What is the role of azelastine nasal spray in the management of COVID-19?

Background
SARS-CoV-2, the virus responsible for COVID-19, is transmitted primarily through respiratory droplets.1 Even individuals who are asymptomatic or presymptomatic often carry substantial viral loads in the nasal cavity and nasopharynx. This has generated interest in intranasal drug delivery as a practical strategy for both the prevention and treatment of COVID-19. Among the agents under investigation, azelastine nasal spray has emerged as particularly promising, owing to its broad antiviral activity and widespread availability.2

Azelastine is a relatively selective H1-receptor blocker with established anti-allergic, anti-asthmatic, and anti-inflammatory properties, and minimal anticholinergic effects.3 Furthermore, in vivo studies have demonstrated that azelastine nasal spray has antiviral activity against several respiratory pathogens, including SARS-CoV-2, respiratory syncytial virus (RSV), and influenza A (H1N1).4 A few of azelastine’s proposed antiviral mechanisms of action include reduction of viral load in the nasopharyngeal area, interactions with angiotensin converting enzyme 2 (ACE2), and inhibition of the SARS-CoV-2 protease Mpro. Notably, Mpro is the main protease involved in SARS-CoV-2 replication, and is the target of nirmatrelvir, an orally administered COVID-19 therapy used in combination with ritonavir (ie, Paxlovid).

Azelastine has demonstrated consistent antiviral activity against all tested SARS-CoV-2 variants in vitro, including the D614G, alpha, beta, delta, and Omicron BA.1 lineages.2,4 Additionally, the literature suggests that SARS-CoV-2 spike mutations do not affect azelastine’s antiviral mechanism, so major antiviral efficacy changes are unlikely with new variants.2 With the changing epidemiology of COVID-19 and the persistence of infection rates and post-acute morbidity despite widespread vaccination and population immunity, there remains an unmet need for therapies that target early infection to reduce progression and transmission.1,5,6 In this context, azelastine nasal spray represents a promising adjunctive strategy.1,2

Clinical evidence
The clinical evidence for azelastine nasal spray in the treatment and prevention of COVID-19 infection is summarized in Table 1.4,7,8

COVID-19 Treatment
The CARVIN-I and CARVIN-II studies investigated azelastine nasal spray as a treatment for COVID-19 in non-hospitalized adults.7,8 CARVIN-I, a proof-of-concept, dose-finding study done in Germany, was the first to show that azelastine 0.1% spray (1 puff per nostril 3 times daily) could accelerate viral load reduction in SARS-CoV-2–positive individuals and improve symptoms.8 A pharmacometric modeling study based on these data further supported a faster decline in both viral load and symptom severity with intranasal azelastine.9 The modeling study also demonstrated that older patients experienced a slower reduction in viral load compared with younger patients, while male patients exhibited higher peak viral loads than females.

Building on findings from CARVIN-I, a larger, multicenter, Phase II trial (CARVIN-II) done in India, randomized participants to receive azelastine 0.1% or placebo sprays (1 puff per nostril, 5 times daily) for 11 days.7 Viral load was measured by nasopharyngeal swabs and quantitative reverse transcription-polymerase chain reaction (RT-PCR) at baseline, and days 3, 6, and 11. Results showed no hospitalizations related to COVID-19 (primary outcome) in either group, but a significant reduction in viral load with azelastine at all timepoints. The azelastine group also showed improvements in fever, weakness, and hypoxia when compared to placebo.

COVID-19 Prevention
The CONTAIN trial investigated azelastine 0.1% nasal spray as pre-exposure prophylaxis in 450 healthy adults in Germany.4 This Phase II study randomized participants to azelastine or placebo sprays, used 3 times daily for 56 days. Twice-weekly rapid antigen tests confirmed by PCR assessed incident infections. The primary outcome, PCR-confirmed COVID-19 infection, occurred significantly less often with azelastine (2.2%) than with placebo (6.7%). Azelastine also extended the mean time to COVID-19 infection and reduced symptomatic COVID-19 cases. Additionally, azelastine reduced the incidence of laboratory-confirmed respiratory infections, particularly rhinovirus, confirming broader antiviral potential shown in earlier in vitro studies.

In all 3 studies, azelastine was generally well tolerated, with the prophylaxis study reporting an increased incidence of mild local effects (eg, bitter taste, nosebleeds) with azelastine compared to placebo.

Table 1. Clinical Evidence for Azelastine Nasal Spray in Management of COVID-19.4,7,8
StudyDesign and PopulationInterventionKey Results
Treatment
Meiser et al 20247

CARVIN-II Trial		DB, PC, RCT, MC (India)

Conducted from September 2022 to May 2023 (dominant variant: Omicron)

N=294 adults (mean age, 40 years; 78.5% received ≥1 dose of vaccine against COVID-19) with mild COVID-19 illness		Azelastine, 0.1% NS (n=145)

Placebo NS (n=149)

One puff per nostril, 5 times daily, preferably at 3-hour intervals during the day, from days 2 to 10.

Duration: 11 days
  • No hospitalizations in either group
  • VL significantly reduced from baseline in both groups
  • Significantly greater VL reduction from baseline with azelastine vs placebo on days 3 (p<0.0001), 6 (p=0.0013), and 11 (p=0.0041)
  • Significant improvements in fever (p=0.0046), weakness (p=0.0012), and hypoxia (p<0.0001) with azelastine vs placebo
  • Time to cure was similar in both groups (median, 225 hours; HR, 0.32; 95% CI, 0.83 to 2.32)
Klussmann et al 20238

CARVIN Trial		DB, PC, RCT, SC (Germany)

Conducted from March 2021 to April 2021 (dominant variant: alpha)

N=90 adults aged 18 to 60 years (mean age, 35 years) with COVID-19 illness		Azelastine, 0.02% NS (n=31)

Azelastine, 0.1% NS (n=29)

Placebo NS (n=30)

One puff per nostril, 3 times daily (morning, mid-day, and evening)

Duration: 11 days
  • VL significantly reduced from baseline in all groups (p<0.0001)
  • Greater VL reduction with azelastine 0.1% vs placebo (p=0.007)
  • Negative PCR was earlier and more frequent in the azelastine groups: 18.5% (azelastine 0.1%), 21.4% (azelastine 0.02%) vs 0% (placebo) on day 8
  • Improvement in shortness of breath was significantly greater in the azelastine groups on days 3 (p=0.004) and 4 (p=0.011)
Prevention
Lehr et al 20254

CONTAIN study		DB, PC, SC (Germany)

Conducted from March 2023 to July 2024 (dominant variant: Omicron)

N=450 healthy adults aged 18 to 65 years (mean age, 35 years; 99% received ≥1 dose of vaccine against COVID-19)		Azelastine, 0.1% NS (n=227)

Placebo NS (n=223)

One puff per nostril, 3 times daily (morning, midday, and evening)

Duration: mean, 56 days

In case of acute respiratory symptoms, confirmed COVID-19 infection, or suspicion of close contact with a COVID-19-infected person, 1 puff of the nasal spray per nostril was applied 5 times daily for a period of 3 days
  • Reduced rate of PCR-confirmed COVID-19 infection with azelastine (2.2% vs 6.7%; OR, 0.31; 95% CI, 0.11 to 0.87)
  • Fewer PCR-confirmed symptomatic COVID-19 infections with azelastine (1.8% vs 6.3%; MD, -4.5; 95% CI, -8.1 to -0.9)
  • Longer mean time to PCR-confirmed COVID-19 infection with azelastine (31.2 vs 19.5 days; MD, 11.73; 95% CI, 9.45 to 14.01)
  • Fewer overall PCR-confirmed infections with azelastine (21 vs 49 participants)
  • Fewer PCR-confirmed rhinovirus infections with azelastine (1.8% vs 6.3%)
Abbreviations: DB, double blind; HR, hazard ratio; MC, multicenter; MD, mean difference; NS, nasal spray; OR, odds ratio; PC, placebo controlled; PCR, polymerase chain reaction; RCT, randomized controlled trial; SC, single center; VL, viral load.

Limitations
The available clinical trials investigating azelastine nasal spray for COVID-19 management show encouraging evidence, but several limitations must be considered when applying the data in clinical practice.4,7,8 First, participants were generally younger, healthy outpatients with mild or no symptoms; individuals at high risk for severe COVID-19, such as those with significant comorbidities or older age, were largely excluded. This limits generalizability to the populations who stand to benefit most, given their increased risk for progression to severe disease.10 Second, many measured outcomes were surrogate endpoints, such as viral load reduction or PCR negativity.4,7,9 Thus, while azelastine has proven its antiviral efficacy, its impact on clinically meaningful outcomes (hospitalizations, etc) remains unknown. Third, the trials were relatively small and none included centers in the United States. Variability in study design, including dosing frequency and placebo formulations, further complicates interpretation. The inclusion of vaccinated individuals, who generally carry lower viral loads and are less contagious, likewise complicates the assessment of treatment effects.8 Moreover, the risk of inducing viral shedding is unknown, as aerosolized nasal sprays could elicit sneezing or coughing. Collectively, these limitations underscore the need for larger, multicenter studies in high-risk populations with clinically relevant outcomes. At the time of this review, COVID-19 clinical practice guidelines do not include azelastine among recommended therapies for treatment or prevention.5,6

Conclusion
Azelastine nasal spray shows promise as a widely accessible therapy for COVID-19 management, with early trials suggesting potential benefits in both treatment and prevention; however, current evidence is limited to small studies in low-risk populations that primarily assess surrogate outcomes.

References:

  1. Higgins TS, Wu AW, Illing EA, et al. Intranasal antiviral drug delivery and Coronavirus Disease 2019 (COVID-19): A State of the Art Review. Otolaryngol Head Neck Surg. 2020;163(4):682-694. doi:10.1177/0194599820933170
  2. Fischhuber K, Bánki Z, Kimpel J, et al. Antiviral potential of azelastine against major respiratory viruses. Viruses. 2023;15(12):2300. doi:10.3390/v15122300
  3. Micromedex. Merative. 2025. Accessed October 1, 2025. https://www.micromedexsolutions.com/
  4. Lehr T, Meiser P, Selzer D, et al. Azelastine nasal spray for prevention of SARS-CoV-2 Infections: A Phase 2 Randomized Clinical Trial. JAMA Intern Med. Published online September 2, 2025. doi:10.1001/jamainternmed.2025.4283
  5. Bhimraj A, Falck-Ytter Y, Kim AY, et al. IDSA guidelines on the treatment and management of patients with COVID-19. Updated June 4, 2025. Accessed October 1, 2025. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
  6. World Health Organization (WHO). Clinical management of COVID-19: living guideline, June 2025. Updated August 18, 2023. Accessed October 1, 2025. https://www.who.int/publications/i/item/B09467
  7. Meiser P, Flegel M, Holzer F, et al. Azelastine nasal spray in non-hospitalized subjects with mild COVID-19 Infection: A Randomized Placebo-Controlled, Parallel-Group, Multicentric, Phase II Clinical Trial. Viruses. 2024;16(12):1914. doi:10.3390/v16121914
  8. Klussmann JP, Grosheva M, Meiser P, et al. Early intervention with azelastine nasal spray may reduce viral load in SARS-CoV-2 infected patients. Sci Rep. 2023;13(1):6839. doi:10.1038/s41598-023-32546-z
  9. Dings C, Meiser P, Holzer F, et al. Pharmacometric modeling of the impact of azelastine nasal spray on SARS-CoV-2 viral load and related symptoms in COVID-19 Patients. Pharmaceutics. 2022;14(10):2059. doi:10.3390/pharmaceutics14102059
  10. Centers for Disease Control and Prevention. Underlying conditions and the higher risk for severe COVID-19. Updated February 6, 2025. Accessed October 1, 2025. https://www.cdc.gov/covid/hcp/clinical-care/underlying-conditions.html

Prepared by:
Katherine Sarna PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago Retzky College of Pharmacy

November 2025

The information presented is current as of October 1, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.