recommended.
Effects of other medicinal products on Remdesivir: In vitro, Remdesivir is a substrate for esterases in plasma and tissue, drug metabolizing enzymes CYP2C8, CYP2D6, and CYP3A4, and is a substrate for Organic Anion Transporting Polypeptides 1B1 (OATP1B1) and P-glycoprotein (P-gp) transporters.
The potential of interaction of Remdesivir with inhibitors/inducers of the hydrolytic pathway (esterase) or CYP2C8, 2D6 or 3A4 has not been studied. The risk of clinically relevant interaction is unknown. Strong inhibitors may result in increased Remdesivir exposure. The use of strong inducers (e.g. rifampicin) may decrease plasma concentrations of Remdesivir and is not recommended.
Dexamethasone is reported to be a moderate inducer of CYP3A and P-gp. Induction is dose-dependent and occurs after multiple doses. Dexamethasone is unlikely to have a clinically significant effect on Remdesivir as Remdesivir has a moderate-high hepatic extraction ratio, and is used for a short duration in the treatment of COVID-19.
Effects of Remdesivir on other medicinal products: In vitro, Remdesivir is an inhibitor of CYP3A4, OATP1B1 and OATP1B3. The clinical relevance of these in vitro drug interactions has not been established. Remdesivir may transiently increase plasma concentrations of medicinal products that are substrates of CYP3A or OATP 1B1/1B3. No data is available, however it can be suggested that medicinal products that are substrates of CYP3A4 or substrates of OATP1B1/1B3 should be administered at least 2 hours after Remdesivir. Remdesivir induced CYP1A2 and potentially CYP3A in vitro. Co-administration of Remdesivir with CYP1A2 or CYP3A4 substrates with narrow therapeutic index may lead to loss of their efficacy.
Dexamethasone is a substrate of CYP3A4 and although Remdesivir inhibits CYP3A4, due to Remdesivir's rapid clearance after I.V administration, Remdesivir is unlikely to have a significant effect on dexamethasone exposure.

Do not reuse or save unused Remdesivir lyophilized powder, injection solution, or diluted solution for infusion for future use. This product contains no preservative.
Lyophilized powder: Store Remdesivir for injection, 100 mg, vials below 30°C until required for use. Do not use after expiration date.
After reconstitution with sterile water, the solution is stable for 4 hours at room temperature (20°C to 25°C) or 24 hours at refrigerated temperature (2°C to 8°C).
After dilution for infusion: The prepared diluted solution is stable for 4 hours at room temperature (20°C to 25°C) or 24 hours at refrigerated temperature (2°C to 8°C).

FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF REMDESIVIR: Badan POM, the Indonesia Food and Drug Administration, has issued an Emergency Use Authorization (EUA) to permit the emergency use of Remdesivir is for treatment or laboratory confirmed coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) patients hospitalized with severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤ 94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO).
The Emergency Use Authorization of Remdesivir is for treatment or laboratory confirmed coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) patients hospitalized with severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤ 94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO).
ADMINISTRATION: Remdesivir must be administered by a healthcare professional pursuant to a valid prescription of a licensed practitioner. Use of Remdesivir is confined to healthcare facilities in which patients can be monitored closely.
Remdesivir must be administered by intravenous (IV) infusion over 30 to 120 minutes. The optimal dosing and duration of treatment is unknown.
The suggested dose under this EUA for Remdesivir to treat laboratory confirmed COVID-19 adults and adolescents (aged 12 years and older with body weight at least 40 kg) patients hospitalized with severe disease, which is: single loading dose of Remdesivir 200 mg given by intravenous infusion on the first day, continue with 100 mg given once daily by intravenous infusion on day 2 onwards. The total duration of treatment should be at least 5 days and not more than 10 days.
For patients requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO), the recommended total treatment duration is 10 days.
For patients not requiring invasive mechanical ventilation and/or ECMO, the recommended total treatment duration is 5 days. If a patient does not demonstrate clinical improvement, treatment may be extended for up to 5 additional days for a total treatment duration of up to 10 days.
Remdesivir is available as a lyophilized powder injection.
See the Full EUA Prescribing Information for complete dosage, administration, and preparation instructions.
Health care providers must submit a report on all medication errors and ALL SERIOUS ADVERSE EVENTS related to Remdesivir.
For information on clinical trials that are testing the use of Remdesivir in COVID-19, please see www.clinicaltrials.gov
Instructions for Healthcare Providers: As the health care provider, you must communicate to your patient or parent/caregiver information consistent with the "Informasi Produk untuk Pasien (Fact Sheet for Patients and Parents/Caregivers)" (and provide a copy of the Fact Sheet) prior to the patient receiving Remdesivir, including: 1. That the Badan POM has authorized emergency use of Remdesivir.
2. That the patient has the option to accept or refuse administration of Remdesivir.
3. The potential consequences of refusing Remdesivir.
4. The significant known and potential risks and benefits of Remdesivir, as supplied under this EUA.
5. The alternative products that are available and their benefits and risks, including clinical trials. If providing this information will delay the administration of Remdesivir to a degree that would endanger the lives of patients, the information must be provided to the patients as soon as practicable after Remdesivir is administered.
Mandatory Requirements for Remdesivir Administration under Emergency Use Authorization: In order to mitigate the risks of using this unapproved product under EUA and to optimize the potential benefit of Remdesivir, the following items are required. Use of unapproved Remdesivir under this EUA is limited to the following (all requirements must be met): 1. Treatment of laboratory confirmed coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) patients hospitalized with severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤ 94% on room air or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO). Specifically, Remdesivir is authorized only for the following patients who are admitted to a hospital and under the care or consultation of a licensed clinician (skilled in the diagnosis and management of patients with potentially life-threatening illness and the ability to recognize and manage medication-related adverse events): a. Adult patients for whom use of an IV agent is clinically appropriate.
b. Adolescent patients for whom use of an IV agent is clinically appropriate.
2. As the health care provider, communicate to your patient or parent/caregiver information consistent with the "Informasi Produk untuk Pasien" prior to the patient receiving Remdesivir. Health care providers (to the extent practicable given the circumstances of the emergency) must document in the patient's medical record that the patient/caregiver has been: a. Given the "Informasi Produk untuk Pasien", b. Informed of alternatives to receiving Remdesivir, and c. Informed that Remdesivir is an unapproved drug that is authorized for use under Emergency Use Authorization.
3. Adult and adolescents patients (> 12 years old) must have an eGFR determined prior to Remdesivir first administration.
4. Hepatic laboratory testing should be performed in all patients prior to starting Remdesivir and daily while receiving Remdesivir.
5. Patients with known hypersensitivity to any ingredient of Remdesivir must not receive Remdesivir.
6. The prescribing health care provider and/or the provider's designee are/is responsible for mandatory responses to requests from Badan POM for information about adverse events and medication errors following receipt of Remdesivir.
7. The prescribing health care provider and/or the provider's designee are/is responsible for mandatory reporting of all medication errors and adverse events (death, serious adverse events*) considered to be potentially related to Remdesivir occurring during Remdesivir treatment within 7 calendar days from the onset of the event. The reports should include unique identifiers and the words "Remdesivir under Emergency Use Authorization (EUA)" in the description section of the report.
Submit adverse event reports to: Pusat Farmakovigilans/MESO Nasional; Direktorat Pengawasan Keamanan, Mutu, dan Ekspor Impor Obat, Narkotika, Psikotropika, Prekursor dan Zat Adiktif; Badan Pengawas Obat dan Makanan; https://e-meso.pom.go.id/ADR.
Submitted reports should include in the field name, "Describe Event, Problem, or Product Use/Medication Error'' the statement "Remdesivir Treatment under EUA".
*Serious Adverse Events are defined as: death; a life-threatening adverse event; inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect; a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.
APPROVED AVAILABLE ALTERNATIVES: There is no approved available alternative product. There are EUAs for other COVID-19 treatments. The health care provider should visit https://clinicaltrials.gov/ to determine whether the patient may be eligible for enrollment in a clinical trial.
AUTHORITY FOR ISSUANCE OF THE EUA: Indonesian Government has declared an emergency situation as a result of pandemic outbreak of COVID-19 that justifies the emergency need of using Remdesivir as a treatment option in this situation. In response to that situation, the Badan POM has issued an Emergency Use Authorization (EUA) for the use of the Badan POM-approved product Remdesivir for treatment of laboratory confirmed coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) patients hospitalized with severe disease. As a health care provider, you must comply with the mandatory requirements of the EUA listed above. Although limited scientific information is available, it is reasonable to believe that Remdesivir may be effective for treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) patients hospitalized with severe disease, as specified in this Fact Sheet. You may be contacted and asked to provide information to help with the assessment of the use of the product during this emergency. Serious adverse events related to the use of Remdesivir must be reported to Badan POM through Pusat Farmakovigilans/MESO Nasional, Badan Pengawas Obat dan Makanan online http://e-meso.pom.go.id/ADR. Please include in the field name, "Describe Event, Problem, or Product Use/Medication Error" the following statement: Remdesivir Treatment under Emergency Use Authorization (EUA).
This EUA for Remdesivir will end when the Badan POM determines that the circumstances justifying the EUA no longer exist or when there is a change in the approval status of the product such that an EUA is no longer needed.

Antivirals

J05AB16 - remdesivir ; Belongs to the class of nucleosides and nucleotides excluding reverse transcriptase inhibitors. Used in the systemic treatment of viral infections.

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