Drug Description
Each vial contains 100 mg azacitidine. After reconstitution, each ml suspension contains 25 mg azacitidine
Presentation
Powder for suspension for injection. White lyophilised powder.
Indications
Vidaza is indicated for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation with:• intermediate and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS)• chronic myelomonocytic leukaemia (CMML) with 1029 % marrow blasts without myeloproliferative disorder• acute myeloid leukaemia (AML) with 2030 % blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification.
Adult Dosage
Vidaza treatment should be initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic agents. Patients should be premedicated with anti-emetics for nausea and vomiting.PosologyThe recommended starting dose for the first treatment cycle, for all patients regardless of baseline haematology laboratory values, is 75 mg/m2 of body surface area, injected subcutaneously, daily for 7 days, followed by a rest period of 21 days (28day treatment cycle).It is recommended that patients be treated for a minimum of 6 cycles. Treatment should be continued as long as the patient continues to benefit or until disease progression.Patients should be monitored for haematologic response/toxicity and renal toxicities; a delay in starting the next cycle or a dose reduction as described below may be necessary.Dose adjustment due to haematological toxicityHaematological toxicity is defined as the lowest count reached in a given cycle (nadir) if platelets fall below 50.0 x 109/l and/or absolute neutrophil count (ANC) below 1 x 109/l.Recovery is defined as an increase of cell line(s) where haematological toxicity was observed of at least half of the difference of nadir and the baseline count plus the nadir count (i.e. blood count at recovery Nadir Count + (0.5 x [Baseline count – Nadir count]).Patients without reduced baseline blood counts (i.e. White Blood Cells (WBC)> 3.0 x 109/l and ANC>1.5 x 109/l, and platelets> 75.0 x 109/l) prior to the first treatmentIf haematological toxicity is observed following Vidaza treatment, the next cycle of Vidaza therapy should be delayed until the platelet count and the ANC have recovered. If recovery is achieved within 14 days, no dose adjustment is necessary. However, if recovery has not been achieved within 14 days, the dose should be reduced according to the following table. Following dose modifications, the cycle duration should return to 28 days.Nadir countsNadir counts% Dose in the next cycle, if recovery* is not achieved within 14 daysANC (x 109 /l)Platelets (x 109 /l)≤ 1.0≤ 50.050%> 1.0> 50.0100%*Recovery = counts Nadir count + (0.5 x [Baseline count – Nadir count])Patients with reduced baseline blood counts (i.e. WBC < 3.0 x 109/l or ANC < 1.5 x 109/l or platelets < 75.0 x 109/l) prior to the first treatmentFollowing Vidaza treatment, if the decrease in WBC or ANC or platelets from that prior to treatment is less than 50 %, or greater than 50 % but with an improvement in any cell line differentiation, the next cycle should not be delayed and no dose adjustment made.If the decrease in WBC or ANC or platelets is greater than 50 % from that prior to treatment, with no improvement in cell line differentiation, the next cycle of Vidaza therapy should be delayed until the platelet count and the ANC have recovered. If recovery is achieved within 14 days, no dose adjustment is necessary. However, if recovery has not been achieved within 14 days, bone marrow cellularity should be determined. If the bone marrow cellularity is> 50 %, no dose adjustments should be made. If bone marrow cellularity is 50 %, treatment should be delayed and the dose reduced according to the following table:*Recovery = counts Nadir count + (0.5 x [Baseline count – Nadir count])Following dose modifications, the cycle duration should return to 28 days.Bone marrow cellularity% Dose in the next cycle if recovery is not achieved within 14 days% Dose in the next cycle if recovery is not achieved within 14 daysRecovery* 21 daysRecovery*> 21 days15-50%100%50%<15%100%33%Special populationsRenal impairment: No formal studies have been conducted in patients with decreased renal function. Patients with severe organ impairment should be carefully monitored for adverse events. No specific modification to the starting dose is recommended in patients with renal impairment (e.g. baseline serum creatinine or blood urea nitrogen [BUN] 2fold above upper limit of normal [ULN] or serum bicarbonate less than 20 mmol/l) prior to starting treatment; subsequent dose modifications should be based on haematology and renal laboratory values. If unexplained reductions in serum bicarbonate levels to less than 20 mmol/l occur, the dose should be reduced by 50 % on the next cycle. If unexplained elevations in serum creatinine or BUN to 2fold above baseline values and above 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: 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. Vidaza is contraindicated in patients with advanced malignant hepatic tumours.Elderly: No specific dose adjustments are recommended for the elderly. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.Children and adolescents: Vidaza is not recommended for use in children below 18 years due to insufficient data on safety and efficacy.Laboratory testsLiver function tests and serum creatinine should be determined prior to initiation of therapy and prior to each treatment cycle. Complete blood counts should be performed prior to initiation of therapy and as needed to monitor response and toxicity, but at a minimum, prior to each treatment cycle.Method of administrationReconstituted Vidaza should be injected subcutaneously into the upper arm, thigh or abdomen. Injection sites should be rotated. New injections should be given at least 2.5 cm from the previous site and never into areas where the site is tender, bruised, red, or hardened.
Child Dosage
Acute attack, 1 puff as necessary. Higher doses may be used if response is inadequate. Allergen or exercise-induced asthma, 1 puff 10 - 15 minutes before challenge. On demand, maximum 1 puff four times daily.
Contra Indications
Known hypersensitivity to the active substance or to any of the excipients.Advanced malignant hepatic tumours.Lactation
Special Precautions
Haematological toxicityTreatment with azacitidine is associated with anaemia, neutropenia and thrombocytopenia, particularly during the first 2 cycles. Complete blood counts should be performed as needed to monitor response and toxicity, but at least prior to each treatment cycle. After administration of the recommended dose for the first cycle, the dose for subsequent cycles should be reduced or its administration delayed based on nadir counts and haematological respons. Patients should be advised to promptly report febrile episodes. Patients and physicians are also advised to be observant for signs and symptoms of bleeding.Hepatic impairmentNo formal studies have been conducted in patients with hepatic impairment. Patients with extensive tumour burden due to metastatic disease have been rarely reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline serum albumin < 30 g/l. Azacitidine is contraindicated in patients with advanced malignant hepatic tumours.Renal impairmentRenal abnormalities ranging from elevated serum creatinine to renal failure and death were reported rarely in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to < 20 mmol/l in association with an alkaline urine and hypokalaemia (serum potassium < 3 mmol/l) developed in 5 subjects with chronic myelogenous leukaemia (CML) treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate (< 20 mmol/l) or elevations of serum creatinine or BUN occur, the dose should be reduced or administration delayed. Patients with renal impairment should be closely monitored for toxicity since azacitidine and/or its metabolites are primarily excreted by the kidney.Cardiac and pulmonary diseasePatients with a history of severe congestive heart failure, clinically unstable cardiac disease or pulmonary disease were excluded from the pivotal clinical study and therefore the safety and efficacy of Vidaza in these patients has not been established.
Interactions
Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450 isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and glutathione transferases (GSTs); interactions related to these metabolizing enzymes in vivo are therefore considered unlikely.Clinically significant inhibitory or inductive effects of azacitidine on cytochrome P450 enzymes are unlikely.No formal clinical drug interaction studies with azacitidine have been conducted.
Adverse Reactions
Adverse reactions considered to be possibly or probably related to the administration of Vidaza have occurred in 97 % of patients.The most commonly reported adverse reactions with azacitidine treatment were haematological reactions (71.4 %) including thrombocytopenia, neutropenia and leukopenia (usually Grade 34), gastrointestinal events (60.6 %) including nausea, vomiting (usually Grade 12) or injection site reactions (77.1 %; usually Grade 12).The most common serious adverse reactions (> 2 %) noted from the pivotal study (AZA PH GL 2003 CL 001) and also reported in the supporting studies (CALGB 9221 and CALGB 8921) included febrile neutropenia (8.0 %) and anaemia (2.3 %). Other less frequently reported serious adverse reactions (< 2 %) included neutropenic sepsis, pneumonia, thrombocytopenia and haemorrhagic events (e.g. cerebral haemorrhage).The table below contains the adverse reactions for which a causal relationship with azacitidine treatment could reasonably be established. Frequencies given are based on the observations during the pivotal clinical study or two supporting clinical studies.Frequencies are defined as: very common ( 1/10), common ( 1/100 to < 1/10); uncommon ( 1/1,000 to < 1/100); rare ( 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.System Organ ClassVery commonCommonUncommonInfections and infestationspneumonia, nasopharyngitisneutropenic sepsis, upper respiratory tract infection, urinary tract infection, sinusitis, pharyngitis, rhinitis, herpes simplexImmune system disordershypersensitivity reactionsMetabolism and nutrition diseaseanorexiahypokalemiaPsychiatric disordersconfusional state, anxiety, insomniaNervous system disordersdizziness, headacheintracranial haemorrhage, lethargyEye disorderseye haemorrhage, conjunctival haemorrhageVascular disordershypertension, hypotension, haematomaRespiratory, thoracic and mediastinal disordersdyspnoeadyspnoea exertional, pharyngolaryngeal painGastrointestinal disordersdiarrhoea, vomiting, constipation, nausea, abdominal paingastrointestinal haemorrhage, haemorrhoidal haemorrhage, stomatitis, gingival bleeding, dyspepsiaSkin and subcutaneous tissue disorderspetechiae, pruritus, rash, ecchymosispurpura, alopecia, erythema, rash macularMusculoskeletal, and connective tissue disordersarthralgiamyalgia, musculoskeletal painRenal and urinary disordershaematuriaGeneral disorders and administration site conditionsfatigue, pyrexia, chest pain, injection site erythema, injection site pain, injection site reaction (unspecified) injection site: bruising, haematoma, induration, rash, pruritus, inflammation, discoloration, nodule and haemorrhage. malaiseInvestigationsWeight decreasedHaematologic adverse reactionsThe most commonly reported adverse reactions associated with azacitidine treatment were haematological including thrombocytopenia, neutropenia and leukopenia, and were usually Grade 3 or 4. There is a greater risk of these events occurring during the first 2 cycles, after which they occur with less frequency in patients with restoration of haematological function. Most haematological adverse reactions were managed by routine monitoring of complete blood counts and delaying azacitidine administration in the next cycle, prophylactic antibiotics and/or growth factor support (e.g. GCSF) for neutropenia and transfusions for anaemia or thromobocytopenia as required.InfectionsMyelosupression may lead to neutropenia and an increased risk of infection. Serious adverse reactions such as neutropenic sepsis (0.8 %) and pneumonia (2.5 %) were reported in patients receiving azacitidine. Infections may be managed with the use of anti-infectives plus growth factor support (e.g. GCSF) for neutropenia.Bleeding Bleeding may occur with patients receiving azacitidine. Serious adverse reactions such as gastrointestinal haemorrhage (0.8 %) and intracranial haemorrhage (0.5 %) have been reported. Patients should be monitored for signs and symptoms of bleeding, particularly those with pre-existing or treatment-related thrombocytopenia.HypersensitivitySerious hypersensitivity reactions (0.25 %) have been reported in patients receiving azacitidine. In case of an anaphylactic-like reaction, treatment with azacitidine should be immediately discontinued and appropriate symptomatic treatment initiated.Skin and subcutaneous tissue adverse reactionsThe majority of skin and subcutaneous adverse reactions were associated with the injection site. None of these adverse reactions led to temporary or permanent discontinuation of azacitidine, or reduction of azacitidine dose in the pivotal study. The majority of adverse reactions occurred during the first 2 cycles and tended to decrease with subsequent cycles. Subcutaneous adverse reactions such as injection site rash/inflammation/pruritus, rash, erythema and skin lesion may require management with concomitant medicinal products, such as antihistamines, corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs).Gastrointestinal adverse reactionsThe most commonly reported gastrointestinal adverse reactions associated with azacitidine treatment included constipation, diarrhoea, nausea and vomiting. These adverse reactions were managed symptomatically with anti-emetics for nausea and vomiting; antidiarrhoeals for diarrhoea, and laxatives and/or stool softeners for constipation.
Manufacturer
Celgene Europe Ltd
Drug Availability
(POM)
Updated
25 June 2009
