Azacitidine

Registered South African indications:

• Treatment of myelodysplastic syndromes, including the following subtypes of the French-American-British classification: 
  - Refractory anaemia or refractory anaemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions)
  - Refractory anaemia with excess blasts
  - Refractory anaemia with excess blasts in transformation
  - Chronic myelomonocytic leukaemia

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Breastfeeding
• Advanced malignant hepatic tumours 

Cautions

• Pregnancy
• Renal impairment
  - Unexplained reductions in serum bicarbonate (<20mmol/L) or elevations of serum creatinine or blood urea nitrogen (BUN)
• Hepatic impairment
• Elderly
• Porphyria
• Extensive tumour burden due to metastatic disease, especially if baseline serum albumin <30g/L
• History of severe congestive heart failure
• Clinically unstable cardiac disease or pulmonary disease, including known history of cardiovascular or pulmonary disease
• High tumour burden prior to treatment
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Patients who are not eligible for haematopoietic stem cell transplantation (HSCT) with:
- Intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS)
- Chronic myelomonocytic leukaemia (CMML) with 10-29 % marrow blasts without myeloproliferative disorder
- Acute myeloid leukaemia (AML) with 20-30% blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification
- AML with >30% marrow blasts according to the WHO classification

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Consult specialist for doses and regimens

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South African manufacturer recommendations

Treatment of myelodysplastic syndromes, including the following subtypes of the French-American-British classification: 
- Refractory anaemia or refractory anaemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions)
- Refractory anaemia with excess blasts
- Refractory anaemia with excess blasts in transformation
- Chronic myelomonocytic leukaemia

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Consult specialist for doses and regimens

Not established for use in children

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According to international manufacturer recommendations, the safety and efficacy of azacitidine in children aged 0-17 years has not yet been established

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According to South African manufacturer recommendations, the safety and efficacy of azacitidine in children and adolescents
under 18 years of age has not been established

Pregnancy

• Caution; not recommended
• There are no adequate data from the use of azacitidine in pregnant women. Studies in mice have shown reproductive toxicity, the potential risk for humans is unknown
• Based on results from animal studies and its mechanism of action, azacitidine should not be used during pregnancy, especially during the first trimester, unless clearly necessary
• The advantages of treatment should be weighed against the possible risk for the foetus in every individual case
• Women of childbearing potential and men are advised to use effective contraception during and up to 3 months after treatment

Breastfeeding

• Contraindicated
• It is unknown whether azacitidine/ metabolites are excreted in human milk
• Due to the potential serious adverse reactions in the breastfeeding child, breastfeeding is contraindicated during azacitidine therapy

Fertility

• There is no human data on the effect of azacitidine on fertility
• In animals, adverse reactions with azacitidine use on male fertility have been documented
• Men should be advised not to father a child while receiving treatment and must use effective contraception during and up to 3 months after treatment
• Before starting treatment, male patients should be advised to seek counselling on sperm storage

Renal Impairment

• Caution; no dose adjustment recommended 
  Azacitidine can be administered to patients with renal impairment without initial dose adjustment. If unexplained reductions in serum bicarbonate levels to <20mmol/l occur, the dose should be reduced by 50% on the next cycle. If unexplained elevations in serum creatinine or blood urea nitrogen (BUN) to ≥2-fold above baseline values and above upper limit of normal (ULN) occur, the next cycle should be delayed until values return to normal or baseline and the dose should be reduced by 50% on the next treatment cycle

Hepatic Impairment

• Caution; no information available 
  No formal studies have been conducted in patients with hepatic impairment. Patients with severe hepatic organ impairment should be carefully monitored for adverse events. No specific modification to the starting dose is recommended for patients with hepatic impairment prior to starting treatment; subsequent dose modifications should be based on haematology laboratory values. Azacitidine is contraindicated in patients with advanced malignant hepatic tumours

Elderly

• Caution; no dose adjustment recommended
  Monitor renal function

Porphyria Information

• Probably not porphyrinogenic (PNP)

  Nausea and vomiting, abdominal pain, diarrhoea, obstipation, musculoskeletal pain, neutropenic infections, stress, anxiety and insomnia are reported as common side effects that can be confused with an acute porphyria attack

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dizziness
• Headache
• Intracranial haemorrhage
• Cerebral haemorrhage
• Syncope
• Somnolence
• Insomnia
• Confusional state
• Anxiety
• Fatigue

Cardiovascular Disorders

• Hypotension
• Hypertension
• Orthostatic hypotension
• Haematoma
• Chest pain
• Pericardial effusion
• Pericarditis

Respiratory Disorders

• Pneumonia (including bacterial, viral and fungal)
• Nasopharyngitis
• Respiratory tract infection
  - Upper respiratory tract infection
  - Bronchitis
• Sinusitis
• Pharyngitis
• Rhinitis
• Dyspnoea
  - Exertional dyspnoea
• Epistaxis
• Pleural effusion
• Pharyngolaryngeal pain
• Interstitial lung disease

Gastrointestinal Disorders

• Diverticulitis
• Oral fungal infection
• Diarrhoea
• Nausea and vomiting
• Constipation
• Abdominal pain
  - Upper abdominal pain
  - Abdominal discomfort
• Gastrointestinal haemorrhage
  - Mouth haemorrhage
• Haemorrhoidal haemorrhage
• Stomatitis
• Gingival bleeding
• Dyspepsia

Hepatobiliary Disorders

• Hepatic failure
• Progressive hepatic coma

Genitourinary Disorders

• Urinary tract infection
• Renal failure
• Haematuria
• Elevated serum creatinine
• Renal tubular acidosis

Endocrine and Metabolic Disorders

• Anorexia
• Decreased appetite
• Hypokalemia
• Dehydration
• Tumour lysis syndrome
• Decreased weight

Musculoskeletal Disorders

• Arthralgia
• Musculoskeletal pain
  - Back pain
  - Bone pain
  - Pain in extremity
• Muscle spasms
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Skin infection
• Necrotising fasciitis
• Cellulitis
• Petechiae
• Pruritus
  - Generalised pruritus
• Rash
• Ecchymosis
• Purpura
• Alopecia
• Urticaria
• Erythema
• Macular rash
• Acute febrile neutrophilic dermatosis
• Pyoderma gangrenosum
• Injection site erythema
• Injection site pain
• Injection site nodule and haemorrhage
• Injection site necrosis
• Injection site reaction
• Bruising
• Haematoma
• Induration
• Inflammation
• Discolouration

Immune, Blood and Lymphatic System Disorders

• Sepsis (including bacterial, viral and fungal)
• Neutropenic sepsis
• Herpes simplex
• Febrile neutropenia
• Neutropenia
• Leukopenia
• Thrombocytopenia
• Anaemia
• Pancytopenia
• Bone marrow failure
• Hypersensitivity reactions
• Fever
• Chills

Sensory Disorders

• Eye haemorrhage
• Conjunctival haemorrhage

Other

• Catheter site haemorrhage

No information available

• Hepatic function
• Renal function
  - Serum creatinine
  - Blood urea nitrogen (BUN)
• Electrolytes
• Full blood count with differential and platelets

Some cases may require

• Hepatitis B virus screening
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Additional observations

• Tumour lysis syndrome risk (prior to treatment)
• Monitor haematologic response
• Signs and symptoms of:
  - Tumour lysis syndrome
  - Nausea and vomiting
  - Injection site reactions

The control of nausea and vomiting as a side effect

• Patients should be premedicated with anti-emetics for nausea and vomiting

Method of administration

• Reconstituted azacitidine should be injected subcutaneously (insert the needle at a 45-90° angle) using a 25-gauge needle into the upper arm, thigh or abdomen
• Injection sites should be rotated. New injections should be given at least 2.5cm from the previous site and never into areas where the site is tender, bruised, red, or hardened
• Doses >4ml should be injected into two separate sites

Reconstitution procedure 

• Azacitidine should be reconstituted with water for injection as follows:
  - 4ml of water for injection should be drawn into the 5ml injection syringe, making sure to purge any air trapped within the syringe
• The needle of the syringe containing the 4ml water for injection should be inserted through the rubber top of the azacitidine vial followed by injection of the water for injection into the vial
• Following the removal of the syringe and needle, the vial should be vigorously shaken until a uniform cloudy suspension is achieved. The reconstituted product is a homogeneous, cloudy suspension, free of agglomerates
• The product should be discarded if it contains large particles or agglomerates. Do not filter the suspension after reconstitution since this could remove the active substance. It must be taken into account that filters are present in some adaptors, spikes and closed systems; therefore such systems should not be used for administration of the medicinal product after reconstitution
• The rubber top should be cleaned and a new syringe with needle is inserted into the vial
• The vial should then be turned upside down, ensuring the needle tip is below the level of the liquid
• The plunger should then be pulled back to withdraw the amount of medicinal product required for the proper dose, ensuring any air trapped within the syringe is purged
• The syringe with needle should then be removed from the vial and the needle disposed of
• A fresh subcutaneous needle (recommended 25-gauge) should then be firmly attached to the syringe. The needle should NOT be purged prior to injection, in order to reduce the incidence of local injection site reactions
• When >1 vial is needed, all of the above steps for preparation of the suspension should be repeated. For doses requiring >1 vial, the dose should be equally divided e.g. dose 150mg = 6ml, 2 syringes with 3ml in each syringe
• Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial
• The contents of the dosing syringe must be re-suspended immediately prior to administration. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved. The product should be discarded if it contains large particles or agglomerates
• The syringe filled with reconstituted suspension should be allowed up to 30 minutes prior to administration to reach a temperature of approximately 20-25°C. If the elapsed time is >30 minutes, the suspension should be discarded appropriately and a new dose prepared

Recommendations for safe handling

• Azacitidine is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution should be exercised when handling and preparing azacitidine suspensions. Procedures for proper handling and disposal of anticancer medicinal products should be applied
• If reconstituted azacitidine comes into contact with the skin, immediately and thoroughly wash with soap and water. If it comes into contact with mucous membranes, flush thoroughly with water

Azacitidine is believed to exert its antineoplastic effects by multiple mechanisms including cytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of DNA. The cytotoxic effects of azacitidine may result from multiple mechanisms, including inhibition of DNA, RNA and protein synthesis, incorporation into RNA and DNA, and activation of DNA damage pathways. Non-proliferating cells are relatively insensitive to azacitidine. Incorporation of azacitidine into DNA results in the inactivation of DNA methyltransferases, leading to hypomethylation of DNA. DNA hypomethylation of aberrantly methylated genes involved in normal cell cycle regulation, differentiation and death pathways may result in gene re-expression and restoration of cancer-suppressing functions to cancer cells. The relative importance of DNA hypomethylation versus cytotoxicity or other activities of azacitidine to clinical outcomes has not been established.

Injection (per vial) 100mg

• Azacitidine DRL (Dr Reddy's Laboratories)
• Intaza 100 (Accord Healthcare)
• Vidaza (Key Oncologics) originator