• Hospitalised for indications OTHER THAN for the management of acute symptoms of SARS-CoV-2 (COVID-19)

AND

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

  • polymerase chain reaction (PCR) test OR
  • Lateral flow test

AND

• Symptomatic with COVID-19* and showing no signs of clinical recovery

AND

• A member of a “highest” risk group (see appendix 2)

OR

• MDT assessment determines that COVID-19 infection presents a significant risk of destabilising a pre-existing condition or illness or will compromise recovery from surgery or other procedure.

* 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.

• Requirement for hospital-level care for management of acute COVID-19 infection
• New requirement for supplemental oxygen specifically for COVID-19 symptom management
• Children aged less than 12 years
• Adolescents (aged 12 to 17 years) weighing less than 40kg
• Known hypersensitivity to the active ingredient or any excipients of the medications as listed in the Summary of Product characteristics

Nirmatrelvir plus ritonavir (Paxlovid®) (1^st line,  5 day oral course)

ELIGIBILITY CRITERIA

• 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 University of Liverpool COVID-19 drug interaction 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 University of Liverpool COVID-19 drug interaction checker
• Severe renal impairment (eGFR less than 30ml/min)
• Advanced decompensated liver cirrhosis

New information on Liverpool Drug Interactions Group (Crushing nirmatrelvir and ritonavir tablets) suggests Paxlovid tablets can safely be crushed and mixed with food or liquid (including dairy products) for patients with swallowing difficulties or mixed with water when administered via an enteral tube.  Due to lack of stability information, any doses crushed and mixed with food or liquid or suspended in water should be administered immediately.

Remdesivir (2^nd line, 3 day IV infusion course)

ELIGIBILITY CRITERIA

• Treatment with nirmatrelvir plus ritonavir (Paxlovid®) is contra-indicated or not possible

AND

• Treatment is commenced within 7 days of symptom onset

EXCLUSION CRITERIA

• eGFR less than 30ml/min (except haemodialysis patients)
• Alanine transaminase (ALT) at or above 5 times the upper limit of normal

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

Stop therapy if eGFR falls below 30ml/min or ALT rises above 5 times the upper limit of normal.

Sotrovimab (3^rd line, single IV infusion)

ELIGIBILITY CRITERIA

• Clinical judgement deems that an nMAB 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)

EXCLUSION CRITERIA

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

In children and young people (aged < 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 2 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 <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).

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 and sotrovimab.

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.

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 8 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.

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.

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. Reduce dose in moderate renal impairment, see below

Prescribe each drug as separate entries on the drug chart e.g.

Nirmatrelvir and ritonavir tablets can be crushed or split and mixed with food or liquid (including dairy-containing products).  Crushed tablets mixed with water can also be considered for administration via feeding tubes, flushing the tube with water after administration.  Due to a lack of stability data, crushed tablets mixed with water or food should be taken or administered immediately.  Administration in this way is unlicensed.  See prescribing resources for Paxlovid: https://www.covid19-druginteractions.org/prescribing_resources.

As the patient may be discharged before the 5 day course is completed, Pharmacy will dispense the whole course of treatment from the outset.  Please complete the prescription form (appendix 3) and send to the hospital Pharmacy in either Raigmore or Lorn and Islands Hospital. 

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 in Pharmacy will remove the extra nirmatrelvir tablets from the blister to ensure the correct dose will be taken.  This should be explained to the patient before discharge if the course is not yet complete and an additional information leaflet should be given to the patient to explain the reduced dose (appendix 4).   A patient information leaflet from the manufacturer is included with the medicines supplied. 

Remdesivir:

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

Reconstitute each 100mg vial with 19mls of water for injection.  Add 200mg to 250mls of sodium chloride 0.9% for infusion and 100mg to 100mls of sodium chloride 0.9% for infusion.  Administer each dose over 30 to 120 minutes.  Using the longer, slower administration time can be considered to potentially prevent signs and symptoms of infusion-related reactions such as hypotension, nausea, vomiting and diaphoresis (sweating).   The patient should be given the paper information leaflet supplied with the drug. 

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 5 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. 

As noted before, nirmatrelvir plus ritonavir has many drug interactions which should be checked before prescribing and also when any other new medication is started. 

There is no interaction expected between remdesivir, sotrovimab and other treatments for COVID-19.  Interactions with concomitant medications should be checked using the University of Liverpool COVID-19 Drug Interaction checker accessed via https://www.covid19-druginteractions.org/   As not all drugs are included on this website, please seek advice from the ward pharmacist, Medicines Information (ext 4288) or the on-call pharmacist.

Please see TAM for guidance on other therapies for management of COVID-19 infection.

Any suspected adverse drug reactions (ADRs) for patients receiving remdesivir should be reported directly to the MHRA via the dedicated COVID-19 Yellow Card reporting site at https://coronavirus-yellowcard.mhra.gov.uk/

Hospitals managing COVID-19 patients are encouraged to submit data through the ISARIC 4C Clinical Characterisation Protocol (CCP) case report forms, as co-ordinated by the COVID-19 Clinical Information Network (CO-CIN) (https://isaric4c.net/protocols/)

Please note: this interim advice will be reviewed following submission and assessment by Scottish Medicines Consortium in due course.

Click here 

Table 1 : updated findings of the independent advisory group (published 5^thApril 2023)

Down’s syndrome and other genetic disorders

All individuals with Down’s Syndrome or other chromosomal disorders known to affect immune competence.

Solid cancer

• metastatic or locally advanced inoperable cancer
• lung cancer (at any stage)
• people receiving any chemotherapy (including antibody-drug conjugates), PI3K inhibitors or radiotherapy within 12 months
• people who have had cancer resected within 3 months and who received no adjuvant chemotherapy or radiotherapy
• people who have had cancer resected within 3 to 12 months and receiving no adjuvant chemotherapy or radiotherapy are expected to be at less risk (and thus less priority) but still at increased risk compared with the non-cancer populations

Haematological diseases and recipients of haematological stem cell transplant (HSCT)

• allogeneic HSCT recipients in the last 12 months or active graft versus host disease (GVHD) regardless of time from transplant (including HSCT for non-malignant diseases)
• autologous HSCT recipients in the last 12 months (including HSCT for non-malignant diseases)
• individuals with haematological malignancies who have received CAR-T cell therapy in the last 24 months, or until the lymphocyte count is within the normal range
• individuals with haematological malignancies receiving systemic anti-cancer treatment (SACT) within the last 12 months, or radiotherapy in the last 12 months
• all people who do not fit the criteria above, and are diagnosed with:
  • myeloma (excluding monoclonal gammopathy of undetermined significance (MGUS))
  • AL amyloidosis
  • chronic B-cell lymphoproliferative disorders (chronic lymphocytic leukaemia, follicular lymphoma)
  • myelodysplastic syndrome (MDS)
  • chronic myelomonocytic leukaemia (CMML)
  • myelofibrosis
  • any mature T-cell malignancy
• all people with sickle cell disease
• people with thalassaemia or rare inherited anaemia with any of the following:
  • severe cardiac iron overload (T2 * less than 10ms)
  • severe to moderate iron overload (T2 * greater than or equal to 10ms) plus an additional co-morbidity of concern (for example, diabetes, chronic liver disease or severe hepatic iron load on MRI)
• individuals with non-malignant haematological disorders (for example, aplastic anaemia or paroxysmal nocturnal haemoglobinuria) receiving B-cell depleting systemic treatment (for example, anti-CD20, anti-thymocyte globulin (ATG) and alemtuzumab) within the last 12 months

Renal disease

• renal transplant recipients (including those with failed transplants within the past 12 months), particularly those who have:
  • received B cell depleting therapy within the past 12 months (including alemtuzumab, rituximab [anti-CD20], anti-thymocyte globulin)
  • an additional substantial risk factor which would in isolation make them eligible for monoclonals or oral antivirals
• non-transplant renal patients who have received a comparable level of immunosuppression^{[footnote 3]}
• patients with chronic kidney stage (CKD) 4 or 5 (an estimated glomerular filtration rate (eGFR) less than 30ml per min per 1.73m²) without immunosuppression

Liver diseases

• people with cirrhosis Child-Pugh (CP) class A,B and C, whether receiving immune suppressive therapy or not. Those with decompensated liver disease (CP B and C) are at greatest risk
• people with a liver transplant
• people with liver disease on immune suppressive therapy (including people with and without cirrhosis)

Solid organ transplant recipients

Solid organ transplant recipients not in any of the above categories.

Immune mediated inflammatory disorders

• people who have received a B-cell depleting therapy (anti-CD20 drug for example, rituximab, ocrelizumab, ofatumab, obinutuzumab) in the last 12 months.
• people who have been treated with cyclophosphamide (IV or oral) in the 6 months prior to positive PCR or relevant COVID test
• people who are on corticosteroids (equivalent to greater than 10mg per day of prednisolone) for at least the 28 days prior to positive PCR
• people who are on current treatment with mycophenolate mofetil, oral tacrolimus, azathioprine, mercaptopurine (for major organ involvement such as kidney, gastro-intestinal tract, liver and/or interstitial lung disease), methotrexate (for interstitial lung disease or asthma only) and/or ciclosporin. No minimum dose threshold is suggested.
• people who exhibit at least one of: (a) uncontrolled or clinically active disease (that is, required recent increase in dose or initiation of new immunosuppressive drug or IM steroid injection or course of oral steroids within the 3 months prior to positive PCR); and/or (b) other high risk comorbidities (for example, body mass index (BMI) greater than 30, diabetes mellitus, hypertension, major organ involvement such as significant kidney, liver or lung inflammation or significantly impaired renal, liver and/or lung function)

Respiratory

• asthma in people on oral corticosteroids (defined above. Any asthma patient taking immunosuppressants for their asthma including but not exclusively methotrexate, ciclosporin
• COPD on long term home non-invasive ventilation (NIV). Patients on long term oxygen therapy. People with moderate or severe disease (FEV1 greater than or equal to 50% predicted) who have required 4 or more courses of prednisolone 30mg for 5 days or greater in last 12 months
• interstitial lung disease (ILD) - all patients with idiopathic pulmonary fibrosis
• sub-types of ILD - for example, connective tissue disease related, sarcoidosis, hypersensitivity pneumonitis, NSIP (non specific interstitial pneumonia) who have received a B-cell depleting therapy in last 12 months, or IV or oral cyclophosphamide in the 6 months prior to testing positive for COVID-19. Any ILD patient on current treatment with corticosteroids, mycophenolate mofetil, azathioprine, tacrolimus, cyclosporin or methotrexate. No minimum dose criteria
• any people with any type of ILD who may not be on treatment due to intolerance but has severe disease with an FVC predicted less than 60%
• NIV - all patients requiring this type of support regardless of the underlying disorder (which might include COPD, obesity hypoventilation syndrome, scoliosis, bronchiectasis, genetic muscular diseases refer to neurology section)
• lung cancer patients, refer to ‘Solid cancer’ section above
• lung transplant patients (refer to solid organ transplant section)
• pulmonary hypertension (PH): groups 1 and 4 from PH classification

Immune deficiencies

• common variable immunodeficiency (CVID)
• undefined primary antibody deficiency on immunoglobulin (or eligible for Ig)
• hyper-IgM syndromes
• Good’s syndrome (thymoma plus B-cell deficiency)
• severe combined immunodeficiency (SCID)
• autoimmune polyglandular syndromes or autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED syndrome)
• primary immunodeficiency associated with impaired type I interferon signalling
• x-linked agammaglobulinaemia (and other primary agammaglobulinaemias)
• any person with secondary immunodeficiency receiving, or eligible for, immunoglobulin replacement therapy

HIV/AIDS

• people with high levels of immune suppression, have uncontrolled or untreated HIV (high viral load) or present acutely with an AIDS defining diagnosis
• people on treatment for HIV with CD4 less than 350 cells per mm³and stable on HIV treatment or CD4 greater than 350 cells per mm³ and additional risk factors (for example, age, diabetes, obesity, cardiovascular, liver or renal disease, homeless, alcoholic dependency)

Neurological disorders

• Conditions associated with neuromuscular respiratory failure requiring chronic ventilatory support:
  • motor neurone disease
  • Duchenne muscular dystrophy
• Conditions that require use of specific immunotherapies:
  • multiple sclerosis (MS)
  • myasthenia gravis (MG)
  • other immune mediated disorders Dementia and neurodegenerative disorders when associated with severe frailty:
    • Alzheimer’s disease, vascular disease, Lewy body disease, or frontotemporal atrophy
    • Parkinson’s Disease
    • Huntington’s disease
    • progressive supranuclear palsy and multiple system atrophy

Table 2:

Children and young people (CYP) at substantial risk

Complex life-limiting neurodisability with recurrent respiratory infections or compromise.

CYP at significant risk of 2 or more or these risk factors are present

Primary immunodeficiency

• common variable immunodeficiency (CVID)
• primary antibody deficiency on immunoglobulin (or eligible for immunoglobulin replacement)
• hyper-IgM syndromes
• Good’s syndrome (thymoma plus B-cell deficiency)
• severe combined immunodeficiency (SCID)
• autoimmune polyglandular syndromes or autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED syndrome)
• primary immunodeficiency associated with impaired type I interferon signalling
• x-linked agammaglobulinaemia (and other primary agammaglobulinaemias)

Secondary immunodeficiency:

• HIV CD4 count less than 200 cells per mm³
• solid organ transplant
• HSCT within 12 months, or with GVHD
• CAR-T therapy in last 24 months
• induction chemotherapy for acute lymphoblastic leukaemia (ALL), non-Hodgkin’s lymphoma, chemotherapy for acute myeloid leukaemia (AML), relapsed and/or refractory leukaemia or lymphoma

Immunosuppressive treatment:

• chemotherapy within the last 3 months
• cyclophosphamide within the last 3 months
• corticosteroids greater than 2mg per kg per day for 28 days in last 4 weeks
• B cell depleting treatment in the last 12 months

Other conditions:

• high BMI (greater than 95th Centile)
• severe respiratory disease (for example, cystic fibrosis or bronchiectasis with FEV1 less than 60%)
• tracheostomy or long-term ventilation
• severe asthma (PICU admission in 12 months)
• neurodisability and/or neurodevelopmental disorders
• severe cardiac disease
• severe chronic kidney disease
• severe liver disease
• sickle cell disease or other severe haemoglobinopathy
• trisomy 21
• complex or chromosomal genetic or metabolic conditions associated with significant comorbidity
• multiple congenital anomalies associated with significant comorbidity
• bronchopulmonary dysplasia - decisions should be made taking in to account degree of prematurity at birth and chronological age
• infants less than 1 year with congenital heart disease (CHD):
  • cyanotic congenital heart disease
  • haemodynamically significant acyanotic CHD and history of prematurity
  • those due for corrective surgery, to avoid complications or delay due to SARS-CoV-2 infection

Footnotes:

1. This advice is gathered from evidence in people over 18 years - risks for those under 18 years are summarised in Box 2.
2. Physician discretion is advised for each of the conditions provided and decision to treat should follow evaluation of individual circumstances.
3. Please refer also to IMID section.
4. IMIDs comprise diseases in which auto-immune or auto-inflammation based pathways are implicated in disease for example, inflammatory arthritis, connective tissue diseases, inflammatory skin diseases, inflammatory gastrointestinal disease.
5. Please cross refer to the ‘Respiratory’ section in Box 1.
6. The IAG gave detailed consideration to the risks posed by TNF inhibitors and other cytokine inhibitors, including JAK inhibitors, used in rheumatology, dermatology and gastroenterology practice. As detailed in the appendix, there is consistent evidence of reduced serology responses in a variety of IMIDs to some these medications, but little consistent evidence as yet of increased severity of outcomes upon infection.
7. Please cross reference to advice in the sections on in Box 1 on IMIDs, solid cancer and neurology. Note also advice regarding glucocorticoids in evaluation in IMID section.
8. Note, exceptionally, that frequent exacerbations requiring 4 or more courses of prednisolone per year, usually 40mg per day for 5 days or more, may render an asthma patient eligible.
9. Patients using continuous positive airway pressure (CPAP) only for treatment of obstructive sleep apnoea (OSA) are not deemed to be particularly high risk and do not require prioritised access to treatments for COVID-19 disease.
10. Refer to respiratory section for details.
11. The use of CD4 counts to assess eligibility for treatment applies only to those patients for whom CD4 counts are used to monitor for treatment compliance and/or levels of immune compromise. Where CD4 counts are not known, but concerns remain around potential immune compromise, discussion with the patient’s HIV team is advised.
12. These should be managed according to the recommendations contained in the broader section on immune-mediate inflammatory disorders with the individual drugs - for example, rituximab, ocrelizumab, used as the ‘gatekeeper’, rather than the specific diagnosis.
13. For example, levels 7 or 8 on Clinical Frailty Scale, as part of a personalised care plan.
14. Complex congenital heart disease and severe bronchopulmonary dysplasia are rare and as such do not offer a readily available dataset upon which to base advice. As such, we propose a practical approach to adopt clinical criteria similar to those used to administer palivizumab for respiratory syncytial virus (RSV) prevention in the same groups of very young infants. Where clinical judgement of other individual patient circumstances not covered above strongly suggests that prophylaxis would prevent serious outcome upon SARS-CoV-2 infection in infants who are at particular risk of complications from this virus, use of appropriate antiviral approaches should be considered by an MDT.

Hospital prescription form for Paxlovid®)

(NHS Highland intranet access required. Right click the link and copy and paste into a new browser window for the form to open).

Patient information leaflet for Paxlovid® reduced dose in renal impairment

Sotrovimab clinical area preparation record (NHS Highland intranet access required)