Consumer medicine information

Veklury Concentrate for Injection

Remdesivir

BRAND INFORMATION

Brand name

Veklury Concentrate for Injection

Active ingredient

Remdesivir

Schedule

1. Why am I using VEKLURY?

VEKLURY contains the active ingredient remdesivir.

VEKLURY is an anti-virus medicine.

VEKLURY is used to treat COVID-19.

COVID 19 is caused by a virus called a coronavirus. VEKLURY stops the virus in cells from reproducing, and this stops the virus multiplying in the body. This can help your body to overcome the virus infection and may help you get better faster.

VEKLURY will be given in hospital to some people with COVID 19. It is suitable for adults and adolescents (aged 12 years and over) weighing at least 40 kg. It will only be given to patients who have pneumonia, and need extra oxygen to help them breathe. It will be given to you by a doctor or nurse, as a drip into a vein (an intravenous infusion), lasting 30 to 120 minutes, once a day. You will be given VEKLURY every day for at least 5 days. Your doctor may extend the treatment up to a total of 10 days. You will be closely monitored during your treatment.

2. What should I know before I use VEKLURY?

Warnings

Do not use VEKLURY if:

You are allergic to remdesivir, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

have any other medical conditions
take any medicines for any other condition
if you have liver problems. Some people developed increased liver enzymes when given VEKLURY. Your doctor will do blood tests before starting treatment to check whether you can be given it safely.
have kidney problems. Some people with severe kidney problems may not be given this medicine. Your doctor will do blood tests to check whether you can be given it safely.
if you are pregnant or breast-feeding. Talk to your doctor or nurse if you are pregnant (or you might be), or if you are breast-feeding.

Reactions following the infusion

VEKLURY can cause allergic reactions or reactions following the infusion. Symptoms can include:

Changes to blood pressure or heart rate.
Low oxygen level in blood
Shortness of breath, wheezing
Swelling of the face, lips, tongue or throat (angioedema)
Rash
Feeling sick (nausea)
Sweating
Shivering.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

This is because the effects of VEKLURY in pregnant or breastfeeding women are not known, and it may harm your unborn baby or your breastfeeding child. VEKLURY will only be given if the potential benefits of treatment outweigh the potential risks to the mother and the unborn baby.

It is not yet known whether VEKLURY or the COVID 19 virus pass into human breast milk, or what the effects might be on the baby or milk production. Your doctor will help you decide whether to continue breast-feeding or to start treatment with VEKLURY. You will need to consider the potential benefits of treatment for you, compared with the health benefits and risks of breast-feeding for your baby.

Blood tests before and during treatment

If you are prescribed VEKLURY, you will be given blood tests before treatment starts. Patients being treated with VEKLURY will have blood tests every day during their treatment. These tests are to check for kidney or liver problems. VEKLURY will be stopped if your kidney or liver show signs of damage during treatment.

Children and adolescents

VEKLURY is suitable for adults and adolescents (12 years and over) weighing at least 40 kg.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Do not take chloroquine or hydroxychloroquine at the same time as VEKLURY.

Certain medicines e.g. midazolam or pitavastatin should be taken at least 2 hours after VEKLURY as VEKLURY can affect the way they work

VEKLURY may affect the way certain medicines (e.g. theophylline or midazolam) work.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect VEKLURY.

VEKLURY can be used with dexamethasone.

It is not yet known if VEKLURY affects other medicines or is affected by them. Your doctor will monitor you for signs of medicines affecting each other.

4. How do I use VEKLURY?

How much to take / use

VEKLURY be given to you in hospital, by a nurse or doctor, as a drip into a vein (an intravenous infusion) lasting 30 to 120 minutes, once a day. You will be closely monitored during your treatment.

The recommended dose is

a single starting dose of 200 mg on day 1
then daily doses of 100 mg starting on day 2.

How long a course of treatment lasts depends on how unwell you are:

You will be given VEKLURY every day for at least 5 days. Your doctor may extend the treatment up to a total of 10 days.

If you forget to use VEKLURY

As VEKLURY is only used in hospital, it is very unlikely that you will miss a dose. If you have missed one tell your doctor immediately.

If you use too much VEKLURY

As VEKLURY is only used in hospital, it is very unlikely that you will receive too much. If you have been given an extra dose tell your doctor immediately.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using VEKLURY?

Blood tests before and during treatment.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how VEKLURY affects you. VEKLURY is not expected to have any effect on your ability to drive.

Looking after your medicine

This medicine will usually be stored in the hospital pharmacy.

Concentrate for injection:

Before use, store unopened VEKLURY concentrated solution in a fridge (2 °C to 8 °C) until the day it is needed. Before diluting it, allow the concentrated solution to come up to room temperature (20 °C to 25 °C).
Once diluted, VEKLURY should be used immediately. If necessary, bags of diluted solution can be stored for up to 4 hours at room temperature (20 °C to 25 °C), or for up to 24 hours in a fridge (2 °C to 8 °C). Do not allow more than 24 hours between dilution and administration.
Do not use this medicine if you see particles in the vial, or if the solution does not appear colorless to yellow.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell. Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effect you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only used in hospital.

What VEKLURY contains

Do not take this medicine if you are allergic to any of these ingredients.

What VEKLURY looks like

VEKLURY 100 mg concentrate for injection is a clear, colorless to yellow, aqueous-based concentrated solution, to be diluted into 0.9% saline prior to administration by intravenous infusion. It is sterile, preservative-free, and supplied in a single-use clear glass vial.

(AUST R 338420).

VEKLURY is available in cartons containing 1 vial.

Who distributes VEKLURY

Gilead Sciences Pty Ltd
Level 6, 417 St Kilda Road
Melbourne, Victoria 3004

This leaflet was prepared in July 2020

VEKLURY and GILEAD are registered trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Veklury Concentrate for Injection

Active ingredient

Remdesivir

Schedule

1 Name of Medicine

Remdesivir.

2 Qualitative and Quantitative Composition

Veklury 100 mg concentrate for injection.

Each vial contains 100 mg of remdesivir.
Each mL of concentrate contains 5 mg of remdesivir.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Veklury (remdesivir) concentrate for injection, 100 mg/20 mL (5 mg/mL), available as a sterile, preservative-free, clear, colourless to yellow, aqueous-based concentrated solution that is to be diluted into 0.9% sodium chloride infusion bag prior to administration by intravenous infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Veklury has provisional approval for the treatment of coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older, weighing at least 40 kg) with pneumonia requiring supplemental oxygen (see Section 5.1).
The decision to approve this medicine has been made based on limited data. More comprehensive evidence is required to be submitted.

4.2 Dose and Method of Administration

Use of Veklury is confined to healthcare facilities in which patients can be monitored closely. Veklury is for single use in one patient only.
The recommended dosage of Veklury in patients 12 years of age and older and weighing at least 40 kg is:
Day 1 - a single loading dose of Veklury 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.

Veklury Concentrate for Injection, 100 mg/20 mL (5 mg/mL).

Prepare solution for infusion under aseptic conditions and on the same day as administration. Veklury 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.
Veklury must be diluted in sodium chloride 9 mg/mL (0.9%) solution for injection before being administered via intravenous infusion over 30 to 120 minutes.

Dilution instructions.

Care should be taken during admixture 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 medication immediately after preparation when possible.
Remove the required number of single dose vial(s) from storage. For each vial:
Equilibrate to room temperature (20°C to 25°C).
Inspect the vial to ensure the container closure is free from defects and the solution is free of particulate matter.
Using Table 1, determine the volume of 0.9% sodium chloride 9 mg/mL (0.9%) to withdraw from the infusion bag.

Withdraw and discard the required volume of sodium chloride 9 mg/mL from the bag per Table 1 using an appropriately sized syringe and needle.
Withdraw the required volume of Veklury concentrate for solution for infusion from the Veklury vial using an appropriately sized syringe per Table 1.
Pull the syringe plunger rod back to fill the syringe with approximately 10 mL of air.
Inject the air into the Veklury injection vial above the level of the solution.
Invert the vial and withdraw the required volume of Veklury injection concentrated solution into the syringe. The last 5 mL of solution requires more force to withdraw.
Discard any unused solution remaining in the Veklury vial.
Transfer the required volume of Veklury concentrate for solution for infusion to the infusion bag.
Gently invert the bag 20 times to mix the solution in the bag. Do not shake.
The prepared infusion solution is stable for 4 hours at room temperature (20°C to 25°C) or 24 hours in the refrigerator at 2°C to 8°C.
After infusion is complete, flush with at least 30 mL of sodium chloride 9 mg/mL.

Administration instructions.

For intravenous use.
Veklury is for administration by intravenous infusion after further dilution.
It must not be given as an intramuscular (IM) injection.
The prepared diluted solution should not be administered simultaneously with any other medication. The compatibility of Veklury injection with IV solutions and medications other than 0.9% sodium chloride is not known.
Administer the diluted solution with the infusion rate described in Table 2.

Special populations.

Elderly.

No dose adjustment is required in patients over the age of 65 years (see Section 5.1; Section 5.2).

Renal impairment.

The pharmacokinetics of Veklury have not been evaluated in patients with renal impairment. Patients with eGFR greater than or equal to 30 mL per minute have received Veklury for treatment of COVID-19 with no dose adjustment of Veklury.
All patients must have an eGFR determined before dosing of Veklury and while receiving Veklury as clinically appropriate. Because the excipient SBECD is renally cleared and accumulates in patients with decreased renal function, administration of drugs formulated with SBECD (such as Veklury) is not recommended in patients with eGFR less than 30 mL per minute unless the potential benefit outweighs the potential risk.

Hepatic impairment.

The pharmacokinetics of Veklury have not been evaluated in patients with hepatic impairment. It is not known if dosage adjustment is appropriate in patients with hepatic impairment (see Section 4.4; Section 5.2).

Paediatric 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.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed (see Section 6.1).

4.4 Special Warnings and Precautions for 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.

Transaminase elevations.

Transaminase elevations have been observed in Veklury clinical development program, including in healthy volunteers and patients with COVID-19. Hepatic laboratory testing should be performed in all patients prior to starting Veklury and should be monitored while receiving Veklury as clinically appropriate. No clinical studies with remdesivir have been conducted in patients with hepatic impairment. Veklury should only be used in patients with hepatic impairment if the potential benefit outweighs the potential risk.
Veklury should not be initiated in patients with Alanine Aminotransferase (ALT) ≥ 5 times the upper limit of normal at baseline.
Veklury should be discontinued in patients who develop:
ALT ≥ 5 times the upper limit of normal during treatment with Veklury. Veklury 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) (see Section 4.8; Section 5.2).

Renal impairment.

In animal studies on rats and monkeys, severe renal toxicity was observed (see Section 5.3). 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 Veklury and while receiving it as clinically appropriate. Veklury should not be used in patients with eGFR < 30 mL/min.

Excipients.

The excipient sulfobutyl betadex sodium is renally cleared and accumulates in patients with decreased renal function, which may potentially adversely affect renal function. Therefore Veklury should not be used in patients with eGFR < 30 mL/min (see Section 4.2; Section 5.2).

Risk of reduced antiviral activity when coadministered with chloroquine or hydroxychloroquine.

Coadministration of Veklury 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 Veklury (see Section 4.5; Section 5.1).

Use in the elderly.

See Section 4.2; Section 5.1; Section 5.2.

Paediatric use.

See Section 4.2.

Effects on laboratory tests.

See Section 4.8.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drug-drug interaction trials of Veklury and other concomitant medications have not been conducted. The overall potential for interactions is currently unknown; patients should remain under close observation during the days of Veklury administration. Due to antagonism observed in vitro, concomitant use of Veklury 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 OATP 1B1/1B3 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.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No human data on the effect of Veklury 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 (see Section 5.3). The relevance for humans is unknown.
(Category B2)
No adequate and well-controlled studies of Veklury use in pregnant women have been conducted. Veklury should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the foetus.
Women of child-bearing potential have to use effective contraception during treatment.
There is no information regarding the presence of remdesivir in human milk, the effects on the breastfed infant, or the effects on milk production.
In animal studies, the nucleoside analogue 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 breastfeeding infants, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Veklury and any potential adverse effects on the breastfed child from Veklury or from the underlying maternal condition.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Veklury on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Experience from clinical studies.

Summary of the safety profile.

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%).

Tabulated summary of adverse reactions.

The adverse reactions in Table 3 are listed 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).

Description of selected adverse reactions.

Transaminases increased.

In healthy volunteer studies, increases in ALT, aspartate aminotransferase (AST) or both in subjects who received Veklury were grade 1 (10%) or grade 2 (4%). In a randomised, double-blind, placebo-controlled clinical study of patients with COVID-19 (NIAID ACTT-1), the incidence of grade ≥ 3 non-serious adverse events of increased aminotransferase levels including ALT, AST, or both was 4% in patients receiving Veklury compared with 6% in receiving placebo. In a randomised, open-label multi-centre clinical trial (Study GS-US-540-5773) in hospitalised patients with severe COVID-19 receiving Veklury for 5 (n=200) or 10 days (n=197), any grade (≥ 1.25 × upper limit of normal (ULN)) laboratory abnormalities of increased AST and increased ALT occurred in 40% and 42% of patients, respectively, receiving Veklury. Grade ≥ 3 (≥ 5.0 × ULN) laboratory abnormalities of increased AST and increased ALT both occurred in 7% of patients receiving Veklury. In a randomised, open-label multi-centre clinical trial (Study GS-US-540-5774) in hospitalised patients with moderate COVID-19 receiving Veklury for 5 (n=191) or 10 days (n=193) compared to standard of care (n=200), any grade laboratory abnormalities of increased AST and increased ALT occurred in 32% and 33% of patients, respectively, receiving Veklury, and 33% and 39% of patients, respectively, receiving standard of care. Grade ≥ 3 laboratory abnormalities of increased AST and increased ALT occurred in 2% and 3% of patients, respectively, receiving Veklury and 6% and 7%, respectively, receiving standard of care.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important.
It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no human experience of acute overdosage with Veklury. Treatment of overdose with Veklury 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 Veklury.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals, other antivirals, ATC code: not yet assigned.

Mechanism of action.

Remdesivir is an adenosine nucleotide prodrug that distributes into cells where it is metabolised to form the pharmacologically active nucleoside triphosphate metabolite. Metabolism of remdesivir to remdesivir triphosphate has been demonstrated in multiple cell types. Remdesivir triphosphate acts as an analogue 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. Remdesivir triphosphate is a weak inhibitor of mammalian DNA and RNA polymerases with low potential for mitochondrial toxicity.

Antiviral activity.

Remdesivir exhibited in vitro activity against a clinical isolate of SARS-CoV-2 in primary human airway epithelial (HAE) cells with a 50% effective concentration (EC₅₀) of 9.9 nanoM after 48 hours of treatment. The EC₅₀ values of remdesivir against SARS-CoV-2 in Vero cells were 137 nanoM at 24 hours and 750 nanoM 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.

No clinical data are available on the development of SARS-CoV-2 resistance to remdesivir. The cell culture development of SARS-CoV-2 resistance to remdesivir has not been assessed to date.
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. The mutant viruses showed reduced viral fitness in vitro. Introduction of the corresponding mutations (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.

Clinical trials.

Clinical trials in patients with COVID 19.

NIAID ACTT 1 study (CO-US-540-5776).

A randomised, double-blind, placebo-controlled clinical trial evaluated Veklury 200 mg once daily for 1 day followed by Veklury 100 mg once daily for 9 days (for a total of up to 10 days of intravenously administered therapy) in hospitalised adult patients with COVID 19 with evidence of lower respiratory tract involvement. The trial enrolled 1,063 hospitalised patients: 120 (11.3%) patients with mild/moderate disease (defined by SpO₂ > 94% and respiratory rate < 24 breaths/min without supplemental oxygen) and 943 (88.7%) patients with severe disease (defined by SpO₂ ≤ 94% on room air, or respiratory rate ≥ 24 breaths/min and requiring supplemental oxygen or ventilatory support). Patients were randomised 1:1, stratified by disease severity at enrolment, to receive Veklury (n=541) or placebo (n=522), plus standard of care.
The baseline mean age was 59 years and 36% of patients were aged 65 or older. Sixty-four percent were male, 21% were Black, 13% were Asian. The most common comorbidities were hypertension (49.6%), obesity (37.0%), type 2 diabetes mellitus (29.7%), and coronary artery disease (11.6%).
Approximately 33% (180/541) of the patients received a 10 day treatment course with Veklury.
The primary clinical endpoint was time to recovery within 28 days after randomisation, defined as either discharged from hospital (with or without limitations of activity and with or without home oxygen requirements) or hospitalised but not requiring supplemental oxygen and no longer requiring ongoing medical care. In a preliminary analysis performed after all patients had been followed up for 14 days, the median time to recovery in the overall population was 11 days in the Veklury group compared to 15 days in the placebo group (recovery rate ratio 1.32; [95% CI 1.12 to 1.55], p < 0.001). The outcome differed relevantly between the two strata. In the severe disease stratum time to recovery was 12 days in the Veklury group and 18 days in the placebo group (recovery rate ratio 1.37 [95% CI: 1.15 to 1.63]; Table 4). For the mild/moderate disease stratum, time to recovery was not different between the two groups (5 days for both, Veklury and placebo).

There was no difference in efficacy in patients randomised during the first 10 days after onset of symptoms as compared to those with symptoms for more than 10 days.
The clinical benefit of Veklury was most apparent in patients receiving oxygen, however, not on ventilation, at Day 1 (rate recovery ratio 1.47 [95% CI 1.17-1.84]). For patients who were receiving mechanical ventilation or ECMO on Day 1 no difference in recovery rate was observed between the treatment groups (0.95 [95% CI 0.64 to 1.42]).

QT.

Current non-clinical and clinical data do not suggest a risk of QT prolongation, but QT prolongation has not been fully evaluated in humans.

Study GS-US-540-5773 in patients with severe COVID 19.

A randomised, open-label multi-centre clinical trial (Study GS-US-540-5773) of patients at least 12 years of age with confirmed SARS-CoV 2 infection, oxygen saturation ≤ 94% on room air, and radiological evidence of pneumonia compared 197 patients who received Veklury for 10 days with 200 patients who received Veklury for 5 days. Patients on mechanical ventilation at screening were excluded.
At baseline, the median age of patients was 61 years (range, 20 to 98 years); 64% were male, 75% were White, 12% were Black, and 12% were Asian. More patients in the 10-day group than the 5-day group required invasive mechanical ventilation or ECMO (5% vs 2%), or high-flow oxygen support (30% vs 25%), at baseline. Median duration of symptoms and hospitalization prior to first dose of Veklury were similar across treatment groups.
Overall, after adjusting for between-group differences at baseline, patients receiving a 5-day course of Veklury had similar clinical status at Day 14 as those receiving a 10-day course (odds ratio for improvement: 0.75; [95% CI 0.51 to 1.12]). In addition, recovery rates were 70% and 58%, and mortality rates were 8% and 11%, in the 5-day and 10-day groups, respectively. There were no significant differences once adjusted for between group differences at baseline.

Study GS-US-540-5774.

A randomized, open-label multi-centre clinical trial (Study GS-US-540-5774) of hospitalized patients at least 12 years of age with confirmed SARS-CoV-2 infection and radiological evidence of pneumonia without reduced oxygen levels compared treatment with Veklury for 5 days (n=191) and treatment with Veklury for 10 days (n=193) with standard of care (n=200). Patients treated with Veklury received 200 mg on Day 1 and 100 mg once daily on subsequent days. The primary endpoint was clinical status on Day 11 assessed on a 7-point ordinal scale ranging from hospital discharge to increasing levels of oxygen and ventilatory support to death.
At baseline, the median age of patients was 57 years (range, 12 to 95 years); 61% were male, 61% were White, 19% were Black, and 19% were Asian. Baseline clinical status, oxygen support status, and median duration of symptoms and hospitalization prior to first dose of Veklury were similar across treatment groups.
Overall, the odds of improvement in the ordinal scale were higher in the 5-day Veklury group at Day 11 when compared to those receiving only standard of care (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 standard of care were not statistically significant (odds ratio 1.31; [95% CI 0.88 to 1.95]; p=0.18). At Day 11 observed mortality rates for the 5-day, 10-day, and standard of care groups were 0, 1%, and 2%, respectively.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of Veklury 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 Veklury adult dosage regimen, remdesivir was absorbed with a peak plasma concentration observed at end of infusion, regardless of dose level. Peak plasma concentrations of GS-441524 were observed at 1.51 to 2.00 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.

Metabolism.

Remdesivir is extensively metabolized into the pharmacologically active nucleoside analogue triphosphate GS-443902. 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 results in the formation of nucleoside metabolite GS-441524 that is not efficiently re-phosphorylated.

Biotransformation.

Remdesivir is extensively metabolized to the pharmacologically active nucleoside analogue 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.

Excretion.

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 faeces, 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 age, gender, or race on the exposures of remdesivir 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 sulfobutyl betadex sodium is renally cleared and accumulates in patients with decreased renal function. Veklury 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.

Interactions.

The potential of interaction of remdesivir as a victim was not studied with regards to the inhibition of the hydrolytic pathway (esterase). The risk of clinically relevant interaction is unknown.
Remdesivir inhibited CYP3A4 in vitro (see Section 4.5). At physiologically relevant concentrations (steady-state), remdesivir or its metabolites GS 441524 and GS 704277 did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 in vitro. Remdesivir may however transiently inhibit CYP2B6, 2C8, 2C9 and 2D6 on the first day of administration. The clinical relevance of this inhibition was not studied. The potential for time-dependent inhibition of CYP450 enzymes by remdesivir was not studied.
Remdesivir induced CYP1A2 and potentially CYP3A4, but not CYP2B6 in vitro (see Section 4.5).
In vitro data indicates no clinically relevant inhibition of UGT1A1, 1A3, 1A4, 1A6, 1A9 or 2B7 by remdesivir or its metabolites GS 441524 and GS 704277.
Remdesivir inhibited OATP1B1 and OATP1B3 in vitro (see Section 4.5). No data is available for OAT1, OAT3 or OCT2 inhibition by remdesivir.
At physiologically relevant concentrations, remdesivir and its metabolites did not inhibit PgP and BCRP in vitro.

5.3 Preclinical Safety Data

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

Genotoxicity.

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.

Carcinogenicity.

Long-term animal studies to evaluate the carcinogenic potential of remdesivir have not been performed.

Impairment of fertility.

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 analogue 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.

Animal toxicology and/or pharmacology.

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 (see Section 5.2). 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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Veklury 100 mg concentrate for injection.

Sulfobutyl betadex sodium, hydrochloric acid, sodium hydroxide, water for injection.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in Section 6.6 (see Section 6.6). The compatibility of Veklury concentrate for infusion with IV solutions and medications other than saline is not known.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Do not reuse or save unused Veklury for future use. This product contains no preservative; therefore, partially used vials should be discarded.

Veklury 100 mg/20 mL (5 mg/mL) concentrate for injection.

Store in a refrigerator (2°C - 8°C). Dilute within the same day as administration.

Diluted solution for infusion.

Store diluted Veklury solution for infusion up to 4 hours below 25°C or 24 hours at refrigerated temperature (2°C to 8°C).

6.5 Nature and Contents of Container

Type I clear glass vial, an elastomeric closure, and an aluminium overseal with a flip-off cap.
Pack size: 1 vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

CAS number.

1809249-37-3.

7 Medicine Schedule (Poisons Standard)

S4.

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