Azacitidine

Azacitidine (5-azacytidine) is a chemical analogue of the nucleoside cytidine. It is thought to act both by hypomethylating DNA and by being directly toxic to abnormal haematopoietic cells in the bone marrow. The injectable form (Vidaza) and the oral form (Onureg) contain the same active substance, but oral exposure is much lower, so their doses and schedules differ.

Mechanism of Action

• Cellular activation: inside the cell, azacitidine is phosphorylated by uridine-cytidine kinase and then by pyrimidine kinases to the triphosphate, which is built into RNA. A reduced form is converted to a deoxy analogue triphosphate that is built into DNA. Being a ribonucleoside, more of it is incorporated into RNA than into DNA.
• Cytotoxicity: incorporation into RNA disrupts RNA metabolism and protein synthesis; incorporation into DNA inhibits DNA synthesis and activates DNA damage pathways. Cells in S phase are the most sensitive, and non-dividing cells are relatively insensitive.
• DNA hypomethylation: azacitidine built into DNA inactivates DNA methyltransferases, which lowers DNA methylation. Hypomethylation of abnormally silenced genes that control the cell cycle, differentiation and cell death may switch these genes back on and restore cancer-suppressing functions. At low doses the methyltransferase effect predominates; at high doses cytotoxicity does.
• Relative importance: how much DNA hypomethylation, cytotoxicity and other effects each contribute to clinical outcomes has not been established.
• Oral form: with Onureg 300 mg daily for 14 or 21 days of a 28-day cycle, the fall in global DNA methylation in blood was sustained and correlated with plasma exposure.

Pharmacokinetics

Injection (Vidaza)

• Absorption: rapid after subcutaneous injection; after a single 75 mg/m² dose, the peak plasma concentration was 750 ± 403 ng/mL at 0.5 hours (the first sampling point). Bioavailability relative to intravenous dosing is about 89%, and Cmax and AUC are roughly proportional to dose between 25 and 100 mg/m².
• Distribution: after intravenous dosing, mean volume of distribution 76 ± 26 L and systemic clearance 147 ± 47 L/h.
• Metabolism: spontaneous hydrolysis and deamination by cytidine deaminase. Metabolism does not appear to depend on CYP enzymes, UGTs, SULTs or GSTs, and at clinically achievable concentrations azacitidine neither induces nor inhibits the CYP enzymes tested.
• Elimination: mean half-life after subcutaneous dosing 41 ± 8 minutes; no accumulation after 75 mg/m² daily for 7 days. Urine is the main route: 85% of radioactivity after intravenous and 50% after subcutaneous dosing, and under 1% in faeces.
• Special populations: the effects of hepatic impairment, sex, age and race have not been formally studied. In a study with subcutaneous dosing, severe renal impairment raised exposure by about 70% after a single dose and 41% after repeated doses, without a rise in adverse events.

Oral tablets (Onureg)

• Absorption: rapid, with a median Tmax of 1 hour. Oral bioavailability relative to subcutaneous dosing is about 11%. Exposure rises roughly in proportion to dose, with high variability between patients; after a single 300 mg dose the geometric mean Cmax was 145.1 ng/mL and the AUC 241.6 ng·h/mL. There is no accumulation with the recommended schedule, and food has minimal effect.
• Distribution: apparent volume of distribution 12.6 L/kg (for a 70 kg person); plasma protein binding 6 to 12%.
• Metabolism and elimination: same pathway as the injection. Apparent clearance about 1,242 L/h and half-life about 0.5 hours; under 2% of the dose appears unchanged in urine after oral or subcutaneous dosing.
• Special populations: age (46 to 93 years) and mild hepatic impairment had no clinically meaningful effect; the effect of moderate to severe hepatic impairment is unknown. Mild, moderate and severe renal impairment raised AUC by 19%, 25% and 38%, which does not call for a dose change. The effect of race or ethnicity is unknown.

Vidaza and Onureg have different indications and are not interchangeable.

Vidaza (Subcutaneous Injection)

Treatment of adults 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 the World Health Organisation (WHO) classification;
• AML with more than 30% marrow blasts, according to the WHO classification.

Onureg (Oral Tablets)

• AML maintenance: maintenance therapy in adults with AML who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) after induction therapy, with or without consolidation, and who are not candidates for HSCT, including those who choose not to proceed to it.

• Both forms: hypersensitivity to azacitidine or to any of the excipients; breastfeeding.
• Vidaza only: advanced malignant hepatic tumours.

Azacitidine mainly affects blood counts and the gut. The frequencies below come from the Vidaza SmPC (clinical studies in MDS and AML, and post-marketing use) and, separately, from the Onureg SmPC (a pivotal study in AML maintenance).

Vidaza (Subcutaneous Injection)

Reactions considered possibly or probably related to Vidaza occurred in 97% of patients. The most common were haematological reactions (71.4%; thrombocytopenia, neutropenia and leukopenia, usually grade 3–4), gastrointestinal events (60.6%, including nausea and vomiting, usually grade 1–2) and injection site reactions (77.1%, usually grade 1–2). The most common serious reactions in the pivotal study were febrile neutropenia (8.0%) and anaemia (2.3%). In adults aged 65 or older with AML and more than 30% marrow blasts, the most common serious reactions were febrile neutropenia (25.0%), pneumonia (20.3%) and pyrexia (10.6%).

Very common (≥1/10): pneumonia, nasopharyngitis, febrile neutropenia, neutropenia, leukopenia, thrombocytopenia, anaemia, anorexia, decreased appetite, hypokalaemia, insomnia, dizziness, headache, dyspnoea, epistaxis, diarrhoea, vomiting, constipation, nausea, abdominal pain, petechiae, pruritus, rash, ecchymosis, arthralgia, musculoskeletal pain, pyrexia, fatigue, asthenia, chest pain, injection site erythema, injection site pain and other injection site reactions, weight decreased.

Common (≥1/100 to <1/10): sepsis (including neutropenic sepsis), respiratory tract infection, urinary tract infection, cellulitis, diverticulitis, oral fungal infection, sinusitis, pharyngitis, rhinitis, herpes simplex, skin infection, pancytopenia, bone marrow failure, dehydration, confusional state, anxiety, intracranial haemorrhage, syncope, somnolence, lethargy, eye and conjunctival haemorrhage, pericardial effusion, hypotension, hypertension, orthostatic hypotension, haematoma, pleural effusion, exertional dyspnoea, pharyngolaryngeal pain, gastrointestinal, haemorrhoidal and gingival bleeding, stomatitis, dyspepsia, purpura, alopecia, urticaria, erythema, macular rash, muscle spasms, myalgia, renal failure, haematuria, raised serum creatinine, malaise, chills, catheter site haemorrhage, and further injection site reactions (bruising, haematoma, induration, rash, pruritus, inflammation, discolouration, nodule, haemorrhage).

Uncommon (≥1/1,000 to <1/100): hypersensitivity reactions, pericarditis, hepatic failure, progressive hepatic coma, acute febrile neutrophilic dermatosis, pyoderma gangrenosum, renal tubular acidosis.

Rare (≥1/10,000 to <1/1,000): tumour lysis syndrome, interstitial lung disease, injection site necrosis.

Not known: necrotising fasciitis, differentiation syndrome, cutaneous vasculitis.

Fatal outcomes have rarely been reported for some of these reactions, including pneumonia, sepsis, febrile neutropenia, pancytopenia, intracranial and gastrointestinal haemorrhage, hypotension, hepatic failure, renal failure, pyrexia, necrotising fasciitis and differentiation syndrome.

Onureg (Oral Tablets)

The most common reactions were nausea (64.8%), vomiting (59.7%), diarrhoea (50.4%), neutropenia (44.5%), fatigue or asthenia (44.1%), constipation (38.6%), thrombocytopenia (33.5%) and abdominal pain (21.6%). Serious reactions occurred in 16.1% of patients, most often febrile neutropenia (6.8%) and pneumonia (5.1%). Adverse reactions led to permanent discontinuation in 6.8% of patients (mainly nausea, diarrhoea and vomiting), to dose interruption in 36.4% and to dose reduction in 14%. New or worsening grade 3 or higher neutropenia (41.1%), thrombocytopenia (22.5%) and febrile neutropenia (11.4%) were commonly reported, and grade 3 or higher diarrhoea, vomiting and nausea occurred in 5.1%, 3.0% and 2.5%. The lists below combine the trial reactions seen in at least 5% of Onureg patients and at least 2% more often than with placebo with post-marketing reports.

Very common (≥1/10): pneumonia, respiratory tract infection, neutropenia, thrombocytopenia, febrile neutropenia, leukopenia, decreased appetite, nausea, vomiting, diarrhoea, constipation, abdominal pain, arthralgia, back pain, pain in extremity, fatigue or asthenia.

Common (≥1/100 to <1/10): sepsis, influenza, urinary tract infection, bronchitis, rhinitis, anxiety, weight decreased.

Uncommon (≥1/1,000 to <1/100): neutropenic sepsis.

Not known: differentiation syndrome.

No formal clinical drug interaction studies have been conducted with azacitidine.

• Metabolising enzymes: in vitro, azacitidine is not metabolised by CYP enzymes (and, for Vidaza, not by UGTs, SULTs or GSTs), so interactions with enzyme inducers or inhibitors are considered unlikely. Clinically significant inhibitory or inductive effects of azacitidine on CYP enzymes are also unlikely.
• Other anticancer medicines (Onureg): caution and monitoring are recommended, because antagonistic, additive or synergistic effects cannot be excluded and may depend on dose, sequence and schedule.
• Proton pump inhibitors and other pH modifiers (Onureg): omeprazole minimally affected Onureg exposure, so no dose change is needed.
• Transporters (Onureg): no clinically relevant interactions are expected with substrates of P-glycoprotein, BCRP, OAT1, OAT3, OATP1B1, OATP1B3 or OCT2, and azacitidine is not a P-glycoprotein substrate.
• Food (Onureg): can be taken with or without food.

Treatment with either form must be started and monitored under the supervision of a physician experienced in chemotherapeutic agents. The two forms must not be used interchangeably, because exposure, dose and schedule differ; the product name, dose and route are verified before use. Anti-emetics are given with both.

Vidaza: Dose and Schedule

• 75 mg/m² of body surface area, injected subcutaneously once daily for 7 days, followed by a rest period of 21 days (28-day cycle). The first-cycle dose is the same for all patients, whatever their baseline blood counts. The dose in mg is body surface area (m²) × 75 mg/m².
• At least 6 cycles are recommended; treatment continues for as long as the patient benefits or until disease progression.
• Patients are premedicated with anti-emetics for nausea and vomiting.
• Liver function tests, serum creatinine and serum bicarbonate are measured before starting and before each cycle; a complete blood count is done before starting and at least before each cycle.

Vidaza: Dose Adjustments

Haematological toxicity means a nadir (lowest count in a cycle) with platelets of 50.0 × 10⁹/L or less and/or an absolute neutrophil count (ANC) of 1.0 × 10⁹/L or less. Recovery means a rise of at least half the difference between the baseline and nadir counts above the nadir.

• Normal baseline counts (white cells at least 3.0, ANC at least 1.5 and platelets at least 75.0 × 10⁹/L): with haematological toxicity, the next cycle is delayed until platelets and ANC recover. Recovery within 14 days needs no dose change; if recovery takes longer, the next cycle is given at 50% of the dose. The cycle length then returns to 28 days.
• Reduced baseline counts (white cells below 3.0, ANC below 1.5 or platelets below 75.0 × 10⁹/L): if the fall from pre-treatment values is 50% or less, or more than 50% with improved cell-line differentiation, the next cycle is not delayed and the dose is unchanged. If the fall is more than 50% without improvement, the next cycle is delayed until recovery; recovery within 14 days needs no change. If there is no recovery by 14 days, bone marrow cellularity is checked: above 50%, no change; 50% or below, the dose depends on cellularity and recovery time. At 15–50% cellularity, recovery within 21 days allows 100% of the dose and later recovery 50%. Below 15%, recovery within 21 days allows 100% and later recovery 33%.
• Kidney: for unexplained serum bicarbonate below 20 mmol/L, the next cycle’s dose is reduced by 50%. For unexplained serum creatinine or blood urea nitrogen at least 2-fold above baseline and above the upper limit of normal, the next cycle is delayed until values return to normal or baseline, and the dose is reduced by 50%.

Vidaza: Preparation and Injection

• Reconstitution (by healthcare staff): each 100 mg vial is reconstituted with 4 mL of water for injections to give a uniform cloudy suspension of 25 mg/mL. Refrigerated water for injections extends how long the suspension keeps (see Shelf Life). The suspension is not filtered, is discarded if it contains large particles or agglomerates, and administration systems with built-in filters are not used.
• Injection: subcutaneously into the upper arm, thigh or abdomen, with the needle inserted at a 45–90° angle (a 25-gauge needle is recommended). Sites are rotated, each new injection is at least 2.5 cm from the previous one, and never into tender, bruised, red or hardened areas. Doses above 4 mL are divided between two sites.
• Timing: a filled syringe may stand for up to 30 minutes to reach about 20–25 °C before injection; after longer, the suspension is discarded and a new dose prepared.
• Handling: Vidaza is cytotoxic (see Special Instructions).

Onureg: Dose and Schedule

• 300 mg by mouth once daily for 14 days, followed by 14 days without treatment (28-day cycle).
• An anti-emetic is given 30 minutes before each dose for the first 2 cycles; it may be omitted after 2 cycles if there has been no nausea or vomiting.
• Treatment is discontinued if more than 15% blasts are seen in the peripheral blood or bone marrow, at the physician’s discretion, or for unacceptable toxicity. If AML relapses with 5% to 15% blasts, extending the schedule from 14 to 21 days of the 28-day cycle may be considered, and dosing must not exceed 21 days in any 28-day period.
• Complete blood counts are done before starting, every other week for the first 2 cycles (56 days), every other week for the next 2 cycles after a dose adjustment, and monthly thereafter before each cycle.
• The tablets are swallowed whole with a glass of water at about the same time each day, with or without food. They are not split, crushed, dissolved or chewed.

Onureg: Dose Adjustments

• Neutropenia (grade 4, or grade 3 with fever): first occurrence, interrupt and resume the cycle at the same dose once neutrophils return to grade 2 or lower, with supportive care such as G-CSF as clinically indicated. Occurring in 2 consecutive cycles, resume at 200 mg after recovery; if it continues after the dose reduction, shorten treatment by 7 days; if it continues or recurs after dose and schedule reduction, discontinue.
• Thrombocytopenia (grade 4, or grade 3 with bleeding): the same steps, based on platelets returning to grade 2 or lower.
• Grade 3 or higher nausea, vomiting or diarrhoea: interrupt and resume at the same dose once grade 1 or lower, with supportive care (anti-emetics; diarrhoea treated at onset). If it recurs, interrupt until grade 1 or lower and reduce to 200 mg; then shorten by 7 days, and discontinue if it continues or recurs.
• Other grade 3 or higher non-haematological events: interrupt with medical support and resume at the same dose once grade 1 or lower. If it recurs, reduce to 200 mg, then shorten by 7 days, and discontinue if it continues or recurs.

Onureg: Missed or Vomited Dose

If a dose is missed or not taken at the usual time, take it as soon as possible on the same day, then take the next dose at the normal time the following day. Two doses are never taken on the same day. If a dose is vomited, do not take another that day; return to the normal time the next day.

Special Populations

• Elderly: no dose adjustment for either form. With Vidaza, renal function may be worth monitoring because older patients are more likely to have reduced kidney function.
• Renal impairment: Vidaza can be given without initial dose adjustment (see Dose Adjustments); Onureg can be given without initial adjustment in mild, moderate or severe impairment.
• Hepatic impairment: Vidaza has not been formally studied; the starting dose is not modified, patients with severe impairment are monitored carefully, and later changes follow blood counts. Onureg needs no adjustment in mild impairment; in moderate (bilirubin above 1.5 to 3 times the upper limit of normal) and severe (above 3 times) impairment, patients are monitored more often and the dose adjusted as described under Onureg: Dose Adjustments.
• Children and adolescents: safety and efficacy below 18 years have not been established for either form.

Two Medicines, Not Interchangeable

Vidaza (subcutaneous injection) and Onureg (oral tablets) differ in exposure, dose and schedule and must not be used interchangeably. Healthcare professionals should verify the product name, dose and route of administration.

Cytotoxic Handling

Both are cytotoxic medicinal products.

• Vidaza: caution is needed when handling and preparing the suspension, and the procedures for proper handling and disposal of anticancer medicinal products apply. If reconstituted azacitidine contacts the skin, wash immediately and thoroughly with soap and water; if it contacts mucous membranes, flush thoroughly with water.
• Onureg: if powder from the film-coated tablets contacts the skin, wash immediately and thoroughly with soap and water; if it contacts mucous membranes, flush the area thoroughly with water.
• Disposal: any unused medicine or waste material is disposed of in accordance with local requirements.

Haematological Toxicity

Azacitidine is associated with anaemia, neutropenia and thrombocytopenia, with Vidaza particularly during the first 2 cycles. Blood counts are monitored at the intervals given above, and doses are delayed, reduced or stopped accordingly. Patients should report fever promptly and watch for signs of bleeding. With Onureg, supportive care (antibiotics or antipyretics for infection and fever, G-CSF for neutropenia) is given according to the individual patient and current clinical guidelines.

Gastrointestinal Toxicity (Onureg)

Gastrointestinal toxicity was the most frequent adverse reaction with Onureg. Prophylactic anti-emetics are given for the first 2 cycles and diarrhoea is treated promptly at onset; interruption, dose reduction or discontinuation may be needed.

Differentiation Syndrome

Differentiation syndrome (also called retinoic acid syndrome) has been reported with both injectable and oral azacitidine and may be fatal. Symptoms and findings include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary oedema, peripheral oedema, rapid weight gain, pleural and pericardial effusions, hypotension and renal dysfunction. At the first signs, high-dose intravenous corticosteroids and haemodynamic monitoring should be considered, and temporary discontinuation until symptoms resolve, with caution if treatment is resumed.

Renal and Hepatic Disease (Vidaza)

• Kidney: renal abnormalities ranging from raised serum creatinine to renal failure and death were reported with intravenous azacitidine given with other chemotherapy. Renal tubular acidosis (serum bicarbonate below 20 mmol/L with alkaline urine and low potassium) developed in 5 patients with chronic myelogenous leukaemia given azacitidine with etoposide. Patients should report oliguria (low urine output) or anuria (no urine) at once, and patients with renal impairment are monitored closely because azacitidine and its metabolites are mainly excreted by the kidney.
• Liver: patients with extensive tumour burden from metastatic disease have developed progressive hepatic coma and death during treatment, especially with baseline serum albumin below 30 g/L. Vidaza is contraindicated in advanced malignant hepatic tumours.

Cardiac and Pulmonary Disease (Vidaza)

Patients with a history of severe congestive heart failure, clinically unstable cardiac disease or pulmonary disease were excluded from the pivotal studies, so safety and efficacy in them are not established. A later study in patients with known cardiovascular or pulmonary disease found significantly more cardiac events, so caution is advised and cardiopulmonary assessment before and during treatment should be considered.

Necrotising Fasciitis and Tumour Lysis Syndrome (Vidaza)

Necrotising fasciitis, including fatal cases, has been reported; Vidaza is discontinued in patients who develop it and appropriate treatment started promptly. Patients with a high tumour burden before treatment are at risk of tumour lysis syndrome and are monitored closely, with appropriate precautions.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment and for 6 months after it. Men must not father a child during treatment and must use effective contraception during treatment and for 3 months after it.
• Pregnancy: there are no adequate data in pregnant women, and studies in animals showed reproductive toxicity. Azacitidine should not be used in pregnancy, especially the first trimester, unless clearly necessary, weighing the benefit against the possible risk to the foetus in each case; Onureg is not recommended in pregnancy or in women of childbearing potential not using contraception. If a patient or a patient’s partner becomes pregnant while taking Onureg, the patient should be told of the potential risk to the foetus.
• Breastfeeding: contraindicated, because it is unknown whether azacitidine or its metabolites pass into human milk and serious reactions in the nursing child are possible.
• Fertility: there are no human data; animal studies documented adverse effects on male fertility. Before starting Vidaza, men should seek counselling on sperm storage. Before Onureg, patients who wish to conceive should seek reproductive counselling and cryo-conservation of ova or sperm.

Lactose and Sodium (Onureg)

The tablets contain lactose (3.61 mg in the 200 mg tablet, 5.42 mg in the 300 mg tablet). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Azacitidine has a minor or moderate influence on the ability to drive and use machines (Vidaza SmPC). Fatigue has been reported, so caution is recommended when driving or operating machines.

Neither form needs special storage conditions. Vidaza is supplied as a single 100 mg vial per pack (colourless type I glass with a butyl stopper and aluminium seal). Reconstituted Vidaza suspension is kept only for the short periods given under Shelf Life.

• Vidaza, unopened vial: 4 years.
• Vidaza, after reconstitution: reconstituted with water for injections that has not been refrigerated, chemical and physical in-use stability is shown for 45 minutes at 25 °C and for 8 hours at 2–8 °C. Reconstituted with refrigerated (2–8 °C) water for injections, it is shown for 22 hours at 2–8 °C. From a microbiological point of view, the reconstituted product should be used immediately.
• Onureg tablets: 3 years.

Prescription only (Rx), started and monitored by a physician experienced in the use of chemotherapeutic agents. Vidaza is a cytotoxic injection prepared and given by healthcare staff, so it is supplied to the hospital or clinic that administers it. Onureg tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.