Azacitidine 150 mg Accord Injection

AZACITIDINE 150 mg ACCORD is indicated for treatment of patients with 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 and chronic myelomonocytic leukaemia.

AZACITIDINE 150 mg ACCORD should be administered under the supervision of a doctor qualified in the use of cytotoxic medicines.

Posology

The recommended starting dose is 75 mg/m2 subcutaneously, daily for seven days, every four weeks. Patients should be pre-medicated for nausea and vomiting. The dose may be increased to 100 mg/m2 if no beneficial effect is seen after two treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is recommended that patients be treated for a minimum of 4 cycles. However, a complete or partial response may require more than 4 treatment cycles. Treatment may be continued as long as the patient continues to benefit.

Patients should be monitored for a haematologic response and renal toxicities, and dosage delay or reduction as described below may be necessary.

Dosage adjustment based on haematology laboratory values:

• For patients with baseline (start of treatment) WBC u2265 3,0 x 109/L, ANC u2265 1,5 x 109/L and platelets u2265 75,0 x 109/L, adjust the dose as follows, based on nadir counts for any given cycle:

Nadir counts % Dose in the next course

• ANC (x109/L)
• < 0,5 0%
• 0,5 u2013 1,5 67%
• > 1,5 100%

Platelets (x109/L)

• < 25,0 50%
• 25,0 u2013 50,0 67%
• > 50,0 100%

For patients whose baseline counts are WBC < 3,0 x109/L, ANC < 1,5 x109/L, or platelets < 75,0 x 109/L, dose adjustments should be based on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case the dose of the current treatment should be continued.

WBC or platelet nadir % decrease in counts from baseline

• Bone marrow biopsy cellularity at time of nadir (%)

30 u2013 60 50 u2013 75

• % Dose in the next course

100 50

• 15 - 30 33
• < 15 75

Electrolytes: If unexplained elevations of serum creatinine or blood urea 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 course. Similarly, if unexplained reductions in serum bicarbonate levels to less than 20 mEq/L occur, the dosage should be reduced by 50% on the next course.

Laboratory tests: Liver chemistries and serum creatinine should be obtained prior to initiation of therapy. Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle.

Special populations

Patients with renal impairment No studies have been conducted in myelodysplastic syndrome (MDS) patients with decreased renal function. Since AZACITIDINE 150 mg ACCORD and its metabolites are primarily excreted by the kidneys, patients with renal impairment should be monitored closely and the dose adjusted as described.

Patients with hepatic impairment No studies have been conducted in MDS patients with hepatic impairment. Since AZACITIDINE 150 mg ACCORD may be metabolised in the liver and is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution is needed in patients with liver disease.

Elderly AZACITIDINE 150 mg ACCORD and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to AZACITIDINE 150 mg ACCORD may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Paediatric population The safety and efficacy of AZACITIDINE 150 mg ACCORD in children and adolescents under 18 years of age has not been established.

Method of administration Reconstituted AZACITIDINE 150 mg ACCORD should be injected subcutaneously. Rotate sites for injection (thigh, abdomen, or upper arm). New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, red, or hard. For instructions on reconstitution and dilution see section 6.6.

• Hypersensitivity to azacitidine or to any of the excipients in AZACITIDINE 150 mg ACCORD (see section 6.1)
• Patients with advanced malignant hepatic tumours
• Patients with severe renal impairment (creatinine clearance < 30 mLs/min)
• Pregnancy and lactation (see section 4.6)
• Children under the age of 18 years (see section 4.2)

Haematological toxicity Treatment with azacitidine is associated with anaemia, neutropenia and thrombocytopenia, particularly during the first 2 cycles (see section 4.8). 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 response (see section 4.2).

Patients should be advised to promptly report febrile episodes. Patients and medical practitioners are also advised to be observant for signs and symptoms of bleeding.

Hepatic impairment No formal studies have been conducted in patients with hepatic impairment. Patients with extensive tumour burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline serum albumin < 30 g/L. AZACITIDINE 150 mg ACCORD is contraindicated in patients with advanced malignant hepatic tumours (see section 4.3).

Renal impairment Renal abnormalities ranging from elevated serum creatinine to renal failure and death were reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic medicines for non-MDS conditions. 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 patients 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 (see section 4.2). Patients should be advised to report oliguria and anuria to the medical professional immediately.

Although no clinically relevant differences in the frequency of adverse reactions were noted between subjects with normal renal function compared to those with renal impairment, patients with renal impairment should be closely monitored for toxicity since azacitidine and/or its metabolites are primarily excreted by the kidney (see section 4.2).

Laboratory tests Liver function tests, serum creatinine and serum bicarbonate 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, see section 4.8.

Cardiac and pulmonary disease Patients with a known history of cardiovascular or pulmonary disease showed a significantly increased incidence of cardiac events with azacitidine (see section 4.8). It is therefore advised to exercise caution when prescribing azacitidine to these patients. Cardiopulmonary assessment before and during the treatment should be considered.

Necrotising fasciitis Necrotising fasciitis, including fatal cases, have been reported in patients treated with azacitidine. AZACITIDINE 150 mg ACCORD therapy should be discontinued in patients who develop necrotising fasciitis and appropriate treatment should be promptly initiated.

Tumour lysis syndrome The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

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 (see section 5.2). No formal clinical drug interaction studies with azacitidine have been conducted.

Women of childbearing potential Women of child bearing age and men should use effective contraception during and up to 3 months after treatment.

Pregnancy Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with AZACITIDINE 150 mg ACCORD. There is no adequate data on the use of AZACITIDINE 150 mg ACCORD in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. AZACITIDINE 150 mg ACCORD should not be used during pregnancy (see section 4.3), if the patient becomes pregnant while taking AZACITIDINE 150 mg ACCORD the patient should be informed of the potential hazard to the foetus.

Lactation It is not known whether azacitidine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for AZACITIDINE 150 mg ACCORD in animal studies and the potential for serious adverse reactions, women treated with AZACITIDINE 150 mg ACCORD should not breastfeed (see section 4.3).

Fertility Men should be advised not to father a child while receiving treatment with AZACITIDINE 150 mg ACCORD.

Since AZACITIDINE 150 mg ACCORD may cause blurred vision and less frequently somnolence and fatigue (see section 4.8), the ability to drive and operate machines may be negatively affected.

Table 1: Undesirable effects as per System Organ Class

SYSTEM ORGAN CLASS INCIDENCE ADVERSE REACTION

Infections and infestations Frequent Pneumonia* (including bacterial, viral and fungal), nasopharyngitis, sepsis* (including bacterial, viral and fungal), neutropenic sepsis*, respiratory tract infection (includes upper and bronchitis), urinary tract infection, cellulitis, diverticulitis, oral fungal infection, sinusitis, pharyngitis, rhinitis, herpes simplex, skin infection

Unknown frequency Necrotising fasciitis*

Blood and lymphatic system disorders Frequent Febrile neutropenia*, neutropenia, leukopenia, thrombocytopenia, anaemia, pancytopenia*, bone marrow failure

Immune system disorders Less frequent Hypersensitivity reactions

Metabolism and nutrition disorders Frequent Anorexia, decreased appetite, hypokalemia, dehydration

Less frequent Tumour lysis syndrome

Psychiatric disorders Frequent Insomnia, confusional state, anxiety

Nervous system disorders Frequent Dizziness, headache, intracranial haemorrhage*, syncope, somnolence, lethargy, burning sensation, hypoesthesia

Frequency unknown Neurotoxicity

Eye disorders Frequent Eye haemorrhage, conjunctival haemorrhage

Cardiac disorders Frequent Pericardial effusion

Less frequent Pericarditis

Vascular disorders Frequent Hypotension*, hypertension, orthostatic hypotension, haematoma, flushing

Respiratory, thoracic and mediastinal disorders Frequent Dyspnoea, epistaxis, pleural effusion, dyspnoea exertional, pharyngolaryngeal pain, nasal congestion

Less frequent interstitial lung disease

Gastro-intestinal disorders Frequent Diarrhoea, vomiting, constipation, nausea, abdominal pain (includes upper and abdominal discomfort), gastrointestinal haemorrhage* (includes mouth haemorrhage), haemorrhoidal haemorrhage, stomatitis, gingival bleeding, dyspepsia

Less frequent Peri-rectal abscess

Hepatobiliary disorders Less frequent Hepatic failure*, progressive hepatic coma

Skin and subcutaneous tissue disorders Frequent Petechiae, pruritus (includes generalized), rash, ecchymosis, purpura, alopecia, urticaria, erythema, rash macular, increased sweating

Less frequent Acute febrile neutrophilic dermatosis, pyoderma gangrenosum

Musculoskeletal and connective tissue disorders Frequent Arthralgia, musculoskeletal pain (includes back, bone and pain in extremity), muscle spasms, myalgia

Renal and urinary disorders Frequent Renal failure*, haematuria, elevated serum creatinine, dysuria

Less frequent Renal tubular acidosis

General disorders and administrative site conditions Frequent Pyrexia*, fatigue, asthenia, chest pain, injection site erythema, injection site pain, injection site reaction (unspecified), bruising, haematoma, induration, rash, pruritus, inflammation, discoloration, nodule and haemorrhage (at injection site), malaise, chills, catheter site hemorrhage

Less frequent injection site necrosis (at injection site)

Investigations Frequent Weight decreased, increased blood creatine (* = rarely fatal cases have been reported)

Description of selected adverse reactions

Haematologic adverse reactions The most commonly reported haematological adverse reactions associated with azacitidine treatment include anaemia, thrombocytopenia, neutropenia, febrile 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. G-CSF) for neutropenia and transfusions for anaemia or thrombocytopenia as required.

Infections Myelosuppression may lead to neutropenia and an increased risk of infection. Serious adverse reactions such as sepsis, including neutropenic sepsis, and pneumonia were reported in patients receiving azacitidine, some with a fatal outcome. Infections may be managed with the use of antiinfectives plus growth factor support (e.g. G-CSF) for neutropenia.

Bleeding Bleeding may occur with patients receiving azacitidine. Serious adverse reactions such as gastrointestinal haemorrhage and intracranial haemorrhage have been reported. Patients should be monitored for signs and symptoms of bleeding, particularly those with pre-existing or treatment related thrombocytopenia.

Hypersensitivity Serious hypersensitivity reactions 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 reactions The majority of skin and subcutaneous adverse reactions were associated with the injection site. None of these adverse reactions led to discontinuation of azacitidine, or reduction of azacitidine dose in the pivotal studies. The majority of adverse reactions occurred during the first 2 cycles of treatment 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 medicines, such as antihistamines, corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). These cutaneous reactions have to be distinguished from soft tissue infections, sometimes occurring at injection site. Soft tissue infections, including cellulitis and necrotising fasciitis in rare cases leading to death, have been reported with azacitidine in the post marketing setting. For clinical management of infectious adverse reactions, see section-4.8 Infections

Gastrointestinal adverse reactions The 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; anti-diarrhoeals for diarrhoea, and laxatives and/or stool softeners for constipation.

Renal adverse reactions Renal abnormalities, ranging from elevated serum creatinine and haematuria to renal tubular acidosis, renal failure and death were reported in patients treated with azacitidine (see section-4.4).

Hepatic adverse reactions Patients with extensive tumour burden due to metastatic disease have been reported to experience hepatic failure, progressive hepatic coma and death during azacitidine treatment (see section-4.4).

Cardiac events Patients with known history of cardiovascular or pulmonary disease showed an increase in cardiac events in patients with newly diagnosed AML treated with azacitidine (see section 4.4).

Symptoms of overdosage may include diarrhoea, nausea and vomiting. In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for AZACITIDINE 150 mg ACCORD overdosage.