Remdesivir (Veklury)

Number: 0982

Policy

Aetna considers remdesivir (Veklury) medically necessary for treatment of COVID-19 when all of the following criteria are met:

1. Member has a confirmed active infection with COVID-19; and
2. Member is 12 years of age or older and weighs at least 40 kg; and
3. Member has eGFR greater than or equal to 30 mL/min; and
4. Member is sufficiently ill to require hospitalization; and
5. Renal function, hepatic function, and prothrombin time have been taken prior to starting remdesivir and will be monitored while receiving therapy as clinically appropriate; and
6. Member will receive a loading dose of 200mg on Day 1 followed by maintenance dose of 100mg per day starting Day 2; and
7. Member will not receive a total duration of therapy of greater than 10 days for an individual infection; and
8. Remdesivir will not be administered in combination with chloroquine or hydroxychloroquine; and
9. Remdesivir will be administered in a hospital or healthcare setting capable of providing acute care comparable to inpatient hospital care.

Aetna considers all other indications for remdesivir (Veklury) experimental and investigational.

Note: See MCG Guidelines, Viral Illness, Acute (M-280), for clinical indications for hospitalization.

Dosing Recommendations

Veklury is available as a 100 mg Lyophilized Powder in Vial and as 100 mg/20 mL [5 mg/mL] Solution in Vial. Both come as preservative-free single dose vials. The powder requires reconstitution and both require further dilution prior to administration by intravenous infusion.

Perform renal and hepatic laboratory testing and assess prothrombin time in all patients before initiating Veklury and during treatment as clinically appropriate.

The recommended dosage in adults and pediatric patients 12 years of age and older and weighing at least 40 kg: a single loading dose of Veklury 200 mg on Day 1 followed by once-daily maintenance doses of Veklury 100 mg from Day 2 infused over 30 to 120 minutes.

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. 

For patients requiring invasive mechanical ventilation and/or ECMO, the recommended total treatment duration is 10 days.

Administer Veklury via intravenous (IV) infusion over 30 to 120 minutes.

Renal impairment: Veklury is not recommended in patients with eGFR less than 30 mL/min.

Dose preparation and administration: Refer to the full prescribing information for further details for both formulations.

Source: Gilead 2020.

Background

On May 1, 2020, after review of unpublished data from available clinical trials, the US Food and Drug Administration (FDA) issued an emergency use authorization (EUA) to permit the use of remdesivir, a nucleotide analog that inhibits viral RNA-dependent RNA polymerase (RDRP), for treatment of adults and children hospitalized with severe coronavirus disease 2019 (COVID-19). EUA was granted after an interim analysis of 606 recoveries in the randomized, placebo-controlled National Institute of Allergy and Infectious Diseases Adaptive Covid-19 Treatment Trial (n=1063 participants from 47 United States sites and 21 international sites). Remdesivir reduced the median time to recovery (11 versus 15 days; hazard ratio, 1.31; 95% confidence interval, 1.12 to 1.54; P<0.001) compared with placebo, and overall mortality among patients treated with remdesivir was 8.0% compared with 11.6% among those treated with placebo (P=0.59). However, patients with severe acute kidney injury and end-stage kidney disease were excluded from this and all other remdesivir trials on the basis of eGFR cutoffs (either 50 or 30 ml/min per 1.73 m²). As a result, the EUA fact sheet for health care providers states that “The pharmacokinetics of remdesivir have not been evaluated in patients with renal impairment. Adult and pediatric patients (>28 days old) must have creatinine clearance determined and full-term neonates (≥7 days to ≤28 days old) must have serum creatinine determined before dosing. Remdesivir is not recommended in adults and pediatric patients (>28 days old) with eGFR less than 30 mL per minute or in full-term neonates (≥7 days and ≤28 days old) with serum creatinine ≥1 mg/dL, unless the potential benefit outweighs the potential risk. (emphasis added)” (Adamsick 2020).  

On October 22, 2020, the FDA approved Gilead’s antiviral drug Veklury (remdesivir) injection for adults and pediatric patients (12 years of age and older and weighing at least 40 kg) for the treatment of coronavirus disease 2019 (COVID-19) requiring hospitalization. Veklury is a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor and is the first and only FDA-approved drug in the United States for treating the coronavirus. Veklury was initially given Emergency Use Authorization (EUA) on May 1, 2020. Veklury should only be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care.  Although the FDA approval is limited to patients 12 years and older, the FDA has also issued an emergency use authorization (EUA) to ensure access to treatment for hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg or pediatric patients with suspected or laboratory confirmed COVID-19 who weigh 3.5 kg to less than 40 kg. Clinical trials assessing the safety and efficacy of Veklury in this pediatric patient population are ongoing.

The FDA approval is based on results from three randomized, controlled clinical trials that included patients hospitalized with mild, moderate, and severe COVID-19. The first trial, NIAID ACTT-1, was a randomized, double-blind, placebo-controlled clinical trial in hospitalized adults with mild, moderate, or severe SARS-CoV-2 infection and had evidence of lower respiratory tract infection (Beigel 2020; NCT04280705). A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Patients were randomly assigned to receive either intravenous remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. At baseline, mean age was 59 years (with 36% of subjects aged 65 or older); 64% of subjects were male, 53% were White, 21% were Black, and 13% were Asian; 24% were Hispanic or Latino; 105 subjects had mild/moderate disease (10% in both treatment groups); 957 subjects had severe disease (90% in both treatment groups). A total of 285 subjects (27%) (n=131 received remdesivir) were on invasive mechanical ventilation or ECMO. The most common comorbidities were hypertension (51%), obesity (45%), and type 2 diabetes mellitus (31%); the distribution of comorbidities was similar between the two treatment groups. 

The primary clinical endpoint was time to recovery within 29 days after randomization. Recovery was defined as discharged from the hospital without limitations on activities, discharged from the hospital with limitations on activities and/or requiring home oxygen, or hospitalized but not requiring supplemental oxygen and no longer requiring ongoing medical care. A key secondary endpoint was clinical status on Day 15 assessed on an 8-point ordinal scale consisting of the following categories:

1. not hospitalized, no limitations on activities;
2. not hospitalized, limitation on activities and/or requiring home oxygen;
3. hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care;
4. hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise);
5. hospitalized, requiring supplemental oxygen;
6. hospitalized, on noninvasive ventilation or high-flow oxygen devices; 
7. hospitalized, on invasive mechanical ventilation or ECMO; and
8. death.

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). 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]). 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]). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). The authors concluded that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Beigel 2020).

A second study, Study GS-US-540-5773, was a randomized, open-label multi-center clinical trial in adult subjects with confirmed severe SARS-CoV-2 infection, an oxygen saturation (SpO2) of  less than or equal to 94% on room air, and radiological evidence of pneumonia (Goldman 2020; NCT04292899). In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). Treatment with remdesivir was stopped in subjects who were discharged from the hospital prior to completion of their protocol-defined duration of treatment. Subjects 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 via intravenous infusion, plus standard of care. At baseline, the median age of subjects was 61 years (range, 20 to 98 years); 64% were male, 75% were White, 12% were Black, and 12% were Asian; 22% were Hispanic or Latino. More subjects 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 remdesivir were similar across treatment groups. 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.

Overall, after adjusting for between-group differences at baseline, subjects receiving a 5-day course of remdesivir 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]). There were no statistically significant differences in recovery rates or mortality rates in the 5-day and 10-day groups once adjusted for between-group differences at baseline. All-cause mortality at Day 28 was 12% vs 14% in the 5- and 10-day treatment groups, respectively. The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).  

The third study, Study GS-US-540-5774, was a randomized, open-label multi-center clinical of hospitalized adult subjects with a confirmed moderate SARS-CoV-2 infection, SpO2 greater than 94% and radiological evidence of pneumonia (Spinner 2020; NCT04292730). This study compared treatment with remdesivir for 5 days (n=191) and treatment with remdesivir for 10 days (n=193) with standard of care (n=200). Treatment with remdesivir was stopped in subjects who were discharged from the hospital prior to completion of their protocol-defined duration of treatment. Subjects treated with remdesivir received 200 mg on Day 1 and 100 mg once daily on subsequent days via intravenous infusion. At baseline, the median age of subjects was 57 years (range, 12 to 95 years); 61% were male, 61% were White, 19% were Black, and 19% were Asian; 18% were Hispanic or Latino. Baseline clinical status, oxygen support status, and median duration of symptoms and hospitalization prior to first dose of remdesivir were similar across treatment groups.  

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. 

Overall, the odds of improvement in the ordinal scale were higher in the 5-day remdesivir 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]). All-cause mortality at Day 28 was ≤2% in all treatment groups.

The manufacturer cautions that hypersensitivity reactions have been observed during and following administration of remdesivir. Slower infusion rates, with a maximum infusion time of up to 120 minutes, can be considered to potentially prevent signs and symptoms of hypersensitivity. If signs and symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. Transaminase elevations have been observed in healthy volunteers and have also been reported in patients with COVID-19 who received remdesivir. Hepatic laboratory testing should be performed in all patients before starting remdesivir and while receiving remdesivir as clinically appropriate. Consider discontinuing remdesivir if ALT levels increase to greater than 10 times the upper limit of normal. Remdesivir should be discontinued if ALT elevation is accompanied by signs or symptoms of liver inflammation. Coadministration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate is not recommended based on cell culture data demonstrating an antagonistic effect of chloroquine on the intracellular metabolic activation and antiviral activity of remdesivir.

The most common adverse reactions (incidence greater than or equal to 5%, all grades) observed with treatment with Veklury are nausea, ALT increased, and AST increased.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
HCPCS codes covered if selection criteria are met::
Remdesivir (Veklury) – No specific code:
Other HCPCS codes related to the CPB:
J0390	Injection, chloroquine hydrochloride, up to 250 mg
ICD-10 codes covered if selection criteria are met:
U07.1	COVID-19

The above policy is based on the following references: