Immunosuppressant Therapy: Azathioprine

Immunosuppressant Therapy

• Suppresses or prevents the immune response.

Azathioprine

• It's an antimetabolite that breaks down into mercaptopurine
• Mercaptopurine inhibits the repair and creation of DNA.
• Azathioprine is broken down by Thiopurine Methyltransferase (TPMT).
• Pre-screening TPMT levels is advised as underactive TPMT can lead to myelosuppression.

Azathioprine Side Effects

• Can cause hypersensitivity
• Hypersensitivity symptoms: malaise, dizziness, N+V, fever, rash, hypotension, myalgia.
• May cause Neutropenia and Thrombocytopenia, indicated by sore throat, bruising, or bleeding.
• Nausea is common at the start of the dose but usually resolves over time.
• It is teratogenic, so should be avoided during pregnancy.

Azathioprine Monitoring

• Monitor Thiopurine Methyltransferase (TPMT).
• Regular Liver Function Tests (LFT) and Full Blood Count (FBC) are needed in severe liver/renal impairment.
• Monitor FBC weekly for the first 4 weeks of treatment, then at least every 3 months.

Azathioprine Interactions

• Azathioprine + Allopurinol increases the risk of haematological toxicity, reduce dose of azathioprine if combined.
• Azathioprine + ACEIs increases the risk of anaemia/leucopoenia, avoid concomitant use.

Ciclosporin

• Calcineurin inhibitor that inhibits lymphokines and suppresses cell-mediated response.
• It must be prescribed and dispensed by BRAND NAME.
• Patients should maintain the same brand due to potential changes in ciclosporin concentration.

Ciclosporin Side Effects

• May cause Hyperglycaemia, Hyperlipidaemia, Hypertension, Hyperuricemia, Hyperkalaemia, Hypomagnesemia.
• May cause Renal/Liver impairment.
• May cause Skin Reactions.
• May cause Gingival hyperplasia.
• May cause Hair changes.
• May cause Eye inflammation and visual disturbances (with topical eye use).
• Should be avoided during pregnancy and breastfeeding.

Ciclosporin Interactions

• Combining Grapefruit juice and Pomelo juice increases ciclosporin exposure.
• Purple grape juice decreases ciclosporin exposure.

Ciclosporin Monitoring

• Pre-screening should exclude malignancies before systemic use.
• Monitor LFT, Magnesium, Potassium, Lipids, CrCl, BP.
• Monitor Trough levels; range depends on indication.

Ciclosporin Patient Advice

• Patients should avoid exposure to UV light/sunlight.
• Topical (eye) use may affect driving/performing skilled tasks.

Tacrolimus

• Calcineurin inhibitor that inhibits lymphokines and suppresses cell-mediated response.
• Prescribed and dispensed by BRAND name.
• Switching between oral products has been associated with reports of toxicity and transplant rejection.
• Different formulations include Adoport, Prograf, Capexion, Tacni (Immediate release capsule, taken BD), Modigraf granules (Immediate release suspension, taken BD) and Advagraf (prolonged release capsule, taken OD in the morning).

Tacrolimus Side Effects

• May cause Hyperglycaemia, Hyperuricemia, Hyperkalaemia.
• May cause Hypo/Hypertension.
• May cause Renal/Liver impairment.
• May cause Skin reactions and Visual disturbances.
• May cause Blood dyscrasia.
• Can cause Cardiovascular diseases like QT prolongation and cardiomyopathy in children.
• Can cause Nervous system disorders, like peripheral neuropathy.
• Should be avoided during pregnancy and breastfeeding.

Tacrolimus Interactions

• Grapefruit + Pomegranate + Pomelo juice increases tacrolimus exposure.
• Is contraindicated in patients with hypersensitivity to macrolides.

Tacrolimus Monitoring

• Monitor BP, ECG, Blood glucose, LFT, Electrolytes, CrCl.

Tacrolimus Patient Advice

• Avoid exposure to UV light/sunlight.
• May affect driving/performing skilled tasks.

Mycophenolate Mofetil

• Inhibits purine synthesis.
• May cause Bone marrow suppression, report infection/bleeding/bruising.
• May cause Pure red cell aplasia, reduce dose or discontinue.
• Monitor immunoglobulin levels in recurrent infections to detect Hypogammaglobulinemia.
• Consider Bronchiectasis if persistent cough and SOB develops.

Mycophenolate Mofetil Contraindications

• MHRA contraception advice: it is Teratogenic.
• Women: use 1 effective contraception during and for 6 weeks after treatment (2 methods preferred).
• Men: use effective contraception during and for 90 days after treatment (for partner as well).

Multiple Sclerosis

• It is a chronic autoimmune disease that demyelinates the CNS.
• Can be relapsing, progressive, or both.
• Active MS is defined as having 2 relapses in the past 2 years despite treatment with interferon beta.

Managing MS Symptoms

• Spasticity can be managed with Baclofen, Diazepam, Tizanidine, Dantrolene
  • Baclofen: increase dose slowly to avoid sedation and hypotonia
• Relapses are managed with Methylprednisolone.
• Oscillopsia (objects appear to vibrate) can be treated with Gabapentin.
• Mood alteration can be treated with Amitriptyline.
• Fatigue can be managed with Amantadine or Fampridine.
• FROMS is a combination of Fatigue, Relapse, Oscillopsia, Mood alteration, and Spasticity.

Cytotoxic Drugs

• The chemotherapy of cancer should be limited to specialists in oncology.
• Handling requires trained personnel and designated pharmacy areas.
• Wear protective clothing, including gloves, gowns, and a mask.
• Use eye protection.
• Pregnant staff should avoid, and females of childbearing age should be informed of the hazard.
• Use local procedures for spillages, safe disposal, including syringes, containers, and absorbent material.
• Monitor staff exposure to cytotoxins.

Drug Classes

• Alkylating agents include Cyclophosphamide, Ifosfamide, and Melphalan.
  • May lead to Urothelial toxicity.
  • Increases the risk of permanent male sterility.
• Anthracyclines include Daunorubicin, Doxorubicin, Epirubicin, and Idarubicin.
  • May cause Rubi-red urine.
  • Formulations are not interchangeable (conventional, liposomal, pegylated liposomal).
  • May have Cardiotoxic side effects.
  • Liposomal formulations reduce cardiotoxicity but cause painful macular skin eruptions
    • Prevent skin eruptions by cooling hands/feet and avoiding gloves/socks
• Antimetabolites include Cytarabine, Fluorouracil, Methotrexate, and Mercaptopurine
  • May cause Mucositis and myelosuppression.
• Cytotoxic Antibiotics include Bleomycin and Mitomycin.
  • May cause Progressive pulmonary fibrosis and Pulmonary toxicity.
• Platinum Compounds include Carboplatin, Cisplatin, and Oxaliplatin.
• Taxanes include Cabazitaxel, Docetaxel, and Paclitaxel.
  • Hypersensitivity reactions may occur, premedicate with corticosteroids and antihistamines.
  • Monitor cardiac output.

Monitoring Cytotoxic Drug Side Effects

• Monitor for signs and symptoms of pneumonitis and sepsis.
• Vinca Alkaloids include Vinblastine, Vincristine, and Vindesine.
  • Only administer INTRAVENOUSLY, Intrathecal administration is FATAL.
  • May cause Bronchospasm.
  • May cause Neurotoxicity, neuropathy, motor weakness, and myalgia.

Cytotoxin Side Effects

• Cytotoxic drug side effects often do not occur at the time of administration, but days or weeks later.
• Extravasation of Intravenous Drugs may cause severe local tissue necrosis due to leakage of the cytotoxin.

Oral Mucositis

• Sore mouth caused may be associated with Fluorouracil, Methotrexate, and Anthracyclines.
• Advice includes good oral hygiene and sucking ice chips with Fluorouracil.
• Treating is less effective than preventing, can be treated with saline mouthwashes.
• If caused by methotrexate, use Folinic acid (levofolinic acid).

Tumour Lysis Syndrome

• Occurs due to rapid destruction of malignant cells.
• Risk is higher in non-Hodgkin’s lymphoma, Burkitt’s lymphoma, acute lymphoblastic leukaemia, and acute myeloid leukaemia.
• Higher risk in pre-existing hyperuricaemia, dehydration and renal impairment.
• Causes HYPER K+, Ph, Ca, uricaemia, which results in renal damage and arrhythmias.

Hyperuricaemia

• More present in high grade Lymphoma and Leukaemia.
• Allopurinol should be started 24 hours before treating those tumours, hydrate patient.
• Febuxostat given 2 days before treatment can be used as an alternative.

Bone Marrow Suppression

• Caused by all drugs other than Vincristine and Bleomycin.
• Occurs 7-10 days after administration.
• Check blood count before treatments, reduce dose if bone marrow hasn’t recovered.
• AVOID treatment during acute infection, or seek medical attention if currently taking.
• Neutropenic fever, immediate and requires broad spectrum antibiotics.

Alopecia

• Common with chemotherapy treatments
• Unpreventable, but reversible

Thromboembolism

• Chemotherapy increases risk

Urothelial Toxicity

• Causes haemorrhage in urinary tract
• Common in cyclophosphamide and Ifosfamide
• Treated with Mesna

Myelosuppression

• Can be caused by methotrexate.
• Can be treated with Folinic acid to treat toxicity

Reproductive System Considerations

• Most cytotoxic drugs are teratogenic and should not be administered during pregnancy.
• Exclude pregnancy before cytotoxic treatment with drugs
• Advise on contraception
• Women of childbearing age to use contraception during and after treatment
• Alkylating drugs or procarbazine:
  • Increased risk of permanent male sterility
  • Consider sperm storage
  • May cause a premature menopause in women.

Nausea and Vomiting

• Symptoms can be acute, delayed or anticipatory.
• Delayed and anticipatory symptoms are more difficult to control than acute symptoms.
• More common in women, patients <50, anxiety and repeated exposure.

Nausea and Vomiting: Severity

• Mild emetogenic risk is associated with Fluorouracil, etoposide, methotrexate, and vinca alkaloids.
• Moderate emetogenic risk is associated with Taxanes, doxorubicin, low cyclophosphamide doses, mitoxantrone and high methotrexate doses.
• High emetogenic risk is associated with Cisplatin, dacarbazine and high cyclophosphamide doses.

Nausea and Vomiting: Prevention

• Prevention of acute symptoms (within 24 hours of treatment)
  • Low risk patients: dexamethasone or lorazepam
  • High risk patients: Ondansetron + dexamethasone + aprepitant.
• Prevention of delayed symptoms (after 24 hours of treatment)
  • Moderately emetogenic drugs: Dexamethasone + ondansetron
  • Highly emetogenic drugs: Dexamethasone + aprepitant
• Prevention of anticipatory symptoms (occurs before treatment)
  • Lorazepam