COVID-19: Non-hospitalised patients with symptomatic infection (Guidelines)

Initial Eligibility Criteria (must meet all)

SARS-CoV-2 (COVID-19) infection confirmed by either

• polymerase chain reaction (PCR) test OR
• Lateral flow test (registered via gov.uk or NHS 119)
• AND Symptomatic* with COVID-19 and showing no sign of clinical recovery
• AND A member of a highest risk group as defined in appendix 1 (see also note below **)

*Symptoms include: feverish, chills, sore throat, cough, shortness of breath or difficulty breathing, nausea, vomiting, diarrhoea, headache, red or watery eyes, body aches, loss of taste or smell, fatigue, loss of appetite, confusion, dizziness, pressure or tight chest, chest pain, stomach ache, rash, sneezing, sputum or phlegm, runny nose.

^** Patients aged between 12 and 17 years should be assessed by a paediatric multi-disciplinary team with input from infectious diseases to determine clinical capacity to benefit from the treatment.  See section on paediatrics.

Exclusion criteria (must not meet any)

• Requirement for hospitalisation for COVID-19 infection
• New requirement for supplemental oxygen for COVID-19 symptom management
• Known hypersensitivity to the active ingredient or any excipients of the medications as listed in the Summary of Product characteristics

Where patients are ineligible for treatment under this policy, recruitment to the PANORAMIC trial, which is building the evidence for novel oral antivirals in a broader cohort of at risk patients, should be supported.

Consider ONLY once initial eligibility and exclusion criteria are met

First line: Nirmatrelvir plus ritonavir (Paxlovid®)

Course: 5 day oral 

Eligibility criteria: 

• Clinical judgement deems that an antiviral is the preferred option
• AND Treatment is commenced within 5 days of symptom onset (may be extended to 7 days if clinically indicated but off-label)
• AND The patient does NOT have a history of stage 3 to 5 chronic kidney disease (requires MDT discussion with specialist)
• AND nirmatrelvir plus ritonavir (Paxlovid®) treatment has been deemed safe following guidance from the appropriate specialty team(s). See: https://www.covid19-druginteractions.org/checker
• Full drug history must be taken.

Exclusion criteria

• Children aged less than 18 years
• Pregnancy
• The patient is taking medication which has a clinically significant drug interaction with nirmatrelvir plus ritonavir (Paxlovid®) as listed on https://www.covid19-druginteractions.org/checker
• Severe renal impairment (eGFR less than 30ml/min)
• Advanced decompensated liver cirrhosis

Second line: Remdesivir

Course: 3 day IV infusion

Eligibility criteria

• Clinical judgement deems that an antiviral is the preferred option and the patient is willing to attend daily for three days for IV infusion
• AND Treatment with nirmatrelvir plus ritonavir (Paxlovid®) is contra-indicated or not possible
• AND Treatment is commenced within 7 days of symptom onset

Exclusion criteria

• Children weighing 40kg and under

If the patient deteriorates clinically and requires admission for supplemental oxygen, they may be considered for treatment with remdesivir for 5 days according to the guidance for hospitalised patients.

Third line: Molnupiravir

Course: 5 day oral 

Eligibility criteria

• Treatment with sotrovimab, Nirmatrelvir plus ritonavir (Paxlovid®) AND remdesivir are  contra-indicated or not possible
• AND Treatment is commenced within 5 days of symptom onset (may be extended to 7 days if clinically indicated but off-label)

Exclusion criteria

• Children aged less than 18 years
• Pregnancy

Fourth line: Sotrovimab

Course: single IV infusion

Eligibility criteria

• Endorsement of treatment has been sought and approved by a relevant MDT
• AND Treatment is commenced within 5 days of symptom onset (may be extended to 7 days if clinically indicated but off-label)

Exclusion criteria

• Children aged less than 12 years
• Adolescents (aged 12 to 17 years) weighing 40kg and under

See also appendix 2 for a flowchart and decision support for therapies plus a summary of treatment advice by speciality for the highest risk patients.

In children and young people (aged under 18yr), risks of hospitalisation or death from COVID are very low. Current evidence suggests that children and young people in the highest risk groups in the national policy (see table in appendix 1 of this policy) do not have equivalent risk to older adults with the same conditions.

Studies of pre-hospital nMAbs and/or anti-virals have largely been in adults and there are minimal data to assess benefit of nMAbs to those under 18yr, even in symptomatic inpatients. Due to low numbers of severely unwell children and young people, it is challenging to estimate the risks vs benefit, or number needed to treat to prevent hospitalisation, and severe disease. Administration of an intravenous or subcutaneous drug to children and young people in hospital brings its own burden, and requires specialised paediatric teams. Nevertheless, equity of care for those deemed to be at risk is vital.

All children and young people who potentially are eligible through the national policy should therefore be discussed with regional paediatric infectious diseases service to confirm eligibility and to consider the risk / benefit and whether to proceed with offer of treatment.

For NHS Highland patients, please refer paediatric patients to the local paediatric team in Inverness or Glasgow, according to the established specialist input for the patient.

Each case will be considered by a national MDT and the paediatric consultant will liaise with the national team to determine if treatment is required.

Nirmatrelvir plus ritonavir (Paxlovid®)

There are no human data on the use of nirmatrelvir plus ritonavir during pregnancy to inform the drug-associated risk of adverse developmental outcomes, women of childbearing potential should avoid becoming pregnant during treatment with nirmatrelvir plus ritonavir (Paxlovid®).  Nirmatrelvir plus ritonavir (Paxlovid®) is not recommended during pregnancy and in women of childbearing potential not using effective contraception.  Use of ritonavir may reduce the efficacy of combined hormonal contraceptives.  Patients using combined hormonal contraceptives should be advised to use an effective alternative contraceptive method or an additional barrier method of contraception during treatment and until after one complete menstrual cycle after stopping nirmatrelvir plus ritonavir(Paxlovid®).

Remdesivir

There are no or limited amount of data from the use of remdesivir in pregnant women. Remdesivir should be avoided in pregnancy unless clinicians believe the benefits of treatment outweigh the risks to the individual (please see SmPC for further information).

Molnupiravir

There are no data from the use of molnupiravir in pregnant women. Studies in animals have shown reproductive toxicity. Molnupiravir is not recommended during pregnancy. Individuals of childbearing potential should use effective contraception for the duration of treatment and for 4 days after the last dose of molnupiravir.

Sotrovimab

There are no data from the use of sotrovimab in pregnant women. The SmPC for sotrovimab states that sotrovimab may be used during pregnancy where the expected benefit to the mother justifies the risk to the foetus.

Please refer to the summary of product characteristics for nirmatrelvir plus ritonavir, Paxlovid®), remdesivir, molnupiravir and sotrovimab as published on www.medicines.org.uk/emc website.

Nirmatrelvir plus ritonavir (Paxlovid®)

There is a risk of serious adverse reactions due to interactions with other medicinal products (see https://www.covid19-druginteractions.org/checker).

Nirmatrelvir plus ritonavir (Paxlovid®) is a CYP3A inhibitor so co-prescription with other drugs metabolised by the same pathway may increase or decrease concentrations of nirmatrelvir plus ritonavir (Paxlovid®) or the co-prescribed drug.

These interactions may lead to:

• Clinically significant adverse reactions, potentially leading to severe, life-threatening or fatal events from greater exposures of concomitant medicinal products.
• Clinically significant adverse reactions from greater exposures of nirmatrelvir plus ritonavir (Paxlovid®).
• Loss of therapeutic effect of nirmatrelvir plus ritonavir (Paxlovid®) and possible development of viral resistance.

Hepatic transaminase elevations, clinical hepatitis and jaundice have occurred in patients receiving ritonavir. Therefore, caution should be exercised when administering nirmatrelvir plus ritonavir (Paxlovid®) to patients with pre-existing liver diseases, liver enzyme abnormalities or hepatitis. Patients should be advised of possible gastro-intestinal side-effects of treatment - anti-emetics that are not contra-indicated may be considered.  

Remdesivir:

Hypersensitivity reactions including infusion-related and anaphylactic reactions have been observed during and following administration of remdesivir. Signs and symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnoea, wheezing, angioedema, rash, nausea, vomiting, diaphoresis, and shivering. Slower infusion rates, with a maximum infusion time of up to 120 minutes, can be considered to potentially prevent these signs and symptoms. Patients should be monitored for hypersensitivity reactions during and following administration of remdesivir as clinically appropriate. If signs and symptoms of a clinically significant hypersensitivity reaction occur, administration of remdesivir should be discontinued immediately and appropriate treatment initiated. Patients receiving remdesivir in an outpatient setting should be monitored according to local medical practice.

Molnupiravir

The most common adverse reactions (≥1% of subjects) reported during treatment and during 14 days after the last dose of molnupiravir were diarrhoea (3%), nausea (2%), dizziness (1%) and headache (1%) all of which were Grade 1 (mild) or Grade 2 (moderate).

Sotrovimab

Hypersensitivity reactions, including serious and/or life-threatening reactions such as anaphylaxis, have been reported following infusion of sotrovimab. Hypersensitivity reactions typically occur within 24 hours of infusion. Signs and symptoms of these reactions may include nausea, chills, dizziness (or syncope), rash, urticaria and flushing. If signs and symptoms of severe hypersensitivity reactions occur, administration should be discontinued immediately and appropriate treatment and/or supportive care should be initiated. If mild to moderate hypersensitivity reactions occur, slowing or stopping the infusion along with appropriate supportive care should be considered.

• Please refer to current COVID-19 vaccination guidance in: the Green Book, Immunisation Against Infectious Disease (chapter 14a).
• Further information is available at: Liverpool COVID-19 interactions 

Nirmatrelvir plus ritonavir (Paxlovid®):

300mg (two x 150mg tablets) nirmatrelvir PLUS 100mg (one x 100mg tablet) ritonavir taken together orally twice daily for 5 days

In moderate renal impairment (eGFR between 30 and 60 mL/min), dose is 150mg (one x 150mg tablets) nirmatrelvir PLUS 100mg (one x 100mg tablet) ritonavir taken together orally twice daily for 5 days.  If a reduced dose is required, the dispenser should remove the extra tablets from the blister to ensure the correct dose will be taken and explain the alteration to the patient.  An additional information leaflet should be given to the patient to explain the reduced dose (appendix 3). Clinicians should assure themselves that patients are able to swallow the oral tablets and understand the dosing regimen.   A patient information leaflet from the manufacturer is included with the medicines supplied. 

A missed dose should be taken as soon as possible and within 8 hours of the scheduled time, and the normal dosing schedule should be resumed. If more than 8 hours has elapsed, the missed dose should not be taken and the treatment should resume according to the normal dosing schedule.

If a patient requires hospitalisation due to severe or critical COVID-19 after starting treatment with nirmatrelvir plus ritonavir(Paxlovid®), the patient should complete the full 5-day treatment course at the discretion of the admitting consultant.

Remdesivir:

200mg by IV infusion on day 1 followed by 100mg by IV infusion on days 2 and 3

Each dose should be diluted in either a 250ml (200mg dose) or 100ml (100mg dose) pre-filled bag of 0.9% sodium chloride solution and infused over a minimum of 30 minutes.  The dose should be given at the same time each day.

Molnupiravir:

800mg (four x 200mg capsules) orally twice a day for 5 days

No dose alteration is required in renal or hepatic impairment.  The treatment course is supplied as 200mg hard capsules which are each 22mm in length and should be swallowed whole with a glass of water and not crushed, chewed or opened. There is no alternative formulation for patients with swallowing difficulties.  Patients should complete the whole course of treatment to reduce the possibility of emerging resistance, even if their symptoms improve.  Advice for missed doses:

• It is important that patients do not miss or skip doses of this medicine.
• If the patient forgets to take a dose within 10 hours of the time it is usually taken, they should take it as soon as possible and take the next one at the usual time.
• If the patient forgets to take a dose by more than 10 hours, they should not take the missed dose and instead take the next one at the usual time.
• Do not take a double dose to make up for a missed dose.

The patient should be directed to read the manufacturer’s patient information leaflet provided with the medicines AND given a copy of the MHRA leaflet highlighting the information in relation to pregnancy (appendix 4). 

If a patient requires hospitalisation due to severe or critical COVID-19 after starting treatment with molnupiravir, the patient should complete the full 5-day treatment course at the discretion of the admitting consultant.

Sotrovimab:

500mg single dose by IV infusion over 30 minutes
No dose alteration is required for renal or hepatic impairment although the drug has not been studied in patients with severe renal or hepatic impairment. Please see appendix 8 3 for a clinical worksheet detailing the preparation and administration information. Patients should be monitored for 30 minutes after the infusion is complete. The patient should be given the paper information leaflet supplied with the drug (appendix 9 4). Administration should be under taken in areas where management of severe hypersensitivity reactions, such as anaphylaxis, is possible.

Patients who test PCR or lateral flow device (LFD) positive will be directed to the NHS Highland single point of contact phone number as detailed on NHS Inform.  An initial review will take place to check eligibility for treatment, patient location and need for immediate medical assistance.  If the eligibility criteria are met, details will be phoned and emailed to the Flow Navigation Team who will phone the patient to discuss and agree the most appropriate therapy using clinical triage and sent form (appendix 5).   Prescriptions for an oral antiviral nirmatrelvir plus ritonavir (Paxlovid®) or molnupiravir) will be completed electronically and emailed to the most appropriate stock holding location.  This will be a  hospital prescription form for Raigmore or Lorn and Islands (appendices 6, and 7) plus a screen shot of the ADASTRA episode of care.   A phone call to alert that area will be required, including arrangements for delivery of the oral antiviral to the patient.  Contact information for locations in Argyll and Bute has been shared with the Flow Navigation Team.  

For future reference, the completed ADASTRA episode of care will automatically be uploaded to SCi Store and a copy sent to the patient’s GP practice once it is closed.

Sotrovimab

Currently, sotrovimab is available for administration in Raigmore Hospital and Lorn and Islands Hospital only.  This will be reviewed regularly for consideration of adding other centres in the future. Although this remains part of the national recommendations, it is not being recommended for use locally, in accordance with WHO recommendations. Please see the note at the top of this TAM entry

Nirmatrelvir plus ritonavir (Paxlovid®)

Stocks are held in a number of locations across NHS Highland to facilitate timely access to treatment. This will also be reviewed in light of improved understanding of the demand for these treatments throughout NHS Highland.

Remdesivir

Stocks are held in the same hospital locations as sotrovimab and reviewed regularly as above.

Molnupiravir

Stocks are held in a number of locations across NHS Highland to facilitate timely access to treatment. This will also be reviewed in light of improved understanding of the demand for these treatments throughout NHS Highland.

No interaction is expected between sotrovimab, nirmatrelvir plus ritonavir (Paxlovid®), remdesivir or molnupiravir and corticosteroids, tocilizumab/sarilumab (IL-6 inhibitors) or remdesivir.  For further information please refer to the University of Liverpool COVID-19 Drug Interactions website. 

A flow chart to aid assessing a patient for treatment with Paxlovid is available as a prescribing resource on this website: https://www.covid19-druginteractions.org/prescribing-resources

Any suspected adverse reactions from treatment with sotrovimab, nirmatrelvir plus ritonavir (Paxlovid®), remdesivir or molnupiravir should be reported directly to the MHRA via the new dedicated COVID-19 Yellow Card reporting site at: https://coronavirus-yellowcard.mhra.gov.uk/.

Outcome reporting

The Deputy Chief Medical Officer recommends that data on all patients with COVID-19 should be captured through the ISARIC 4C Clinical Characterisation Protocol (CCP) case report forms (CRFs), as coordinated by the COVID-19 Clinical Information Network (CO-CIN) (link to forms).

Risk factors for progression to severe COVID-19 infection

• additional prescribing resources on University of Liverpool COVID-19 Drug Interactions website
• Includes evaluating the interaction risk, assessing a patient for treatment with nirmatrelvir plus ritonavir (Paxlovid®) and guidance for resuming paused or dose-adjusted co-medications.