Medicines and COVID-19

This page was last updated: 24 November 2021 at 16:50 PM

This site contains general information for health professionals in NZ regarding medicines and COVID-19. The information is compiled by a multidisciplinary team including pharmacists, pharmacologists and infectious diseases experts.

If you feel there are additional areas we need to cover, or for questions relating to specific patients, please contact us. If you cannot make contact by phone then please use email.

Summary

  • Patients should be advised to keep at least 1-2 weeks’ supply of their medicines.
  • Prescribers should only prescribe the usual maximum supplies of medicines (one month for controlled drugs, three months for non-controlled drugs).
  • The Ministry of Health has released criteria (see Remote prescribing section) to allow remote prescribing of non-controlled medicines.
  • 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 who meet the access criteria.
  • There are no medicines which should be prescribed for the prevention of COVID-19 outside of a clinical trial.
  • Patients should be advised not to stop any regular medicines unless there is a conventional indication to do so.

Medicine supply

The global effects of COVID-19 on manufacturing plants and transportation are likely to result in disruptions to the medicine supply chain. PHARMAC are working closely with the Ministry of Health (MoH) and suppliers to help maintain medicine supply chains. See PHARMAC: Information for coronavirus/COVID-19

Current supply

From 1 August 2020 pharmacists will be able to dispense a 3 month supply of most medicines.

COVID-19 continues to disrupt supply chains and manufacturing overseas. Therefore, dispensing restrictions may need to be reinstated for some medicines if supply issues arise.

Patients should be advised to keep at least a 1-2 week supply of their medicines and discouraged from stockpiling as this will contribute to supply issues.

Medicines with a one month dispensing restriction before lockdown will continue to be dispensed monthly e.g. paracetamol. See, PHARMAC: Dispensing frequency.

A pharmacist may use their discretion for certain people that require stat dispensing, even when there are dispensing restrictions e.g. people who have mobility issues, live rurally, are immunocompromised or are elderly.

For a list of medicines associated with supply issues, see: PHARMAC: Medicine and device supply issues

PHARMAC changed access criteria to some medicines as part of the COVID-19 response. However, pre-COVID-19 special authority criteria have been reinstated, see: PHARMAC: Medicines with amended access criteria.

For access restrictions to hydroxychloroquine, see PHARMAC: COVID-19: Hydroxychloroquine

Remote prescribing

Remote prescribing in the community is possible by NZePS and non-NZePS methods if Ministry of Health (MoH) criteria are met (see below).

The New Zealand ePrescription Service (NZePS) is a secure prescribing system for primary care. For general information, see MoH: NZePS.

To facilitate virtual care during the COVID-19 pandemic, a temporary exemption to the usual rules around physical signatures on prescriptions via NZePS and non-NZePS systems is in place. The Notice and the temporary waiver for non-NZePS signature exempt prescriptions has been extended and will now expire on 19 December 2021.

Prescriptions with a physical signature can be sent to pharmacies via fax and email. For details on the regulations, see MOH: Electronic Transmission of Prescriptions and to find a pharmacy email address, see Healthpoint: Pharmacy.

Vaccines to prevent COVID-19

Vaccines

Vaccination is a key measure to prevent COVID-19.

Medsafe has approved the Pfizer/BioNTech (datasheet and CMI) mRNA vaccine and the Janssen (datasheet and CMI) and AstraZeneca/Oxford (datasheet and CMI) viral vector vaccines. They are highly effective and substantially reduce the risk of COVID-19, especially severe disease.

The Pfizer/BioNTech vaccine is 95% effective against the wild-type SARS-CoV-2 virus, and 88% effective against the delta (B.1.617.2) variant. The Janssen vaccine is 67% -76% effective (depending on study) against the wild-type SARS-CoV-2 virus, with limited data for efficacy against the delta variant. The AstraZeneca/Oxford vaccine is 67% -76% effective (depending on study) against the wild-type SARS-CoV-2 virus and 60% effective against the delta variant.

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. There have also been reports of myocarditis and pericarditis with the viral vector vaccine from AstraZeneca/Oxford. Many viral infections (e.g. influenza) can cause myocarditis and pericarditis, the incidence associated with COVID-19 is unknown.

Adverse events following immunisation (AEFIs) with COVID-19 vaccines are being closely monitored during clinical trials and post marketing surveillance. The data are still accruing. However, there is broad consensus that the benefits of vaccination greatly outweigh any potential risks.

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

Enoxaparin

Enoxaparin should be routinely used for thromboprophylaxis in hospitalised patients with COVID-19.

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 optimal dose is yet to be determined. Standard prophylaxis doses are generally recommended over intermediate- or full treatment-dose regimens in patients without an established indication for higher-dose anticoagulation.

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.

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.

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 appropriate for refractory symptoms (see relevant section below).

There are reports on social media that paracetamol can “cure” COVID-19. There is no scientific evidence to support this claim, or a plausible theory. Patients should be advised to use paracetamol in a supportive role, but warned that it does not protect them from serious harm from COVID-19 and is therefore not a substitute for established methods of infection control.

For information on dispensing paracetamol see PHARMAC: Paracetamol supply issue.

Corticosteroids

Evidence supports the use of systemic corticosteroids in critically ill patients with severe COVID-19 who require oxygen or ventilation.

There is weak evidence to support using systemic or inhaled corticosteroids to treat patients with milder COVID-19.

Patients should continue prescribed systemic or inhaled corticosteroids for usual chronic indications e.g. giant cell arteritis, asthma or COPD.

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.

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.

Inhaled corticosteroids

Two clinical trials have investigated the use of inhaled corticosteroids in the treatment of community patients with COVID-19.

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. 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). See, STOIC trial.

No mortality benefit was found in either trial and they have several limitations including relying on the self-reporting of outcomes. Further clinical trials are required to determine the role of inhaled corticosteroids in COVID-19.

Interleukin-6 (IL-6) inhibitors

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

Tocilizumab stock is limited and expected to run out before new stock arrives in January 2022.

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.

Monoclonal antibodies

Monoclonal antibodies are most likely to be effective 1-10 days from the onset of COVID-19 symptoms.

Monoclonal antibodies have been associated with reduced hospitalisation rates, a more rapid decline in viral loads, and a shorter time to recovery in patients with risk factors for severe COVID-19 disease.

Circulating SARS-CoV-2 variants may be resistant to specific monoclonal antibodies.

Combination (e.g. casirivimab-imdevimab or bamlanivimab-etesevimab) and single agent (e.g. sotrovimab) intravenous monoclonal antibody regimens have been used in clinical trials. None of these agents are available in New Zealand.

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 among those treated within 7 days of symptom onset with casirivimab-imdevimab compared with placebo (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.

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 among those treated within 3 days of laboratory confirmed COVID-19 with bamlanivimab-etesevimab (2800 mg of each) compared with placebo (2.1% versus 7.0%). There was a more rapid decline in the viral load with bamlanivimab-etesevimab than with placebo.

There are currently no published RCTs for sotrovimab.

Serious adverse effects had an incidence of <2% in these trials. Infusion related reactions included fever, chills, urticaria, pruritus, abdominal pain and flushing.

Janus kinase (JAK) inhibitors

JAK inhibitors (e.g. baricitinib and tofacitinib) may be associated with mortality benefits.

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 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.

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

PHARMAC has secured 500 courses of baricitinib. The access criteria are being finalised.

Medicines not recommended for the treatment of COVID-19

The treatment of COVID-19 is largely supportive.

Recommended treatments are largely supportive. Non-pharmacological prevention measures (handwashing, physical distancing, etc.) are the only approved measures to prevent COVID-19. 

The medicines in this section are based on a theoretical mechanism, in vitro data only, or weak observational data. None have sufficient rationale to justify use outside of a clinical trial.

CDHB memo: Specific medicines to treat COVID-19 infection

CDC: Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19)

WHO: Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected

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).

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. 

Antivirals

Most antivirals currently have no role in the management of COVID-19.

Remdesivir may shorten time to recovery in patients who are hospitalised and require supplemental oxygen for COVID-19 with < 7 days duration, but who are not on invasive mechanical ventilation.

Molnupiravir is an oral antiviral that may prevent hospitalisation in patients with mild to moderate COVID-19 if given within 5 days of symptom onset.

  • Oseltamivir
    • 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.
  • Remdesivir
    • An RCT (n=1062) found that patients who received remdesivir had a median recovery time of 10 days compared to 15 days for those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001).
    • Another RCT (n= 397) showed the efficacy of 5-day and 10-day courses of remdesivir are similar for patients with severe COVID-19 not requiring mechanical ventilation.
    • Interim results from the remdesivir arm of the WHO SOLIDARITY trial (n=5451) found no difference in 28 day mortality, ventilation rate or duration of hospital stay with remdesivir compared to usual care.
    • The DISCOVERY trial, an open label, multicentre, RCT (n=857) did not find a clinical benefit with remdesivir in hospitalised patients with COVID-19 requiring oxygen supplementation. The clinical status on a 7-point ordinal scale, was the same at day 15 for patients treated with remdesivir or control (OR, 0·98; 95% CI, 0·77-1·25; P=0·85).
    • PHARMAC has secured a small amount of remdesivir for use in New Zealand. The access criteria and treatment notification form can be found here.
    • Gilead Sciences (New Zealand) has provided a factsheet for remdesivir
  • Lopinavir-ritonavir
    • 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.
  • Favilavir (also known as favipiravir)
    • An RCT (n=156) found favilavir shortened time to recovery by approximately 3 days in patients with moderate COVID-19 who did not require oxygen therapy. Hyperuricaemia occurred in over 75% of patients.
  • Darunavir
    • Has no role in the management of COVID-19 outside a clinical trial setting.
  • Galidesivir
    • Has no role in the management of COVID-19 outside a clinical trial setting.
  • Molnupiravir
    • A nucleoside analogue that inhibits SARS-CoV-2 replication.
    • A phase 3, RCT has been undertaken; however, no published data are available.
    • PHARMAC has negotiated an agreement to purchase molnupiravir subject to Medsafe approval. 

Some studies show increased adverse reactions with the use of antivirals compared to standard care (e.g. nausea/vomiting/diarrhoea with lopinavir-ritonavir). Inappropriate use of antivirals places patients at risk of harm without demonstrated evidence of benefit.

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 receptor antagonist protein, and therefore reduces interleukin-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 reduced the risk of clinical progression compared to placebo (OR 0.36; 95% CI 0.26–0.50; P<0.0001). Most patients also received dexamethasone (86%).
    • Anakinra is an unapproved medicine in NZ.
  • Interferons
    • Interferons are biologic response modifiers that possess antitumour, antiviral, and immunomodulating properties. Interferons are virus specific, binding to specific receptors. Interferons have shown activity against coronaviruses in animal and in vitro studies. In a large retrospective cohort study, interferons were not effective against MERS-CoV. Current clinical trials include interferons in combination with antiviral agents for activity against COVID-19.
    • Early trial results, from 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.

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 recent 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.

The current evidence is insufficient to justify using ivermectin at standard doses to treat COVID-19, even in a clinical trial setting.  

Nitazoxanide

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

The data for COVID-19 is limited to one in vitro study. Nitazoxanide has been used in a placebo-controlled RCT for patients hospitalised with influenza-like illness (n=260); nitazoxanide did not reduce the duration of hospital stay or confer other benefits.

The current evidence is insufficient to justify using nitazoxanide to treat COVID-19 outside a clinical trial setting. 

Acetylcysteine

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

Studies suggest acetylcysteine inhibits formation of proinflammatory cytokines in some strains of influenza. The activity of acetylcysteine is likely to be dependent on the strain of virus. There are no studies showing that acetylcysteine is effective against COVID-19 therefore, we do not recommend its use.

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.

There is a lack of evidence that BCG vaccine protects against COVID-19. However, two clinical trials are ongoing to determine if BCG vaccination protects healthcare workers against COVID-19.

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.

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.

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.

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.

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.

Statins

Patients already taking statins should continue them as they have been associated with improved clinical outcomes in patients with COVID-19.

Observational data for hospitalised patients in the USA with COVID-19 (n=10,541 total, n=4,449 on statins) found that prior outpatient use of statins was associated with a reduced risk of death (adjusted OR 0.59, 95% CI 0.50–0.69) and a lower risk of developing severe disease including; ICU admission, mechanical ventilation or death (adjusted OR 0.73, 95% CI 0.64–0.84). These benefits were greatest in patients with cardiovascular disease or hypertension. These data were collected during 2020, prior to the establishment of several treatments for hospitalised COVID-19 patients that are now routine.

There are several plausible mechanisms how statins may improve outcomes in COVID-19. Statins have anti-inflammatory and immunomodulatory effects, 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).

Antidepressants

Fluvoxamine may reduce hospitalisation rates in community patients with COVID-19 who are at high risk of severe disease.

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).

The evidence does not support starting an antidepressant in patients with 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%).

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.

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.

Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs)

Patients already taking ACEIs or 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.

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.

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.

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).

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

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.

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.

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.

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.

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.

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.

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.

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.

 

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