Last edit: 10 April 2024

This page was developed to provide information for health professionals in NZ regarding medicines and COVID-19 during and immediately following the pandemic. It is no longer regularly updated. Please consult local HealthPathways or national guidelines for the management of COVID-19.

For questions relating to specific patients please contact us via ERMS if in Canterbury, via our website enquiries form, by phone (03 364 0900) or email (medicines.information@cdhb.health.nz). 

Summary

For symptomatic treatment of COVID-19 (pain and fever), paracetamol is preferred. NSAIDs are appropriate for refractory symptoms. Enoxaparin is recommended for hospitalised patients with COVID-19. Corticosteroids are useful for hospitalised patients with severe COVID-19. Tocilizumab is recommended, in conjunction with systemic corticosteroids, in hospitalised patients with moderate or severe COVID-19. Baricitinib is an alternative to tocilizumab. Nirmatrelvir-ritonavir and remdesivir are recommended options in patients with mild to moderate COVID-19 who are at higher risk of severe disease. Patients should be advised not to stop any regular medicines unless there is a conventional indication to do so.

Medicines recommended for the prevention of COVID-19

Vaccines

Vaccination is a key measure to prevent progression to severe COVID-19 disease. Vaccination is associated with reduced risk of developing persistent COVID-19 symptoms.

Vaccine efficacy varies depending on the SARS-CoV-2 variant. Vaccine efficacy for preventing symptomatic infection was highest for the alpha variant ranging from 67%-95% for the COVID-19 vaccines available in NZ.

For the omicron variant, observational studies (in adults and children ≥ 5 years) suggest that COVID-19 vaccines remain effective in preventing severe disease and hospitalisations, but their effectiveness in preventing symptomatic infection is reduced. COVID-19 vaccines in these studies were mRNA and viral vector vaccines. Booster doses help reduce waning immunity and help overcome partial immune evasion of the circulating variants.  The efficacy data for omicron for the recombinant spike protein vaccine, Novavax, are awaited.

Observational data show a fourth dose of an mRNA vaccine in healthcare workers, 4 months after the third dose, produces an immune response similar to that which occurred after the third dose. Further observational data show that in adults ≥ 60 years a fourth dose of mRNA vaccine 4-7 months after the third dose, reduces the rate of infection 2-fold and the rate of severe disease 3-fold, 4 weeks after receiving the fourth dose. Protection from infection peaked at 4 weeks and decreased to the three-dose baseline by 8 weeks. However, protection from severe disease was maintained during the 6 weeks of study observation. Both studies collected data when omicron was the dominant variant. See, study and study.

During an omicron phase, the protective effects of a booster dose (compared to primary series without booster) against infection waned from around 60% effectiveness at one month to below 20% effectiveness after 3 months, while the protective effects against hospitalisation and death waned more slowly from about 80% at one month to about 30% and 50% effectiveness after 5 months, respectively. See, study.

Observational data in adults ≥ 18 years, during an omicron dominant period, found a 10.5-fold higher hospitalisation rate in unvaccinated people and a 2.5-fold higher hospitalisation rate in people vaccinated with a primary series, compared with those who were fully vaccinated with a primary series and booster dose. Risk factors for hospitalisation with COVID-19 in vaccinated patients included older age and increased risk for severe disease such as co-morbidities (e.g. kidney disease and immunosuppressive conditions). See, study.

A phase 1 study and phase 2-3 study have assessed the dose, safety and efficacy of an mRNA vaccine in children 6 months to 4 years. The results of these studies found that a 3-dose primary series (3 mcg per dose of the Pfizer/BioNTech BNT162b2 vaccine) was immunogenic, as defined by neutralising antibody titres at 1 month after dose 3, and safe up to 1 month after dose 3. The rate of adverse events was similar in the vaccine and placebo groups. The omicron (B.1.1.529) variant was dominant. See study. 

Infants are not eligible for vaccination against COVID-19. An observational study found that maternal vaccination during pregnancy with two doses of an mRNA vaccine was associated with a reduced risk of hospitalisation and severe COVID-19, among infants younger than 6 months of age. The study was undertaken when the delta and omicron variants were dominant. See, study.

Bivalent mRNA vaccines contain both ancestral and omicron SARS-CoV-2 strains. An observational study (n = 134,215 bivalent mRNA booster, n = 569,519 total) found in people ≥ 65 years and at high risk of severe COVID-19, the risk of hospitalisation with COVID-19 was lower in those who received a bivalent mRNA booster vaccine (Pfizer-BioNTech original/omicron BA.4-5) compared to no booster (adjusted HR 0·28, 95% CI 0·19-0·40; NNT 1118, 95% CI 993-1341) by day 120. A period of at least 3 months between the previous monovalent mRNA vaccine dose or SARS-CoV-2 infection was required before receiving the bivalent mRNA booster dose. Omicron variants (BA.5 and BQ.1) were circulating during the study period. See, study. Another observational study suggests the bivalent mRNA booster vaccines (Pfizer-BioNTech and Moderna) reduce hospitalisation rates with the more recent strains of omicron (BQ.1 and XBB). See, study. How the bivalent booster dose directly compares to an additional monovalent booster dose has not been studied. However, it appears that the vaccine effectiveness is similar between the published studies of bivalent and monovalent booster doses, acknowledging differences in the virus variants over time.

A multicentre cohort study (n ≈ 10.2 million vaccinated, n ≈ 10.4 million unvaccinated) found that vaccination against COVID-19 reduced the risk of persistent COVID-19 symptoms in adults ≥ 18 years. All the vaccines studied were associated with a reduced risk (Oxford/AstraZeneca ChAdOx1, Pfizer/BioNTech BNT162b2, Janssen Ad26.COV2.S and Moderna mRNA-1273). Patients were enrolled between January and July 2021 and followed up during the alpha and delta waves and the beginning of the omicron wave. The definition of persistent COVID-19 symptoms can vary, in this study it was defined as having at least one of 25 WHO-listed symptoms between 90 and 365 days after diagnosis and with no history of the symptom 180 days before SARS-CoV-2 infection. See, cohort study.

Rare thromboembolic events such as cerebral venous thrombosis (CVT) have been reported in a small number of people after receiving a COVID-19 vaccine. The risk of CVT within 2 weeks of a COVID-19 diagnosis (around 40 per million cases) has been shown to be around 10-fold greater than that with the mRNA and viral vector SARS-CoV-2 vaccines (e.g. Pfizer/BioNTech, Moderna, AstraZeneca/Oxford).

Rare and mild cases of myocarditis and pericarditis have been reported after vaccination with an mRNA vaccine (Pfizer/BioNTech or Moderna), predominantly in young males and mostly within a week after the second dose. In people vaccinated with an mRNA vaccine (Pfizer/BioNTech), it has been reported that the risk of myocarditis was 3 times higher than the matched controls (n = 938,812 per group). This equates to approximately 3 additional cases of myocarditis per 100,000 people vaccinated. The same study found the risk of myocarditis was 18 times higher in the SARS-CoV-2 infected group than in the matched controls (n = 173,106 per group). Hence, compared to controls, SARS-CoV-2 infection poses a greater risk for myocarditis than vaccination. See, study. The incidence of myocarditis in males aged 16-29 years is 11 cases per 100,000 and in adolescents aged 12-15 years (almost 90% males) is 5 cases per 100,000. See, study and study. Many viral infections (e.g. influenza) can cause myocarditis and pericarditis.

Vaccine safety has been intensively monitored in NZ by the COVID-19 Vaccine Independent Safety Monitoring Board (CV-ISMB). See, final report 2022.

See Immunisation Advisory Centre for COVID-19 vaccine information and resources, including pregnancy and lactation advice.

See Immunisation Handbook for COVID-19 vaccination schedule.

See Ministry of Health for information on how to access a third COVID-19 vaccine dose in immunocompromised people.

See CARM for the COVID-19 vaccine adverse reaction reporting form.

See Medsafe for vaccine safety reports.

Medicines recommended for the treatment of COVID-19

Anticoagulants

Enoxaparin should be routinely used for thromboprophylaxis in hospitalised patients with COVID-19. Prophylactic doses are used in hospitalised patients; however, consider therapeutic doses with moderate COVID-19. The evidence does not support continuing anticoagulants, initiated in hospital, after discharge or starting anticoagulant thromboprophylaxis in community patients.

Anticoagulants for thromboprophylaxis in hospitalised patients

COVID-19 induces a hypercoagulable state, particularly in severe cases. A systematic review found the overall incidence rate of venous thromboembolism (VTE) was 17% in hospitalised patients with COVID-19. For those patients in ICU the incidence rate was 28%.

The most appropriate dose regimen should be guided by bleeding risk, clinical judgement and local protocols.

Two multiplatform, RCTs by the investigators for REMAP-CAP, ACTIV-4a and ATTACC, compared treatment dose anticoagulant regimens with prophylaxis dose regimens in critically ill and non-critically ill patients.

The first RCT (n = 1098) in patients in ICU found that therapeutic-dose heparin or LMWH did not improve the primary outcome (1 versus 4 days without organ support) and was associated with more major bleeding complications (3.8% versus 2.3%) than with prophylaxis doses (low- or intermediate-dose). In the prophylaxis arm, 52% received intermediate-dose regimens. See, RCT.

The second RCT (n = 2219) in hospitalised patients (non-critically ill) found that with therapeutic-dose heparin or LMWH there were more patients with organ support-free days (80% versus 76%) and more major bleeding complications (1.9% versus 0.9%) than with prophylaxis doses (low- or intermediate-dose regimens). In the prophylaxis arm, 27% received intermediate-dose regimens. See, RCT.

The HEP-COVID study, a multicentre, RCT (n = 253), in hospitalised patients who required oxygen and were at high risk of severe disease, found that therapeutic-dose enoxaparin (1 mg/kg SC twice daily) reduced the risk of thromboembolism or death compared to prophylactic- or intermediate-dose LMWH or heparin (28.7% versus 41.9%; RR 0.68, 95% CI 0.49-0.96; P = 0.03). Most patients (98%) had elevated D-dimer levels (> 4 times ULN). The majority of patients were not in ICU (67%). For those patients in ICU there was no difference in the risk of thromboembolism or death between the treatment groups (51.1% versus 55.3%, P=0.71). There was no significant difference in major bleeding between groups (4.7% versus 1.6%; P=0.28). See, HEP-COVID study.

The ANTICOVID trial, an open-label, multicentre, RCT (n = 334) in hospitalised patients with severe COVID-19 requiring oxygen supplementation found that standard-dose prophylactic anticoagulation (LMWH or unfractionated heparin for 14 days) was as beneficial for all-cause mortality and time to clinical improvement at day 28 (ranked composite primary outcome) compared to high-dose prophylactic (twice the standard-dose) and therapeutic-dose regimens. The rate of thrombosis was greater with standard-dose prophylactic compared to high-dose prophylactic or therapeutic-dose regimens (20.2%, 5.5% and 5.5%, respectively). The study was undertaken when delta was dominant. See, ANTICOVID trial. 

Anticoagulants for thromboprophylaxis after hospitalisation and in community patients

An open-label, multicentre, RCT (n = 320) found that patients who were at high risk of VTE and who received rivaroxaban (10 mg daily for 35 days) on discharge from hospital, had fewer events (composite of symptomatic/asymptomatic VTE, symptomatic arterial thromboembolism and cardiovascular death) at day 35 than those receiving no anticoagulation (3% versus 9%; RR 0·33, 95% CI 0·12-0·90; P=0·03). Prior to discharge patients received prophylactic doses of unfractionated heparin or LMWH. Further data are awaited on the role of extended VTE prophylaxis after hospital discharge. See, MICHELLE trial.

The evidence does not support starting antiplatelet or anticoagulant agents in community patients with COVID-19 to prevent thromboembolic events. A multicentre, RCT (n = 497) in community patients with mild COVID-19, and who were at high risk of progression to severe disease, found that rivaroxaban (10 mg daily for 21 days) did not reduce the proportion of patients with disease progression at day 28, compared to placebo (21% versus 20%; P=0.8). Patients were symptomatic within 7 days of randomisation. Further data are awaited to establish if rivaroxaban can reduce the risk of disease progression in community patients. See, RCT.

The usual cautions and contraindications apply, for example renal impairment and patients with higher bleeding risk. Hospital HealthPathways gives advice on these issues, and the Medicines Information Service can be contacted for complex cases, particularly for advice on dosing.

Paracetamol

Paracetamol is recommended first-line for symptomatic relief in COVID-19. Paracetamol treats symptoms but does not improve clinical outcomes in COVID-19.

Paracetamol is an effective treatment for pain and fever in COVID-19. It is relatively safe and therefore recommended first-line for symptomatic relief in COVID-19. NSAIDs are an alternative option to paracetamol (see relevant section below).

Patients should be advised to use paracetamol in a supportive role, but warned that it does not protect from progression to more severe COVID-19 disease.

Corticosteroids

Evidence supports the use of systemic corticosteroids in critically ill patients with severe COVID-19 who require oxygen or ventilation. Inhaled corticosteroids should not be initiated to treat COVID-19. Patients should continue prescribed systemic or inhaled corticosteroids for usual chronic indications e.g. giant cell arteritis, asthma or COPD.

Patients who are using long-term oral or inhaled corticosteroids may have an increased risk of contracting coronavirus or developing more severe COVID-19 symptoms. However, patients should not stop long-term corticosteroids abruptly solely because of the current pandemic, or if they are exposed to someone with COVID-19 or develop COVID-19. Abrupt cessation is unlikely to be of benefit and more likely to cause harm e.g. adrenal crisis, uncontrolled asthma, or a flare of their condition. Wherever possible use the lowest necessary dose for the shortest period of time.

Systemic corticosteroids

A prospective meta-analysis of 7 randomised trials (n = 1703, including a subgroup of patients from the RECOVERY trial) found that 28-day all-cause mortality was lower among critically ill patients who received corticosteroids compared with those who received usual care or placebo (summary odds ratio, 0.66 [95% CI, 0.53-0.82]). Mortality benefits were similar for dexamethasone (oral or IV) and hydrocortisone (IV). Low and high dose regimens were included. See, Meta-analysis.

Preliminary findings from the dexamethasone arm of the RECOVERY trial (n = 2104 dexamethasone, n = 4321 usual care) found that dexamethasone (6 mg oral or IV once daily for 10 days compared to usual care) did not reduce mortality in patients not receiving respiratory support at randomisation. See, RECOVERY trial.

A multicentre, RCT (n = 546) in ICU patients with severe COVID-19 did not find a difference in 60-day all-cause mortality in patients treated with high-dose dexamethasone (20 mg daily for 5 days, then 10 mg daily for 5 days) compared to standard dose (6 mg daily for 10 days) (HR 0.96; 95% CI 0.69-1.33; P=0.79). All patients had severe acute hypoxemic respiratory failure and required oxygen supplementation or mechanical ventilation. Patients were randomised between April 2020 and January 2021. See, COVIDICUS trial.

Inhaled corticosteroids

A multicentre, open-label, RCT included 1856 community patients with new onset COVID-19 ≥65 years old or ≥50 years old with comorbidities (e.g. diabetes and hypertension). Treatment with inhaled budesonide 800 mcg twice daily (up to 14 days) reduced the time to self-reported recovery by 3 days compared to usual care (12 versus 15 days). No reduction in the risk of hospitalisation or death at 28 days was found. Patients were randomised between November 2020 and March 2021 prior to the delta variant becoming dominant, about 10% had received one dose of a COVID-19 vaccine. See, PRINCIPLE trial.

A parallel group, open-label, RCT included 139 community patients (> 18 years) with new onset COVID-19. Treatment with inhaled budesonide 800 mcg twice daily (average of 7 days) reduced the number of patients who required urgent medical evaluation or hospitalisation (1 versus 14 %) at 28 days compared to usual care. Self-reported recovery was 1 day shorter in the budesonide group compared to usual care (7 versus 8 days). Patients were randomised in 2020 prior to the delta variant becoming dominant, and prior to COVID-19 vaccines becoming available. See, STOIC trial.

A double-blind, placebo-controlled, RCT included 400 community patients (≥12 years) with new onset COVID-19. Treatment with inhaled ciclesonide 320 mcg twice daily (for 30 days) did not reduce the time to self-reported recovery compared to placebo (19 days for both groups). However, the secondary outcome of the number of patients requiring a subsequent emergency department visit or hospitalisation was lower in the ciclesonide group (1 versus 5.4%) compared to placebo (OR 0.18; 95% CI 0.04-0.85; P =0.03). Patients were randomised in 2020 prior to the delta variant becoming dominant, and prior to COVID-19 vaccines becoming available. In vitro data suggests that ciclesonide inhibits SARS-CoV-2 replication. This action appears unique to ciclesonide and not to all corticosteroids. See, RCT.

No mortality benefit was found in these trials and they have several limitations including relying on the self-reporting of outcomes.

Interleukin-6 (IL-6) inhibitors

IL-6 inhibitors (e.g. tocilizumab and sarilumab) have been associated with a mortality benefit.

IL-6 is a pleiotropic cytokine. A subgroup of patients with COVID-19 appear to develop features of a cytokine storm syndrome. It has been suggested that blocking the inflammatory pathway with an IL-6 inhibitor may prevent disease progression.

A prospective meta-analysis of 27 RCTs (n = 10,930) found a mortality benefit in hospitalised patients with COVID-19 treated with IL-6 inhibitors. The 28-day mortality was 22% in patients in the IL-6 inhibitor group and 26% in patients in the usual care or placebo group (OR, 0.86; 95% CI, 0.79-0.95; P = 0.003). The risk of progression to invasive mechanical ventilation or death at day 28 was also reduced with IL-6 inhibitors compared to usual care or placebo (OR, 0.77; 95% CI, 0.70-0.85; P < 0.001). For context, these results suggest that the use of an IL-6 inhibitor may result in 15 fewer deaths, or 23 fewer patients requiring mechanical ventilation, per thousand patients with severe or critical COVID-19. See, meta-analysis.

The mortality benefit was only significant when IL-6 inhibitors were co-administered with systemic corticosteroids and among patients with substantial oxygen requirements. An increased risk of secondary infection was not identified.

Access to tocilizumab has been widened. See, PHARMAC. The access criteria for its use in COVID-19 can be found here.

Janus kinase (JAK) inhibitors

JAK inhibitors (e.g. baricitinib and tofacitinib) may be associated with mortality benefits. Evidence supports the use of baricitinib in addition to systemic corticosteroids in patients with moderately severe COVID-19 who have elevated inflammatory markers or who are clinically deteriorating.

Baricitinib and tofacitinib are both orally administered JAK inhibitors.

A multicentre, placebo-controlled, RCT (n = 1525) in hospitalised patients with COVID-19 who were not receiving invasive mechanical ventilation but had at least one elevated inflammatory marker, found that adding baricitinib (4 mg once daily for up to 14 days) to usual care reduced 28-day mortality (8% versus 13% with placebo; HR 0.57, 95% CI 0.41-0.78), the reduction in mortality was maintained at 60 days. Most participants (79%) were also receiving glucocorticoids, mainly dexamethasone, and 19% received remdesivir. For patients with renal impairment the baricitinib dose was reduced, as it is mainly renally cleared.

Tofacitinib may also have clinical benefit although data are more limited.

Baricitinib is an alternative to tocilizumab when it is unavailable. PHARMAC has secured 500 courses of baricitinib. The access criteria can be found here. It is a section 29 medicine.

Antivirals

Nirmatrelvir-ritonavir is an oral antiviral agent that reduces the risk of hospitalisation or death in patients with mild to moderate COVID-19, who are at risk of severe disease, if given within 5 days of symptom onset. Remdesivir is an intravenous antiviral agent that may prevent hospitalisation or shorten time to recovery in patients with mild to moderate COVID-19, who do not require oxygen but who are at risk of severe disease, if given within 7 days of symptom onset. Molnupiravir is no longer available. If a patient is thought to have a new infection 29 days after a previous infection, then the prescribing of antivirals should be considered again. The management should be consistent with the treatment of the first infection. Circulating SARS-CoV-2 variants may be resistant to specific antiviral monoclonal antibodies.

• Molnupiravir
  • A nucleoside analogue that inhibits SARS-CoV-2 replication.
  • A phase 3, RCT (n = 1433) in unvaccinated community patients with mild to moderate COVID-19 and at least one risk factor for severe disease, found that treatment with oral molnupiravir (800 mg twice daily for 5 days), reduced the risk of hospitalisation or death (within 29 days of randomisation) compared to placebo (6.8% versus 9.7%; HR 0.69, 95% CI 0.48-1.01). Molnupiravir was started within 5 days of the onset of COVID-19 symptoms. The most frequently reported adverse effects were diarrhoea, nausea and dizziness. The delta variant was dominant during the study period. See, MOVe-OUT trial.
  • A multicentre, open label, RCT (n = 26411) in community patients with mild-moderate COVID-19 and at least one risk factor for severe disease, found that treatment with oral molnupiravir (800 mg twice daily for 5 days) plus usual care, did not reduce the risk of hospitalisation or death (within 28 days of randomisation) compared to usual care alone (1% versus 1%; adjusted OR 1.06, 95% CI 0.81-1.41). Molnupiravir was associated with a reduced time to self-reported recovery (9 days versus 15 days). Molnupiravir was started within 5 days of COVID-19 symptoms. Most patients (94%) had at least 3 vaccine doses. The omicron variant was dominant during the study period. See, PANORAMIC trial.
  • An observational study (n = 2700 molnupiravir, n = 13795 no antiviral) in hospitalised patients with COVID-19 found a reduction in all-cause mortality in patients who took a 5 day course of molnupiravir compared to no antiviral treatment, after 28 days (HR 0.87, 95% CI 0.81-0.93). Molnupiravir was started within 5 days of hospitalisation. Over half the patients had received at least one COVID-19 vaccination dose. The omicron (BA.2) variant was dominant during the study period. See, study.
  • A retrospective, cohort study (n = 5195 molnupiravir, n = 483 nirmatrelvir-ritonavir, n = 8939 no oral antiviral treatment) in older patients living in aged residential care (mean age 84.8 years) with COVID-19 found that treatment with oral antivirals (within 5 days of symptom onset) was associated with a reduced risk of hospitalisation compared to no oral antiviral treatment (molnupiravir: weighted HR 0.46; 95% CI 0.37-0.57; P<0.001; nirmatrelvir-ritonavir: weighted HR 0.46; 95% CI 0.32-0.65; P<0.001). The risk of disease progression (ICU admission, mechanical ventilation, or death) was also reduced (molnupiravir: weighted HR 0.35; 95% CI 0.23-0.51; P<0.001; nirmatrelvir-ritonavir: weighted HR 0.17; 95% CI 0.06-0.44; P<0.001). The vaccination rate was approximately 21%. The omicron (BA.2) variant was dominant during the study period. See, cohort study.
  • A retrospective cohort study (n = 3504 molnupiravir, n = 3504 no treatment) in community patients (mean age 66 years) with COVID-19 and at risk of severe disease found oral molnupiravir (800 mg twice daily for 5 days) reduced the risk of hospitalisation or death (within 30 days) compared to no treatment (43.66 versus 53.37 events per 1000 persons; RR 0.82, 95% CI 0.68-0.98). When nirmatrelvir-ritonavir (n = 1750) was compared to molnupiravir (n = 1750) the risk of hospitalisation or death was similar (28.00 versus 25.14 events per 1000 persons; RR 1.11, 95% CI 0.74-1.68). A mortality benefit remained from 1-6 months for both antivirals compared to no treatment (molnupiravir HR 0.67, 95% CI 0.48-0.95; nirmatrelvir-ritonavir HR 0.66, 95% CI 0.49-0.89). Most participants were vaccinated (82%). The omicron (BA.1, BA.2, BA.4, BA.5) variant was circulating during the study period. See, cohort study.
  • A retrospective, cohort study (n = 5311 molnupiravir, n = 22594 nirmatrelvir-ritonavir, n = 40962 no treatment) in community patients ≥ 12 years (42.7% aged ≥ 65 years) with COVID-19 and at risk of severe disease found treatment with either molnupiravir or nirmatrelvir-ritonavir (within 5 days of symptom onset) was associated with reduced mortality after 90 days compared to no antiviral treatment (HR 0.23; 95% CI 0.16-0.34 for molnupiravir and HR 0.16; 95% CI 0.11-0.23 for nirmatrelvir-ritonavir). There was also a reduction in hospitalisation rate with both antivirals. Most participants were vaccinated (almost 60% boosted). Omicron was circulating during the study period (BA.2, BA.4, BA.5, BQ.1, XBB). See, cohort study.
  • There are no pregnancy safety data in humans. Animal safety data show possible teratogenic effects with doses 8 times the human equivalent dose in rat models, but not in rabbit models. 
  • Molnupiravir is no longer available. See, PHARMAC.
• Nirmatrelvir-ritonavir
  • Nirmatrelvir is an oral antiviral protease inhibitor. Ritonavir inhibits the clearance of nirmatrelvir and thus boosts its concentrations.
  • Consider potential drug interactions predominantly due to the ritonavir component. See, bulletin.
  • A phase 2/3, multicentre, RCT (n = 2246) in unvaccinated community patients with mild to moderate COVID-19 and one or more risk factors for severe disease, found that oral nirmatrelvir-ritonavir (300 mg + 100 mg every 12 hours for 5 days) administered within 3 days of symptom onset, reduced the rate of hospitalisation or death (within 28 days of randomisation) compared with placebo (0.72% versus 6.45%, RRR 89%, P<0.001). Results were similar when the drug was administered within 5 days of symptom onset. Adverse effects attributed to nirmatrelvir-ritonavir were more common than with placebo (7.8% versus 3.8%), largely due to dysgeusia (4.5% versus 0.2%) and diarrhoea (1.3% versus 0.2%). See, EPIC-HR trial.
  • An observational, retrospective, cohort study (n = 3902 nirmatrelvir-ritonavir, n = 105,352 usual care) in community patients ≥40 years at high risk of severe COVID-19 disease found a reduction in hospitalisation and mortality rate in patients ≥ 65 years treated with nirmatrelvir-ritonavir (for 5 days) within 5 days of symptom onset, compared to usual care (adjusted HR 0.27, 95% CI 0.15-0.49; adjusted HR 0.21, 95% CI 0.05-0.82, respectively). This benefit was not seen in younger patients 40-64 years. Most patients had immunity (78%) via vaccination or previous SARS-CoV-2 infection or both. The omicron variant (B.1.1.529) was dominant during the study period. See, study.
  • An observational study (n = 1813 nirmatrelvir-ritonavir, n = 5306 no antiviral) in hospitalised patients with COVID-19 found a reduction in all-cause mortality in patients who took a 5 day course of nirmatrelvir-ritonavir compared to no antiviral treatment, after 28 days (HR 0.77, 95% CI 0.66-0.90). Nirmatrelvir-ritonavir was started within 5 days of hospitalisation. Over half the patients had received at least one COVID-19 vaccination dose. The omicron (BA.2) variant was dominant during the study period. See, study.
  • A retrospective, cohort study (n = 483 nirmatrelvir-ritonavir, n = 5195 molnupiravir, n = 8939 no oral antiviral treatment) in older patients living in aged residential care (mean age 84.8 years) with COVID-19 found that treatment with oral antivirals (within 5 days of symptom onset) was associated with a reduced risk of hospitalisation compared to no oral antiviral treatment (nirmatrelvir-ritonavir: weighted HR 0.46; 95% CI 0.32-0.65; P<0.001; molnupiravir: weighted HR 0.46; 95% CI 0.37-0.57; P<0.001). The risk of disease progression (ICU admission, mechanical ventilation, or death) was also reduced (nirmatrelvir-ritonavir: weighted HR 0.17; 95% CI 0.06-0.44; P<0.001; molnupiravir: weighted HR 0.35; 95% CI 0.23-0.51; P<0.001). The vaccination rate was approximately 21%. The omicron (BA.2) variant was dominant during the study period. See, cohort study.
  • A retrospective cohort study (n = 9607 nirmatrelvir-ritonavir, n = 9607 no treatment) in community patients (mean age 66 years) with COVID-19 and at risk of severe disease found oral nirmatrelvir-ritonavir (300 mg + 100 mg every 12 hours for 5 days) reduced the risk of hospitalisation or death (within 30 days) compared to no treatment (23.00 versus 34.17 events per 1000 persons; RR 0.67, 95% CI 0.58-0.79). When nirmatrelvir-ritonavir (n = 1750) was compared to molnupiravir (n = 1750) the risk of hospitalisation or death was similar (28.00 versus 25.14 events per 1000 persons; RR 1.11, 95% CI 0.74-1.68). A mortality benefit remained from 1-6 months for both antivirals compared to no treatment (nirmatrelvir-ritonavir HR 0.66, 95% CI 0.49-0.89; molnupiravir HR 0.67, 95% CI 0.48-0.95). Most participants were vaccinated (82%). The omicron (BA.1, BA.2, BA.4, BA.5) variant was circulating during the study period. See, cohort study.
  • A retrospective, cohort study (n = 35,717 nirmatrelvir-ritonavir, n = 246,076 control) in community patients (mean age 62 years) with COVID-19 and at least one risk factor for disease progression, found that treatment with nirmatrelvir-ritonavir (within 5 days of testing positive for SARS-CoV-2) reduced the risk of post COVID-19 condition (based on a weighted score from 13 prespecified symptoms) from day 30 to 180 compared to control (RR 0.74; 95% CI 0.72-0.77; ARR 4.51%). The risk of post COVID-19 condition was reduced in vaccinated and unvaccinated people. The risk of hospitalisation or death from day 30 to 180 was also reduced with nirmatrelvir-ritonavir compared to control (HR 0.74; 95% CI 0.70-0.77; ARR 2.15%). The omicron variant (BA.2, BA.5, BQ.1) was circulating during the 12 month study period. The definition of post COVID-19 condition can vary, it describes a wide range of symptoms present 4 weeks or more after SARS-CoV-2 infection. See, cohort study.
  • A retrospective, cohort study (n = 22594 nirmatrelvir-ritonavir, n = 5311 molnupiravir, n = 40962 no treatment) in community patients ≥ 12 years (42.7% aged ≥ 65 years) with COVID-19 and at risk of severe disease found treatment with either nirmatrelvir-ritonavir or molnupiravir (within 5 days of symptom onset) was associated with reduced mortality after 90 days compared to no antiviral treatment (HR 0.16; 95% CI 0.11-0.23 for nirmatrelvir-ritonavir and HR 0.23; 95% CI 0.16-0.34 for molnupiravir). There was also a reduction in hospitalisation rate with both antivirals. Most participants were vaccinated (almost 60% boosted). Omicron was circulating during the study period (BA.2, BA.4, BA.5, BQ.1, XBB). See, cohort study.
  • Pregnancy safety data in humans are limited. Two small studies (n = 47 and n = 7) in pregnant women who took nirmatrelvir-ritonavir in various stages of pregnancy (approximately 60% in third trimester, 30% in second trimester and 10% in first trimester) have not shown an increased risk of congenital malformations or adverse pregnancy outcomes. Animal safety data for nirmatrelvir have not identified teratogenic effects with doses up to 12 times the human equivalent dose in rat or rabbit models. See, study and study.
  • Tablets can be crushed for patients who have trouble swallowing or who require administration via an enteral tube. See, bulletin.
  • Nirmatrelvir-ritonavir has been approved by Medsafe. The access criteria can be found here.

• Remdesivir
  
  • A nucleotide analogue that inhibits SARS-CoV-2 replication.
  • In the following studies the dose regimen for remdesivir was 200 mg on day 1 then 100 mg once daily on subsequent days.
  • An open label, multicentre, RCT (n = 8275) found in hospitalised patients who received remdesivir (up to 10 days) that there was no difference in the rate of mortality compared to control (14.5% versus 15.6%; RR 0.91, 95% CI 0.82-1.09; P=0.12). However, among those who were not on a ventilator, remdesivir reduced both mortality (11.9% versus 13.5%; RR 0·86, 95% CI 0·76-0·98; P=0·02) and progression to ventilation (14.1% versus 15.7%; RR 0.88, 95% CI 0.77-1.00; P=0.04). An accompanying meta-analysis (n=11029, including SOLIDARITY and ACTT-1 trials) reported similar findings. See, SOLIDARITY trial.
  • An RCT (n = 562) in unvaccinated community patients with symptomatic COVID-19 and at least one risk factor for severe disease (the most common were diabetes, obesity and hypertension or age ≥ 60 years), found that treatment with a 3-day course of remdesivir reduced the risk of hospitalisation or death compared to placebo (0.7% versus 5.3%; HR 0.13, 95% CI 0.03-0.59; P=0.008). How these results apply to vaccinated patients is unclear. See, RCT.
  • Limited safety data in pregnant women have not shown an increased risk of congenital malformations or adverse pregnancy outcomes. Avoid in first trimester.
  • Gilead Sciences (New Zealand) has provided a factsheet for remdesivir. The access criteria can be found here.

• Monoclonal antibodies 
  
  • Combination (e.g. casirivimab-imdevimab or bamlanivimab-etesevimab) and single agent (e.g. sotrovimab) intravenous antiviral monoclonal antibody regimens have been used in clinical trials. The delta variant appears to be neutralised by casirivimab-imdevimab, bamlanivimab-etesevimab and sotrovimab regimens, while the omicron variant appears to be neutralised by sotrovimab.
  • A phase 3 RCT (n = 4180) in community patients with mild to moderate COVID-19 and one or more risk factors for severe disease, found a reduction in hospitalisation or death (within 29 days of randomisation) among those treated within 7 days of symptom onset with casirivimab-imdevimab compared with placebo (single infusion of 600 mg each, 1200 mg total dose, 1% versus 3.2%, P=0.002; 2400 mg total dose, 1.3% versus 4.6%, P<0.001). The median time to resolution of symptoms was 4 days shorter and there was a more rapid decline in the viral load with casirivimab-imdevimab than with placebo. See, REGEN-COV trial.
  • A phase 3 RCT (n = 1035) in community patients with mild to moderate COVID-19 and one or more risk factors for severe disease, found a reduction in hospitalisation or death (within 29 days of randomisation) among those treated within 3 days of laboratory confirmed COVID-19 with bamlanivimab-etesevimab (single infusion of 2800 mg each, 5600 mg total dose) compared with placebo (2.1% versus 7.0%, P<0.001). There was a more rapid decline in the viral load with bamlanivimab-etesevimab than with placebo. See, BLAZE-1 trial.
  • A phase 3, multicentre, RCT (n = 1057) in community patients with mild to moderate COVID-19 and one or more risk factors for severe disease, found a reduction in hospitalisation or death (within 29 days of randomisation) among those treated with sotrovimab (single infusion of 500 mg) within 5 days of symptom onset compared to placebo (1% versus 6%, adjusted RR 0.21, P<0.001). See, COMET-ICE trial.
  • Serious adverse effects with the antiviral monoclonal antibody regimens occurred in ≤2% of patients in these trials which was similar to the incidence with placebo (1-6%). Infusion related reactions included fever, chills, urticaria, pruritus, abdominal pain and flushing.
  • Casirivimab-imdevimab has been approved by Medsafe. The access criteria can be found here. See, Ministry: Practical guidance on the use of Ronapreve®. Casirivimab-imdevimab should not be used to treat patients with the omicron variant because mutations to the targeted spike protein significantly reduce efficacy.
• Antivirals that are not recommended: 
  
  • Lopinavir-ritonavir has not been associated with any clinical benefits against COVID-19. The SOLIDARITY (n = 2771) and RECOVERY (n = 1616 lopinavir-ritonavir, n = 3424 usual care) trials did not find any benefit in mortality or ventilation rates or duration of hospital stay.
  • Oseltamivir inhibits neuraminidase, which influenza viruses use to replicate and spread. Coronaviruses do not use neuraminidase so oseltamivir has no activity against coronaviruses. Oseltamivir should be reserved for treating confirmed or suspected influenza. If started, it should be ceased if influenza is excluded.
  • Sabizabulin is an oral, novel microtubule disruptor that has antiviral and anti-inflammatory properties. Interim analysis of a phase 3, multicentre, RCT (n = 134 sabizabulin, n = 70 placebo) in hospitalised patients with moderate to severe COVID-19 and at risk of acute respiratory distress syndrome and death found that sabizabulin (9 mg daily, up to 21 days) reduced 60-day mortality compared to placebo. Final analyses are awaited. See RCT.

Medicines not recommended for the treatment of COVID-19

Acetylcysteine

Acetylcysteine currently has no role in the management of COVID-19.

Antidepressants

The evidence does not support using antidepressants for COVID-19 outside a clinical trial setting.

A multicentre, RCT (n = 1,497) in community patients with COVID-19, within 7 days of symptom onset and at risk for severe disease, found a reduction in hospitalisations among those treated with fluvoxamine (100 mg twice daily for 10 days) compared with placebo (11% versus 16%; RR 0·68, 95% CI 0·52-0·88; P > 0.05). Most participants were unvaccinated (94%). The delta variant was circulating during the study period. See, TOGETHER trial, Jan 2022.

A meta-analysis of 3 trials (n = 2196) found a high probability (94.1% to 98.6%) that fluvoxamine was associated with reduced hospitalisation in community patients with COVID-19. The largest trial was the TOGETHER trial, which heavily weighted the results. See, meta-analysis.

A prospective, open label, cohort trial (n = 102) in hospitalised patients with severe COVID-19 found that treatment with fluvoxamine (100 mg TDS for 15 days then, 50 mg BD for 7 days) was associated with lower mortality compared to usual care (59% versus 77%; HR 0.58, 95% CI 0.36-0.94; P = 0.027). This mortality benefit was only significant in the female participants, and may have been confounded by a 40% higher proportion of diabetes in the control group. Most participants were unvaccinated (88%). The delta variant was circulating during the study period. See, cohort trial.

An RCT (n = 1288) in community patients with mild to moderate COVID-19, did not find a difference in the time to sustained recovery with fluvoxamine (50 mg BD for 10 days) compared to placebo (mean 12 days versus 13 days). Sustained recovery was defined as the third day of 3 consecutive days without symptoms. Fluvoxamine was started within 7 days of developing at least 2 symptoms of COVID-19. Two thirds of patients were vaccinated. Delta and omicron were circulating during the study period. See, ACTIV-6 trial.

A multicentre, RCT (n = 1476) in community patients with symptomatic COVID-19 and risk factors for progression to severe disease, found that combined treatment with both fluvoxamine (100 mg twice daily for 10 days) and inhaled budesonide (800 mcg twice daily for 10 days) was associated with a lower risk of emergency department visits or hospitalisation (within 28 days of randomisation), compared to placebo (1.8% versus 3.7%; RR 0.50, 95% CI 0.25-0.92). Most patients were vaccinated (> 90% at least 2 vaccine doses). Omicron (BA.1, BA.2, BA.4, BA.5) was circulating during the study period. It is not clear if similar results would occur with other antidepressants e.g. SSRIs. See, TOGETHER Trial, May 2023.

A retrospective, cohort study (n = 1547 antidepressant use, n = 5664 total) in patients with a mental health diagnosis found antidepressant use (within 90 days of admission for inpatient mental health care) was associated with a lower incidence of positive COVID-19 test results compared to participants not taking an antidepressant (2.2% versus 4.1%). SSRIs were the most commonly used antidepressants (67%). The study was undertaken prior to vaccines becoming available when the original SARS-CoV-2 strain was circulating. It is not clear if similar results would occur in a vaccinated general population. See, cohort study.

There are a variety of possible mechanisms for how fluvoxamine may improve patient outcomes in COVID-19 including anti-inflammatory activity via activation of sigma-1 receptors, for which fluvoxamine has 10-fold greater affinity than most other SSRIs. Fluvoxamine is not available in NZ. It is not known if the potential clinical benefits associated with fluvoxamine in patients with COVID-19 are a class effect of the SSRIs, or apply to other antidepressants (e.g. SNRIs or TCAs).

Azithromycin

Azithromycin has no role in the management of COVID-19.

Results from the azithromycin arm of the RECOVERY trial (n = 7763) did not find a clinical benefit or survival benefit in patients admitted to hospital with COVID-19. 22% of patients died within 28 days in both the azithromycin group (561/2582) and the usual care group (1162/5181) (P = 0.50).

Interim results from an RCT (n = 263) in patients with COVID-19 managed in the community, found that 50% of patients were symptom free at day 14, in both the group that received a single oral 1.2 g dose of azithromycin (66/131) and the group that received placebo (35/70) (P > 0.99). The lack of effect resulted in the termination of the study.

Azithromycin and hydroxychloroquine are QTc prolonging drugs and their combined use increases this risk. Widespread use of azithromycin increases the potential for bacterial resistance. Azithromycin use in patients with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. 

Bacillus Calmette-Guérin (BCG) vaccine

The BCG vaccine currently has no role in the prevention of COVID-19.

Published evidence from randomised controlled trials and observational studies has shown that BCG vaccination prevents non-tuberculous respiratory infections such as pneumonia and influenza, in children and the elderly. This relates to the non-specific effects of the BCG vaccine on the immune system. These effects have not been well characterised and their magnitude and duration is unknown.

A multicentre, double-blind, RCT (n = 3988) in healthcare workers found that the BCG vaccine (single dose) compared to placebo did not reduce the risk of symptomatic (14.7 % versus 12.3%, P = 0.13) or severe (7.6% versus 6.5%, P = 0.34) COVID-19 infection, after 6 months. Severe infection was defined as 3 consecutive days off work. Approximately 75% of all participants had previously received a BCG vaccine. The study was undertaken prior to the delta variant becoming dominant. See, RCT.

Biologics

Most biologics currently have no clear role in the management of COVID-19 outside a clinical trial setting.

Biologics are being investigated for activity against coronaviruses:

• Anakinra
  • Severe COVID-19 is associated with a marked inflammatory response, which may be the basis of the inflammatory lung damage. Anakinra is a recombinant protein similar to the endogenous interleukin-1 (IL-1) receptor antagonist protein, and therefore reduces IL-1 mediated inflammation.
  • A double-blind, multicentre, RCT (n = 594 total, n = 405 anakinra) in hospitalised patients with moderate to severe COVID-19 and who were at risk of respiratory failure, found treatment with subcutaneous anakinra (100 mg daily for 7-10 days) reduced the risk of clinical progression at day 28 compared to placebo (OR 0.36; 95% CI 0.26–0.50; P < 0.0001). Most patients also received dexamethasone (86%). The study period was December 2020 to March 2021 prior to the delta and omicron variants. See, SAVE-MORE trial.
  • A phase 2/3, multicentre, open label, RCT (n = 179) in hospitalised patients with severe COVID-19 and elevated inflammatory markers found that treatment with intravenous anakinra (100 mg 4 times a day for up to 15 days) did not significantly reduce the proportion of patients not requiring mechanical ventilation after 15 days compared to usual care (71% versus 86%; RR 0.90; 95% CI 0.77-1.04; P = 0.16). The study period was May 2020 to March 2021 prior to the delta and omicron variants. See, ANA-COVID-GEAS trial. 
  • Anakinra is an unapproved medicine in NZ.
• Interferons
  • Interferons are biologic response modifiers that have shown activity against coronaviruses in animal and in vitro studies. There are different types of interferon. In NZ interferon alfa, beta and gamma are available, whereas lambda is not available.
  • Interferon-beta: A double-blind, placebo-controlled trial, found that hospitalised patients with COVID-19 (n = 101) who received inhaled interferon-beta had a lower risk of developing severe disease compared to placebo. See, RCT.
  • Interferon-lambda: A phase 3, multicentre, RCT (n = 1951) in community patients with symptoms of COVID-19 and at least one risk factor for progression to severe disease found that pegylated interferon-lambda (a single 180 µg subcutaneous dose) reduced hospitalisations or emergency department visits (within 28 days of randomisation) compared to placebo (2.7% versus 5.6%; RR 0.49, 95% CI 0.3-0.76). Treatment was administered within 7 days of symptom onset. 83% of patients were vaccinated. Multiple SARS-CoV-2 variants circulated during the study period including delta and omicron (BA.1). See, RCT.
• Tixagevimab-cilgavimab
  • Most omicron subvariants circulating in NZ are resistant to tixagevimab-cilgavimab, therefore it is no longer recommended for pre-exposure prophylaxis or treatment.
  • Preliminary results from a phase 3, multicentre, placebo controlled, RCT (n = 3460 tixagevimab-cilgavimab, n = 1737 placebo) found that symptomatic COVID-19 occurred in fewer participants who received a single dose of tixagevimab-cilgavimab (given as two separate IM injections of 150 mg each) than in those who received placebo, after 3 months (0.2% versus 1%; RRR = 77%, 95% CI 46-90; P < 0.001). Participants included those at risk of either severe disease (e.g. age ≥60 years or comorbidity including immunosuppression) or SARS-CoV-2 exposure (e.g. healthcare workers). None of the participants were vaccinated or had a history of SARs-CoV-2 infection. The study was conducted before the omicron variant was prevalent. See, PROVENT trial.
  • In PROVENT, serious cardiac adverse events including myocardial infarction and heart failure were more frequent with tixagevimab-cilgavimab than placebo (1.1% versus 0.5%). However, two other studies have not shown an increased risk (STORM CHASER 0.3% versus 0.5%, and TACKLE 0.7% versus 0.7% for tixagevimab-cilgavimab versus placebo, respectively). Hence, causality remains to be established. See, analysis.
  • The half-life of tixagevimab-cilgavimab is approximately 90 days. The estimated duration of action is 6 months.

Chloroquine and Hydroxychloroquine

Chloroquine and hydroxychloroquine currently have no role in the treatment of COVID-19.

There are now many published clinical trials investigating the use of hydroxychloroquine (HCQ) or chloroquine (CQ) for COVID-19.

The HCQ arm of the RECOVERY trial (n = 4716) found that there was no difference in 28 day mortality between the HCQ and usual care groups in hospitalised patients with COVID-19. Death at 28 days occurred in 27% of patients (421/1561) in the HCQ group and in 25% of patients (790/3155) in the usual care group (rate ratio, 1.09; 95% confidence interval, 0.97 to 1.23; P = 0.15). Patients in the HCQ group had a longer duration of hospitalisation than those in the usual care group (median, 16 days versus 13 days). There was a small absolute excess of cardiac mortality of 0.4% but no difference in the incidence of new major cardiac arrhythmia among the patients who received HCQ. There was one report of torsades de pointes that was related to HCQ. See, RECOVERY trial

Two open-label RCTs, from China compared HCQ with standard care and involved 30 and 150 patients respectively. Both showed no difference in viral clearance, clinical improvement, or mortality. A trial of high dose vs. low dose CQ was stopped early due to toxicity in the high dose arm. There are also several observational trials published, with a combined total of over 3,000 patients, which show no benefit or harm for HCQ or CQ in multivariate analysis.

Overall, current evidence does not support HCQ or CQ being effective treatments for COVID-19. Inappropriate use outside of clinical trials risks unnecessary adverse effects and creating a shortage of these medicines for established indications e.g. rheumatoid arthritis. Accordingly, PHARMAC has restricted funding of HCQ to approved indications (rheumatoid arthritis, systemic or discoid lupus erythematosus, malaria).

Complementary and Alternative Medicines

Complementary and Alternative Medicines have no role in the prevention or treatment of COVID-19.

A broad range of complementary and alternative medicines, including herbal products and dietary supplements, have been proposed for prevention and treatment of COVID-19. There is no evidence to support these claims. Additionally, these products pose several risks:

• They are unregulated and therefore of uncertain quality
• They risk unnecessary adverse effects and drug interactions
• They potentially reduce adherence with effective prevention (such as handwashing) by providing false reassurance 
• Effective supportive treatments, such as paracetamol, may be deferred
• They are a preventable financial burden to patient

Complementary and alternative medicines are therefore not recommended for prevention or treatment of COVID-19.

Famotidine

Famotidine currently has no role in the management of COVID-19.

Retrospective observational data from Wuhan, combined with computerised modelling data, has led to a theory that famotidine may inhibit an enzyme involved in viral replication. An RCT in hospitalised patients with COVID-19 is underway, using high dose intravenous famotidine. Until the study results become available, we do not recommend the use of famotidine in COVID-19.

Ivermectin

Ivermectin has no role in the management of COVID-19.

The biological plausibility of ivermectin being effective in humans with COVID-19 is low as standard ivermectin dosing achieves blood concentrations approximately 100-fold less than what was needed in vitro to inhibit the SARS-CoV-2 virus.

A number of meta-analyses of RCTs involving ivermectin have been published. However, these have been difficult to make firm conclusions upon, because of the variable quality of the studies included. For example, a meta-analysis of 24 RCTs included 16 non-peer reviewed and unpublished studies. Further, it included a large study from Egypt (n = 400) that reported significant benefits from ivermectin, but has been retracted due to data inconsistencies. Other RCTs that have found improved outcomes with ivermectin have been rated as ‘low’ or ‘very low’ quality evidence by the WHO.

A multicentre, open label, RCT (n = 490) in hospitalised patients ≥ 50 years with mild to moderate COVID-19 and one or more risk factors for progression to severe disease, found that ivermectin (0.4 mg/kg/day for 5 days) did not reduce progression to severe disease compared to usual care (21.6% versus 17.3%; RR 1.25, 95% CI 0.87-1.80; P = 0.25). Ivermectin was given within 7 days of symptom onset. Approximately half the patients had received 2 doses of a COVID-19 vaccine. Adverse effects occurred in more patients in the ivermectin group (13.7%) than in the control group (4.4%) with diarrhoea the most common. The study was undertaken in Malaysia when the delta variant dominated. See I-TECH trial.

A multicentre, double-blind, placebo-controlled, RCT (n = 1591) in community patients ≥ 30 years with symptomatic mild to moderate COVID-19 found that ivermectin (0.3-0.4 mg/kg/day for 3 days, maximum 35 mg daily) did not reduce the median time to recovery compared to placebo (12 days versus 13 days). Adverse effects were similar in both groups (2.8% ivermectin, 3.5% placebo). Ivermectin was started within 10 days of confirmed SARS-CoV-2 infection. The study was undertaken in the United States when the delta and omicron (BA.1, BA.2) variants were dominant. Almost half the patients had received at least 2 doses of a COVID-19 vaccine. See, ACTIV-6 trial, Oct 2022.

A multicentre, double-blind, RCT (n = 1206) in community patients ≥ 30 years with symptomatic mild to moderate COVID-19 found that ivermectin (0.4-0.6 mg/kg/day for 6 days, maximum 70 mg daily) did not reduce the median time to recovery compared to placebo (11 days versus 11 days). Adverse effects were similar in both groups (9.2% ivermectin, 7.1% placebo). Ivermectin was started within 10 days of confirmed SARS-CoV-2 infection. Most patients were vaccinated (> 80% at least 2 vaccine doses). The study was undertaken in the United States when omicron (BA.1, BA.2, BA.4, BA.5) was dominant. See, ACTIV-6 trial, Feb 2023.

Melatonin

Melatonin currently has no role in the management of COVID-19.

Melatonin has been identified as a potential medicine that could be repurposed for use in COVID-19 from a retrospective study using data from a COVID-19 registry.

Analysis of 26,779 people, of whom 8,274 tested positive for COVID-19, found that people who were taking melatonin were 28% less likely to test positive for COVID-19. The observational nature of the study means confounding may have contributed to the finding.

The current evidence is insufficient to justify the use of melatonin for treating COVID-19 outside a clinical trial setting.  Several RCT’s are evaluating the clinical benefits of melatonin in patients with COVID-19.

Nitazoxanide

Nitazoxanide currently has no role in the management of COVID-19.

Povidone-iodine gargle

Povidone-iodine gargle has no role in the management of COVID-19.

An in vitro study suggests that povidone-iodine gargle reduces viral load (including MERS-CoV and SARS-CoV) in the oral cavity and the oropharynx, which could indicate that it might help prevent viral transmission. This study was funded by a pharmaceutical company. The clinical relevance has not been established.

The role of povidone-iodine in COVID-19 is as a topical disinfectant within standard infection control protocols.

Statins

Patients already taking statins should continue them as discontinuation has been associated with worse clinical outcomes in patients with COVID-19.

Observational data supports continued use of statins in patients with COVID-19. A retrospective analysis (n = 146,413 total, n = 34,474 atorvastatin) of hospitalised patients with COVID-19 reported that those who continued outpatient use of atorvastatin had a lower risk of mortality compared to patients who discontinued atorvastatin (OR 0.65, 95% CI 0.59-0.72; P < 0.001). The risk of mechanical ventilation was also lower with continuous atorvastatin therapy (OR 0.70, 95% CI 0.64-0.77; P < 0.001). See, observational study.

A multicentre, RCT (n = 605) found in hospitalised patients with severe COVID-19 treated with atorvastatin (20 mg daily for 30 days) that there was no difference in primary outcome risk (composite of venous or arterial thrombosis, ECMO, or all-cause mortality within 30 days of randomisation) compared to placebo (33% versus 36%; OR 0.84, 95% CI 0.58-1.21; P = 0.35). Patients had no pre-existing indication for statin therapy. See, INSPIRATION-S trial.

There are several plausible mechanisms how statins may improve outcomes in COVID-19. Statins have anti-inflammatory and immunomodulatory effects, and they may also have a direct inhibitory effect on the SARS-CoV-2 virus. The evidence does not support starting statins in patients with COVID-19 unless there are conventional indications for their use (e.g. hypercholesterolaemia or prevention of cardiovascular events).

Vitamin C

There are no clinical studies to support the use of oral vitamin C supplementation in the prevention of COVID-19.

There is currently insufficient evidence to support the use of vitamin C, via any route, in the management of COVID-19. Clinical trials using intravenous high-dose vitamin C in patients hospitalised with COVID-19 are underway.

Two recent open-label studies on the use of intravenous high-dose vitamin C in other types of infections associated with septic shock and acute respiratory distress syndrome (ARDS) infections showed there was no clear benefit of vitamin C. Septic shock and ARDS are conditions leading to ICU admission, ventilator support or death among those with severe COVID-19.

Vitamin D

Vitamin D has no role in the management of COVID-19.

Results from an RCT (n = 240), did not find any clinical benefits associated with a single high dose of vitamin D3 in hospitalised patients with COVID-19. The median length of hospital stay for both the vitamin D3 (n = 120) and placebo (n = 120) groups was 7 days. There was also no difference in mortality, ventilation or ICU admission rates. See RCT.

A phase 3, open label, RCT (n = 6300) in adults ≥ 16 years found that vitamin D supplementation did not reduce the rate of all cause acute respiratory infections or COVID-19 infections. The treatment group (n = 3200) received vitamin D3 (randomly, either 800 or 3200 IU daily for 6 months) only if 25-OH-vitamin D levels were < 75 nmol/L. The control group (n = 3100) were neither tested nor treated with vitamin D. Most of the treatment group (>80%) had 25-OH-vitamin D concentrations < 75 nmol/L (mean ≈ 41 nmol/L). During the study period the number of people who received at least one COVID-19 vaccine increased from < 2% to almost 90%. See, CORONAVIT study.

Vitamin D supplementation is only recommended for patients with documented deficiency, or the usual patient groups who are at risk of deficiency such as elderly people in residential care.

Zinc

Zinc supplements currently have no role in the prevention or treatment of COVID-19.

We found no published reports of zinc being used to prevent or treat COVID-19 infection. The role of zinc is based on a number of theories, including the finding from an in vitro study in 2010 that zinc inhibited RNA-dependent polymerase replication of SARS-CoV virus. The evidence that zinc lozenges can reduce the severity of common cold symptoms is weak and inconsistent.

The evidence to support the use of zinc in the management of COVID-19 is theoretical only and we do not recommend its use. Clinical trials using zinc and other vitamin supplements in COVID-19 have been registered.

Medicines reported to worsen COVID-19

There are no clinical studies showing increased harm from any medicine use in relation to COVID-19. Patients should be advised not to stop any regular medicines unless there is a conventional indication to do so.

COVID-19 uses angiotension-coverting enzyme 2 (ACE2) to enter cells. There is pre-clinical data from in vitro and animal studies that some medicines may upregulate ACE2, raising concerns that these medicines could increase the severity of COVID-19 infection. However, there are no clinical data (including the publications from the large number of cases in China) to support this theory.

Immunosuppression theoretically increases the risk of coronavirus infection but there is no clinical evidence to support this.

Some medicines are associated with pneumonia or respiratory depression, but the risk is too small or uncertain to justify altering usual prescribing of these agents.

Antidiabetic Medicines

Patients already taking thiazolidinediones (e.g. pioglitazone) should continue them unless there is a conventional reason not to (e.g. heart failure, history of bladder cancer).

Thiazolidinediones, such as pioglitazone, upregulate ACE2 in animal studies (see above). Observational studies of patients with COVID-19 have shown increased hospitalisation and mortality for patients with diabetes (7.3% vs 0.9%). Reports have suggested this could be due to ACEI and ARB use, however there are no data to substantiate this. Diabetes has separately been shown to upregulate ACE2 and increases the risk of other infections, both of which add to the confounding in the observational data.

The usual contraindications and cautions still apply to ACEI and ARB use as they did prior to COVID-19, for example patients with heart failure or a history of bladder cancer. We recommend clinicians continue usual practice around the use of pioglitazone during the COVID-19 pandemic.

Antipsychotics

Patients taking antipsychotics should continue to take them unless there is a conventional reason to stop (e.g. falls or sedation).

Antipsychotics are associated with an almost 2-fold increase in risk of pneumonia in observational studies. However, depending on the baseline risk of pneumonia the number needed to treat to cause one case of pneumonia is between 86 and over 1,126. The risk is much lower than other significant adverse effects of antipsychotics. A causal relationship between antipsychotics and pneumonia has not been definitively established.

Antipsychotic cessation could result in withdrawal or destabilisation of the underlying condition. Therefore, we do not advocate changing antipsychotic prescribing solely on the basis of COVID-19 risk.

Drugs affecting the renin-angiotensin system

Patients already taking angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) should continue them unless there is a conventional reason not to (e.g. hyperkalaemia, acute kidney injury).

ACEIs and ARBs upregulate ACE2 in animal studies (see above). ACE2 receptors have been shown to be the entry point into human cells for SARS-CoV-2. However, it is not clear that ACEIs or ARBs upregulate ACE2 in humans.  

A systematic review and meta-analysis of 52 studies (40 cohort studies, 6 case series, 4 case-control studies, 1 RCT, and 1 cross-sectional study) with 101 949 total participants, found reduced mortality, ICU admission and ventilation rates in those patients with COVID-19 taking ACEIs and ARBs. See, meta-analysis.

The evidence does not support starting ACEIs or ARBs in patients with COVID-19 to protect against lung injury caused by a theoretical mechanism of renin-angiotensin-aldosterone system activation by SARs-CoV-2. An RCT (n = 205) found that losartan (50 mg twice daily for 10 days) did not reduce viral-induced acute lung injury in hospitalised patients with COVID-19 compared to placebo. See, RCT. An open-label RCT (n = 779) was stopped early due to concern that initiating ACEIs or ARBs in critically ill patients with COVID-19 may worsen clinical outcomes. See, REMAP CAP trial.

Two multicentre, RCTs (n = 633 total) in hospitalised patients with COVID-19 and hypoxemia, found no difference in the number of oxygen-free days after treatment with either intravenous angiotensin 1-7 (TXA-127) or angiotensin-1 receptor agonist (TRV-027) compared to placebo. These novel drugs are expected to favourably modulate the renin-angiotensin system and mitigate against SARs-CoV-2 infection. Both studies were stopped after the interim analyses due to low probability of efficacy. See, ACTIV-4 trials.

We support the current consensus in New Zealand and internationally (for example European Medicines Agency, International Hypertension Society, American College of Cardiology) to continue normal usage of ACEIs and ARBs. The usual contraindications and cautions still apply, for example patients with hyperkalaemia or hypotension.

Immunosuppressants

Patients should continue immunosuppressants while they remain well, even after potential COVID-19 exposure.

We refer to immunosuppressants as any medicine dampening immune response, including those described as “immunomodulatory” rather than immunosuppressive. Examples of these medicines include corticosteroids, Disease Modifying Anti-Rheumatic Drugs (DMARDs), and monoclonal antibodies that affect the immune system.

Immunosuppressants theoretically increase the chances of contracting coronavirus, or developing more severe infection. However, the extent of this effect is uncertain. Ceasing immunosuppressants could destabilise control of the underlying disease resulting in direct patient harm from disease, risk of hospitalisation (and COVID-19 exposure), and use of more immunosuppressing regimens (such as high-dose corticosteroids) to regain disease control. The long duration of effect of most immunosuppressants means omitting doses after COVID-19 exposure, for example, confers little or no short-term reduction of immunosuppression.

The management of immunosuppression for patients with an active infection is dependent on individual factors, such as the indication for immunosuppression and severity of the infection. It is therefore not possible to provide explicit guidance here, but clinicians are advised to use the same approach as applies to other significant viral infections, such as influenza. Discussion with the relevant specialist is recommended.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs use in patients with COVID-19 should be informed by conventional indications (e.g. pain) and contraindications (e.g. acute kidney injury). Use the lowest necessary dose for the shortest necessary time.

There has been longstanding concern about possible harm from NSAIDs in viral infections. Randomised controlled trials and observational data comparing NSAIDs and paracetamol have produced mixed results with some showing no difference and others a small effect of NSAIDs. Overall, the data do not give a clear signal to draw a convincing conclusion.

In COVID-19 concerns were raised partly because of the potential for NSAIDs to upregulate ACE2 in animal models. Recent studies have not supported an association between NSAID use and poorer outcomes for patients with COVID-19.

In a prospective, multicentre cohort study, patients admitted to hospital with COVID-19 who were taking NSAIDs did not have more severe disease than patients who were not taking NSAIDs. Mortality, ICU admission, respiratory support, and acute kidney injury were also not significantly different across matched NSAID and non-NSAID user groups (n = 4205, per group). See, cohort study.

A meta-analysis of 25 observational studies (n = 101,215) found that NSAID use was not associated with an increased risk of COVID-19 infection (adjusted OR 0.98, 95% CI 0.78-1.24). Prior NSAID use was associated with a reduced risk of severe COVID-19 infection (OR 0.79, 95% CI 0.71-0.89) and reduced all-cause mortality (OR 0.72, 95% CI 0.54-0.96). Safety analysis did not find an increased risk of myocardial infarction, thrombotic events or acute kidney injury in patients with prior NSAID use; however, there was an increased risk of stroke (OR 2.32, 95% CI 1.04-5.2). Prior NSAID use occurred in almost 20% of patients. These findings are largely reassuring regarding prior NSAID use, but have the important limitation of being based on observational data. See, meta-analysis.

The usual contraindications and cautions apply to NSAID use e.g. renal impairment, heart failure or increased risk of gastrointestinal bleeding.

Other anticholinergics

Patients taking anticholinergic medicines, such as oxybutynin, should continue to take them unless there is a conventional reason to stop (e.g. falls or sedation).

Several observational studies of older adults have demonstrated an association between anticholinergic medicines and pneumonia. The extent of the effect is unclear due to variability in study results and design.  A causal relationship between anticholinergic medicines and pneumonia has not been definitively established.

Anticholinergic cessation could result in withdrawal and/or destabilisation of the underlying condition. Therefore, we do not advocate changing anticholinergic prescribing solely on the basis of COVID-19 risk.

Other medicines associated with respiratory depression

Patients should be advised not to stop any regular medicines unless there is a conventional indication to do so.

Gabapentinoids (gabapentin and pregabalin) are rarely associated with respiratory depression, irrespective of concomitant medicines. There is no evidence to suggest that this risk is increased in acute respiratory infections.

Benzodiazepines are associated with respiratory depression and developing pneumonia in observational studies, and this may be worse with underlying lung disease. The precise extent of the risk is unclear. Zopiclone is associated with respiratory depression although there is weak evidence that the extent is less than that of benzodiazepines. There is no evidence to suggest that this risk is increased in acute respiratory infections.

Cessation of all of these medicines is associated with withdrawal and worsening of the underlying condition. We therefore do not recommend changes to prescribing of these medicines solely on the basis of risk of COVID-19.

Opioids

Patients taking long term opioids should continue to take them unless there is a conventional reason to stop (e.g. opioid toxicity). Opioids may be useful for acute dyspnoea from COVID-19 in palliative patients.

Chronic opioid use is appropriate in some circumstances, including for patients with advanced lung disease and chronic, refractory dyspnoea. In these circumstances, respiratory depression is very rare. There is no evidence to suggest that this risk is increased in acute respiratory infections. Opioid cessation risks withdrawal and worsening of the underlying condition. We therefore do not recommend changes to chronic opioids solely on the basis of risk of COVID-19.

Opioids may be beneficial for acute dyspnoea, although studies supporting this are lacking. The frequency of respiratory failure with acute opioid use for dyspnoea is poorly characterised; it is likely to be rare but more common than with chronic use. Consensus guidelines support the use of opioids for dyspnoea in palliative care, but there are no guidelines advocating for or against opioids to treat acute dyspnoea outside of a palliative setting.

Proton pump inhibitors (PPIs)

Patients taking PPIs should continue to take them unless there is a conventional reason to stop (e.g. hyponatraemia or acute kidney injury).

Large meta-analyses of observational studies and randomised trials have demonstrated an association between PPIs and pneumonia with an approximately 1.5-fold increase in risk. The effect appears greatest in the first month of treatment. Randomised data suggests a causal relationship.

The absolute increase in risk, however, is small. PPI cessation could result in worsening reflux (through withdrawal or reduced acid suppression) when PPIs are used for treatment, or gastrointestinal bleeding when PPIs are used prophylactically. Therefore, we do not advocate changing PPI prescribing solely on the basis of COVID-19 risk.

Medicines monitoring in COVID-19

Clozapine

There is currently no need to deviate from standard monitoring requirements. Anyone on clozapine showing signs of infection, including COVID-19, requires an urgent CBC

See HealthPathways: Clozapine Monitoring (includes a link to patient information).

Links

Links to general guidance and emerging evidence from clinical trials:

Hospital HealthPathways: for local guidance and resources.

Ministry of Health: support for healthcare professionals and the public.

Ministry of Health: for variants updates.

Health Quality and Safety Commission: support for healthcare professionals.

Australian COVID-19 Clinical Evidence Taskforce: support for healthcare professionals.

Centre for Evidence-Based Medicine/University of Oxford: for evidence reviews.

Cochrane Library: for evidence reviews.

National Institute for Health and Care Excellence (NICE): for guidance and resources.

COVID-NMA: for trial information and evidence reviews.