8: Malignant Disease and Immunosuppression

8: Malignant disease and immunosuppression

Please select a topic:

8.1 Cytotoxic drugs / 8.2 Drugs affecting the immune response
8.3 Sex hormones and hormone antagonists in malignant disease

Changes to the Formulary since previous version

(20.12.13)

Section / Change / Reason for change
8.1 / ADDED: Cetuximab – importance of establishing wild type RAS (KRAS and NRAS) status before treatment of metastatic colorectal cancer. / MHRA Drug Safety Update
8.1 / ADDED: Abraxane (paclitaxel, formulated as albumin-bound nanoparticles): potential presence of strands in intravenous infusion bag—if visible, filtration advised. / MHRA Drug Safety Update
8.1 / ADDED: Capecitabine – risk of skin reactions – discontinue treatment. / MHRA Drug Safety Update

8.1 Cytotoxic drugs

More than 50 cytotoxic drugs are used in the management of malignant disease, and the recommended doses and schedules vary according to the tumour type and regimen. Anticancer cytotoxic treatment should always be prescribed under the supervision of an oncology specialist. For recommendations regarding dosage refer to the North of England Cancer Network (or NECN) Handbook:

http://www.ncn.nhs.uk/hpSite/groups/networkcrosscuttinggroups/chemotherapy

This handbook lists all the approved chemotherapy protocols, which contain details of prescribing issues, management of toxic effects and supportive care. When oral cytotoxic drugs are used for the treatment of malignant disease, the whole course will be dispensed by the hospital pharmacy. The prescription should not be repeated except on the explicit instruction of a specialist.

Parenteral cytotoxic drugs should be reconstituted and dispensed by trained oncology pharmacy staff who have access to appropriate equipment. The administration of cytotoxic drugs by all routes other than the oral route should be undertaken only by staff with appropriate training in administration and safe handling, within a designated hospital area which is equipped to deal with drug reactions and emergencies. Extravasation of vesicant cytotoxic drugs may cause severe, permanent tissue damage and functional loss. To avoid extravasation, designated oncology staff are specially trained in the intravenous administration of vesicant drugs. Extravasation is a medical emergency, and expert advice and treatment must be obtained immediately.

In addition to their anti-tumour effects, cytotoxic drugs may damage normal tissues and are a potential hazard to patients, relatives and staff. Protective gloves must be worn when handling cytotoxic agents, and staff, patients and relatives must be advised on the safe handling and disposal of drugs and excreta. Most drugs are teratogenic, and particular care must be taken to avoid the exposure of pregnant women to cytotoxic drugs or contaminated excreta. Men and women receiving chemotherapy should avoid conception during treatment.

Cytotoxic drugs are also used for their immunosuppressive or anti-proliferative effects in the treatment of auto-immune conditions, rheumatoid arthritis, psoriasis, or prevention of transplant rejection.

The prescribing notes for the following sub-sections have been combined and do not follow the structure of chapter 8.1 of the BNF.

Most of the oncology drugs listed below are for specialist use only and are not suitable for general use in primary care. They are listed here for information only. The only oncology drugs that may be prescribed on occasion by GPs are cyclophosphamide, azathioprine, methotrexate, mercaptopurine and hydroxycarbamudide (N.B. this would only be where there is a shared care arrangement with individual GP)

Alkylating drugs

·  Busulfan (Busulphan) 2mg tablets

·  Chlorambucil 2mg tablets

·  Cyclophosphamide 50mg tablets – Amber when used for used to suppress inflammatory/autoimmune condtions

·  Cyclophosphamide injection

·  Lomustine 40mg capsules

·  Melphalan 2mg tablets

Cytotoxic antibiotics

·  Bleomycin injection

·  Doxorubicin injection

·  Doxorubicin lipsomal (Caelyx®) injection

·  Epirubicin injection

·  Idarubicin 5mg capsules

·  Mitomycin injection

·  Mitoxantrone (Mitozantrone) injection

Antimetabolites

·  Azacitidine injection

·  Capecitabine 150mg and 500mg tablets

·  Cladribine injection

·  Cytarabine injection

·  Fludarabine injection

·  Fludarabine 10mg tablets

·  Fluorouracil injection

·  Gemcitabine injection

·  Mercaptopurine 50mg tablets Amber when used for used to suppress inflammatory/autoimmune conditions

·  Methotrexate 2.5mg tablets - Amber when used for used to suppress inflammatory/autoimmune

·  Methotrexate injection

·  Pemetrexed injection

Vinca alkaloids and etoposide

·  Etoposide 50mg capsules

·  Etoposide injection

·  Vinblastine injection

·  Vincristine injection

·  Vindesine injection

·  Vinorelbine injection

·  Vinorelbine 20mg, 30mg and 80mg capsules

Other antineoplastic drugs

·  Bevacizumab injection

·  Bortezomib injection

·  Carboplatin injection

·  Cetuximab injection

·  Cisplatin injection

·  Dacarbazine injection

·  Dasatinib 20mg, 50mg, and 70mg tablets

·  Docetaxel injection

·  Eribulin injection

·  Erlotinib 25, 100mg, and 150mg tablets

·  Gefitinib tablets

·  Hydroxycarbamide/Hydroxyurea 500mg capsules - Amber when used for used to suppress inflammatory/autoimmune

·  Imatinib 100mg and 400mg tablets

·  Irinotecan injection

·  Lapatinib 205mg tablets

·  Lenalidomide 5mg, 10mg, 15mg and 25mg capsules

·  Nilotinib 200mg capsules

·  Oxaliplatin injection

·  Paclitaxel injection

·  Pentostatin injection (restricted)

·  Procarbazine 50mg capsules

·  Thalidomide 50mg capsules

·  Topotecan injection

·  Trastuzumab injection

·  Tretinoin 10mg capsules

Drugs for cytotoxic-induced side effects

·  Calcium folinate 50mg and 300mg injection

·  Calcium folinate 15mg tablets

·  Mesna 1g injection

·  Mesna 400mg tablets

Prescribing notes

Common side-effects of cytotoxic drugs include fatigue, reversible alopecia, nausea and vomiting, oral ulceration, diarrhoea, skin rashes, bone marrow suppression and effects on fertility. Possible effects on fertility and gonadal function must be discussed before treatment begins.

Refer to the North of England Cancer Network (or NECN) Handbook for advice on all supportive care:

http://www.ncn.nhs.uk/hpSite/groups/networkcrosscuttinggroups/chemotherapy

MHRA Drug Safety Update

Cetuximab: importance of establishing wild type RAS (KRAS and NRAS) status before treatment of metastatic colorectal cancer

Article date: February 2014

Summary

In the treatment of metastatic colorectal cancer, inferior overall survival, progression-free survival, and objective response rates have been shown in people with RAS mutations (at exons 2, 3, and 4 of KRAS and NRAS) who received cetuximab in combination with FOLFOX4 (oxaliplatin-containing) chemotherapy versus FOLFOX4 alone. Cetuximab is now indicated for the treatment of people with epidermal growth factor receptor (EGFR)- expressing, RAS wild-type metastatic colorectal cancer in combination with irinotecan or oxaliplatin based chemotherapy or as a single agent. Evidence of wild type RAS status at these exons is required before initiating treatment with cetuximab alone or in combination with chemotherapy in metastatic colorectal cancer. Cetuximab combined with oxaliplatin-containing chemotherapy is now contraindicated in people with metastatic colorectal cancer who have mutant RAS at these exons or unknown RAS status.

Link: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON377644

MHRA Drug Safety Update

Abraxane (paclitaxel, formulated as albumin-bound nanoparticles): potential presence of strands in intravenous infusion bag – if visible, filtration advised

Article date: February 2014

Summary

Abraxane (paclitaxel, formulated as albumin-bound nanoparticles) is a treatment for metastatic breast cancer in patients who have not responded to first-line treatment, or for whom standard anthracycline-containing therapy is not indicated.

There have been reports from Europe of thin, translucent or white-to-yellow proteinaceous strands (1–2 mm in length) being observed during visual inspection of bags of reconstituted paclitaxel suspension for intravenous infusion.

The cause of these strands is thought to be an interaction between albumin and silicone oil lubricant within medical devices such as syringes and locks of intravenous bags. There is no evidence of an increased risk of any adverse effect in patients treated with Abraxane containing strands. However, as a precaution we are advising that Abraxane with visible strands should be filtered.

Link: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON377646

MHRA Drug Safety Update

Capecitabine: risk of severe skin reactions – discontinue treatment

Article date: January 2014

Summary

Severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during treatment with capecitabine. Some cases were fatal. Capecitabine should be discontinued if a serious skin reaction occurs, and the reaction should be treated promptly.

Link: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON364168

8.2 Drugs affecting the immune response

Antiproliferative immunosuppressants

·  Azathioprine 25mg and 50mg tablets

·  Azathioprine 50mg injection

·  Mycophenolate mofetil 250mg tablets, 500mg capsules, 1g/5ml oral suspension (Cellcept®)

Prescribing notes

·  Azathioprine should not be given in combination with allopurinol due to myelosuppression.

·  Patients should be warned to report any signs or symptoms of bone marrow suppression i.e. infection, bruising and bleeding.

·  Mycophenolate mofetil is contra-indicated in pregnancy.

Corticosteroids and other immunosuppressants

·  Ciclosporin/Cyclosporin 25mg, 50mg and 100mg capsules (Neoral®)

·  Ciclosporin/Cyclosporin 100mg/ml oral solution (Neoral®)

·  Ciclosporin 50mg/ml infusion (Sandimmun®)

·  Tacrolimus 500microgram, 1mg and 5mg capsules (Prograf®)

Dose

- Ciclosporin capsules 10mg, 25mg, 50mg, 100mg; oral solution 100mg/mL: 5-8mg/kg/day in 2 divided doses (dose adjusted according to trough levels).

- Ciclosporin infusion 50mg/ml, 250mg/5ml: consult BNF and product literature.

- Tacrolimus (Prograf®) capsules 500 micrograms, 1mg and 5mg: 100 micrograms/kg/day in 2 divided doses (dose adjusted according to trough levels

Prescribing notes

·  Trough levels should be sampled prior to drug administration.

·  Target trough levels vary depending on indication

·  Tacrolimus is contra-indicated in pregnancy (seek specialist advice)

·  Two formulations of tacrolimus capsules are available: Prograf® for twice daily administration and Advagraf® for once daily administration. Care should be taken to distinguish clearly between these two preparations when prescribing and dispensing. Prescribe by brand name. Patients should only be changed from one preparation to the other, under supervision of a transplant specialist.

Interferons

·  Interferon alfa 18 million unit pen

·  Peg-inferferon alfa injection

Dose

- Dependant on indication. For use under the supervision of hospital specialist. Seek specialist advice.

Prescribing notes

·  Interferon alpha is used for the treatment of chronic myeloid leukaemia, hairy cell leukaemia, non Hodgkins lymphoma, myeloma, carcinoid tumours, Kaposi?s sarcoma, renal carcinoma, adjuvant treatment of malignant melanoma.

·  Peg-interferon alfa is used for the treatment of chronic hepatitis C in combination with ribavirin.

Monoclonals

·  Rituximab 500mg and 100mg injection

Dose

- Rituximab concentrate for intravenous infusion 10mg/mL: see product information.

Prescribing notes

·  Full resuscitation facilities should be at hand and treatment should only be undertaken with the close supervision of a specialist.

·  Rituximab may exacerbate angina, arrhythmia and heart failure; transient hypotension occurs frequently and antihypertensives may need to be withheld for 12 hours before infusion.

·  Patients should be given paracetamol and an antihistamine before each dose of rituximab to reduce the incidence of infusion-related side-effects. Pre-medication with a corticosteroid should also be considered. See product literature for treatment of infusion-related side-effects.

·  Severe cytokine release syndrome has occurred 1-2 hours after infusion of rituximab. Patients with a high tumour burden as well as those with pulmonary insufficiency or infiltration are at increased risk and should be monitored very closely.

MHRA Drug Safety Update

Rituixmab: screen for hepatitis B virus before treatment

Article date: December 2013

Summary

Screening for hepatitis B virus is now recommended in all patients (not only those at risk of this infection) before starting treatment for all indications. A patient with positive serology for hepatitis B virus should be referred to a specialist in liver disease before starting treatment with rituximab. During treatment, these patients should be monitored and managed to prevent reactivation of the virus.

Link: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON350669

8.3 Sex hormones and hormone antagonists in malignant disease

Progestogens

·  Medroxyprogesterone 100mg, 200mg and 500mg tablets

·  Megestrol 160mg tablets

Dose

Endocrine therapy for cancer should be initiated only on advice from a hospital specialist.

- Medroxyprogesterone acetate tablets 100mg, 200mg, 250mg, 400mg, 500mg: advanced renal cancer, 300mg daily.
- Megestrol acetate tablets 40mg, 160mg: advanced breast or renal cancer, 160mg daily.

Prescribing notes

·  Progestogens are rarely used for third-line endocrine therapy in breast cancer and are occasionally used in frail patients with advanced renal cancer or advanced endometrial cancer.

·  Progestogens should be used with caution in conditions that may worsen with fluid retention and in those susceptible to thromboembolism.

·  Megestrol can be used for anorexia. Megestrol 40mg daily may also be prescribed for menopausal symptoms for women receiving endocrine therapy.

Hormone antagonists

·  Anastrazole 1mg tablets

·  Exemestane 25mg tablets

·  Goserelin 3.6mg injection

·  Letrozole 2.5mg tablets

·  Tamoxifen 10mg and 20mg tablets

·  Tamoxifen 10mg/5ml solution

Dose

Endocrine therapy must only be initiated on the advice of a hospital specialist.

- Tamoxifen tablets 20mg: 20mg daily.
- Letrozole tablets 2.5mg: 2.5mg daily.
- Anastrozole tablets 1mg: 1mg daily.
- Exemestane tablets 25mg: 25mg daily.

- Goserelin implant 3.6mg: 3.6 mg by subcutaneous injection every 28 days.

Prescribing notes

·  The aromatase inhibitors letrozole, anastrozole and exemestane are ineffective in premenopausal women unless concomitant goserelin is given to suppress ovarian function.

·  Tamoxifen is more effective when ovarian function is suppressed in premenopausal women. Concomitant goserelin may be given for the first two years of adjuvant tamoxifen therapy in this group.

·  Oophorectomy is an alternative to goserelin in premenopausal women.

·  Tamoxifen increases the risk of venous and arterial thrombosis in postmenopausal women. Letrozole or anastrozole should be used in patients with an increased risk of thromboembolism.

·  Tamoxifen increases the risk of endometrial cancer. Abnormal vaginal bleeding should be investigated promptly.

·  Endocrine therapy may cause a transient increase in bone pain in patients with bony metastases.

Prostate cancer & gonadorelin analogues

·  Bicalutamide 150mg tablets Consultant Urologists Only

·  Bicalutamide 50mg tablets

·  Cyproterone acetate 50mg tablets

·  Flutamide 250mg tablets

·  Goserelin 3.6mg injection

·  Leuprorelin acetate 3.75mg injection

·  Degarelix 120mg and 80mg injection

Dose

Endocrine therapy must only be initiated on the advice of a hospital specialist.

- Bicalutamide tablets 50mg, 150mg: to prevent tumour flare when a gonadorelin analogue is started, 50mg daily for three weeks starting 2 weeks before the gonadorelin analogue. Used as a single agent for locally advanced disease, 150mg daily. Administered concurrently with a gonadorelin analogue to obtain maximum androgen blockade, 50mg daily.
- Flutamide tablets 250mg: 250mg three times daily.
- Leuprorelin acetate prefilled syringe 3.75mg: by subcutaneous injection, for neo-adjuvant therapy, 3.75mg every 4 weeks for 3 months.An anti-androgen should be started 2 weeks before leuprorelin to prevent tumour flare, and continued for 3 weeks in total.
- Goserelin prefilled syringe 3.6mg: by subcutaneous injection, for neo-adjuvant therapy, 3.6mg every 4 weeks for 3 months. For longer term treatment of locally advanced or metastatic disease, 10.8mg subcutaneously every 3 months. An anti-androgen should be started 2 weeks before goserelin to prevent tumour flare, and continued for 3 weeks in total.