Pneumocystis jirovecii pneumonia (PJP) prophylaxis guidance for patients with solid tumours

Summary of indications for PJP prophylaxis

INDICATION	Details of PJP prophylaxis required
All Tumour sites	Consider in patient with any additional immunosuppressive therapies or conditions* Indicated in patients on treatment with dexamethasone 4mg OD (or equivalent steroid dose) for 4 or more weeks. (Note dexamethasone 4 mg equals prednisolone 26.7mg)
NSCLC (Non Small cell Lung Cancer) – Concurrent	Commence D1 of concurrent chemo /RT (Radiotherapy)
NSCLC – Sequential	Commence D1 (Day 1) of Thoracic RT
NSCLC/SCLC (Small Cell Lung Cancer) – Radiotherapy alone (high dose palliative/ radical dose) Treatment for lung metastasis with high dose palliative/ radical dose	Consider in patient with any additional immunosuppressive therapies or conditions* Indicated in patients on treatment with dexamethasone 4mg OD (or equivalent steroid dose) for 4 or more weeks.
SCLC - Sequential	Commence D1 of Thoracic RT
SCLC – Concurrent	Commence D1 of Thoracic RT

*immunocompromised people living with HIV, people with haematological malignancies receiving treatment for other solid tumours, stem cell transplant patients, renal or other solid organ transplant patients

NOTE: interactions of cotrimoxazole with most common systemic anticancer treatments is minimal but if you have any concerns, discuss with pharmacists

Management of Co-trimoxazole Reactions

Co-trimoxazole 960mg three times weekly is 1st line for PJP prophylaxis.

Management of Co-trimoxazole Reactions:

Mild rash: consider co-trimoxazole de-sensitization (see separate section below) vs 2nd line dapsone 100mg OD (check for G6DP deficiency)
Recurrence of mild rash: switch to dapsone 100mg OD (check for G6DP deficiency)
Severe reaction*: switch to atovaquone 750mg BD (taken with fatty meal)

*DO NOT rechallenge in those with a prior history of drug rash with eosinophilia and systemic symptoms (‘DRESS’), SJS or TEN.

Co-trimoxazole Desensitization Regimen

Consider desensitization protocol for non-severe rash only

DO NOT rechallenge in those with a prior history of drug rash with eosinophilia and systemic symptoms (‘DRESS’), Stevens-Johnson syndrome, or toxic epidermal necrolysis.

Day 1: 80mg sulphamethoxazole/16mg trimethoprim (1mL of oral suspension 400/80mg in 5ml)

Day 2: 160mg sulphamethoxazole/32mg trimethoprim (2mL of oral suspension 400/80mg in 5ml)

Day 3: 240mg sulphamethoxazole/48mg trimethoprim (3mL of oral suspension 400/80mg in 5ml)

Day 4: 320mg sulphamethoxazole/64mg trimethoprim (4mL of oral suspension 400/80mg in 5ml)

Day 5: One single-strength sulphamethoxazole-trimethoprim tablet (400mg sulphamethoxazole/80mg trimethoprim or equivalent in suspension (5mL of oral suspension 400/80mg in 5ml)

Adapted from WHO & BHIVA guidance of desensitization:

OMS GUIDELINES ON CO-TRIMOXAZOLE

https://www.bhiva.org/file/SwhaEzgXmAGOt/hiv_v12_is2_Iss2Press_Text.pdf

When to stop PJP prophylaxis

Continue for at least 6 weeks following completion of Radiotherapy treatment / chemotherapy treatment / high dose steroids (whichever finishes last). Discontinue once lymphocytes ≥0.6 as per table below.

Lymphocyte >0.6	Discontinue, unless indicated due to other immunocompromise/immunosuppressive treatments
Lymphocyte <0.6	Continue with fortnightly GP bloods and discontinue when >0.6

Further Notes - Prescribing PJP Prophylaxis

Use the “Oncology outpatients supportive meds prescriptions” leaflet to prescribe the whole course when identifying an eligible patient for this treatment (found on OOQS Microsoft Word - Radiotherapy oncology outpatients supportive meds prescriptions 2024 v3 FINAL).

Examples of prescription:

All tumour sites with additional immunosuppressive therapies/conditions receiving anticancer treatments: consider PJP prophylaxis for the duration of the anticancer treatment. Prescribe from outpatients using the “Oncology outpatients supportive meds prescriptions” leaflet a course for 4 weeks (24 tablets of 480mg, to take 960mg (2 tablets) OD Monday, Wednesday and Friday. Ask GP in the clinical letter for a repeat prescription, consider discontinuing 6 weeks once anticancer therapies finished, if lymphocytes >0.6 and if clinically indicated.

All tumour sites receiving ≥4mg of dexamethasone for ≥4 weeks: prescribe from outpatients using the “Oncology outpatients supportive meds prescriptions” leaflet a course for the estimated duration of steroids, plus 6 weeks after the date of dexamethasone dose expected to be <4mg. Mention in the letter to GP about this regimen, the rationale and the expected time to stop acknowledging the steroid dose may need to increase, indicating the co-trimoxazole course may be prolonged.

Patients receiving RT to the lung:
- When to start
  - Sequential chemo-RT: (all patients) start the 1^st day of RT
  - RT alone (selected patients- immunosuppressed or on dexamethasone ≥4mg OD): start the 1^st day of RT
  - Concomitant chemo-RT: (all patients) start the 1^st day of RT
- How to start:
  - Prescribe from outpatients using the “Oncology outpatients supportive meds prescriptions” leaflet a course for 4-6 weeks (duration of RT course)+ extra 6 weeks (60-72 tablets of 480mg, to take 960mg (2 tablets) OD Monday, Wednesday and Friday). Note on letter to GP about this prescription, rationale. Book for bloods to be done nearer the time to stop. Stop once lymphocytes ≥0.6, otherwise continue monitoring lymphocytes weekly/ 2-weekly and stop once lymphocytes ≥0.6.

Prescribing responsibility falls under the healthcare professional seeing any patient in clinic who falls within the clinical indications in this protocol. Usually the clinician who prescribes treatments i.e. long course of high dose steroids, lung radiotherapy

Further Notes - PJP Prophylaxis Drug Information

Drug	Co-trimoxazole (1^st choice)	Dapsone (2^nd choice)	Atovaquone (3^rd choice)
Dose	960mg 3 times a week (Monday Wednesday Friday)	100mg OD	750mg BD (with fatty meal)
Formulation	Tablet or suspension	Tablet only (can be dispersed in water)	Suspension only
Toxicities	Fever, rash (including SJS/TEN), photosensitivity, pruritus, myelosuppression, headache, nausea, diarrhoea, transaminase elevation, electrolyte imbalance including hyperkalemia	Agranulocytosis, decreased appetite, haemolysis, haemolytic anaemia (check G6PD levels before use), headache, insomnia, rash, photosensitivity, sulfone syndrome (methemoglobinemia, fever, rash, hepatitis, lymphadenopathy), severe cutaneous adverse reactions	Nausea, diarrhoea, rash, headache, elevated transaminases,anaemia, angioedema, bronchospasm, hyponatraemia, insomnia
Cautions	Asthma, blood disorders, elderly (increased risk of side effects), G6PD deficiency, folate deficiency, predisposition to hyperkalaemia. SLE (atovaquone preferred alternative) Renal impairment- 480mg alternate day dosing if CrCl < 10ml/min	Anaemia, cardiac disease, pulmonary disease. Mild rash with co-trimoxazole (C/I if severe rash)	Hepatic impairment, absorption concerns (diarrhoea, unable to take with food)
C/I	Hypersensitivity to sulfones or trimethoprim,acute porphyrias	Hypersensitivity to sulfones (e.g.co-trimoxazole), sulfone syndrome, severe anaemia, porphyria, deficiency in G6PD, methaemoglobin reductase, or with haemoglobin M.	Hypersensitivity to drug or excipients
Cost	Low	Low	High
Efficacy	High	Moderate	Moderate
Interactions	Phenytoin: co-trimoxazole prolongs the half-life of phenytoin Methotrexate: co-trimoxazole may increase the free plasma levels of methotrexate and exacerbate toxicities. Vitamin K antagonists (e.g. warfarin): anticoagulant effect may be increased requiring a dose reduction.	Caution with any agents associated with increased risk of methaglobinaemia. CYP3A4 inducers: decrease in dapsone concentration and increase in toxic metabolite	Etoposide: Atovaquone can increase the levels of etoposide and its metabolite (8% and 24% respectively). Consider dose reduction if toxicity observed or omitting atovaquone within 24 hours of etoposide. Metoclopramide: reduced atovaquone concentrations. Tetracycline: reduced atovaquone concentrations. Rifampicin: reduced atovaquone concentrations.

Please note: This information is not exhaustive. Please consult product literature or pharmacy if further information is required.

References

Adapted from S\Tox\42 Pneumocystis jirovecii pneumonia (PJP) prophylaxis guidance for patients with solid tumours

Authors: Almu Cascales¹, Stephen Harrow¹, Naomi Bulteel², Simon Dewar³, Anton Slavin⁴.

1.Consultant Clinical Oncologist, 2. Consultant Infectious diseases, 3. Consultant Microbiologist, 4. Clinical Pharmacist

References

Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014
Journal of Antimicrobial Chemotherapy, Volume 71, Issue 9, September 2016, Pages 2397–2404, https://doi.org/10.1093/jac/dkw157
Guidelines for the prophylaxis of Pneumocystis Jirovecii Pneumonia (PJP) in children with solid tumours. https://www.cclg.org.uk/write/MediaUploads/Member%20area/Treatment%20guidelines/PJP_Prophylaxis_Guideline_Final.pdf
BNF Drug monographs. Access 20/04/20
Electronic medicines compendium https://www.medicines.org.uk/ Drug SPC’s. Accessed 20/04/20
Lexicomp Drug monographs via https://www.uptodate.com/ Accessed 20/04/20
Radiotherapy for lung cancer. RCR consensus statements. June 2020.
McAleese J, Mooney L, Walls GM. Reducing the risk of death from Pneumocystis jirovecii Pneumonia after Radical Radiation therapy to the lung. 2021. Clin Onc 33: 780-787