Dacogen 50 mg powder for concentrate for solution for infusion.

Contact details updated from Tel: +353 1 800 709 122 to Tel: +353 1 800 709 122, added medinfo@its.jnj.com

4.6     Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in menmales and womenfemales

Due to the genotoxic potential of decitabine (see section 5.3), wWomen of childbearing potential must use effective contraceptive measures and avoid becoming pregnant while being treated with Dacogen and for 6 months following completion of treatment.The time period following treatment with Dacogen where it is safe to become pregnant is unknown. Men should use effective contraceptive measures and be advised to not father a child while receiving Dacogen, and for 3 months following completion of treatment (see section 5.3).

The use of decitabine with hormonal contraceptives has not been studied.

Pregnancy

There are no adequate data on the use of Dacogen in pregnant women. Studies have shown that decitabine is teratogenic in rats and mice (see section 5.3). The potential risk for humans is unknown. Based on results from animal studies and its mechanism of action, Dacogen should not be used during pregnancy and in women of childbearing potential not using effective contraception. A pregnancy test should be performed on all women of childbearing potential before treatment is started. If Dacogen is used during pregnancy, or if a patient becomes pregnant while receiving this medicinal product, the patient should be apprised of the potential hazard to the foetus.

United Kingdom (Northern Ireland)

Janssen Sciences Ireland UC‑Cilag Ltd.

Tel: +44 1 494 567 444

If you are not sure if any of the above applies to you, talk to your doctor, pharmacist or nurse before using Dacogen.

Dacogen can cause a serious immune reaction called ‘differentiation syndrome’ (see section 4 ‘Possible side effects’).

4.       Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects may happen with this medicine.

Tell your doctor or nurse immediately if you notice any of the following serious side effects

• Fever: this may be a sign of an infection caused by low levels of white blood cells (very common).
• Chest pain or shortness of breath (with or without fever or cough): these may be signs of an infection of the lung called “pneumonia” (very common) or inflamed lungs (interstitial lung disease [frequency not known]) or cardiomyopathy (heart muscle disease [uncommon]) which can be accompanied with swelling of ankles, hands, legs and feet.
• Bleeding: including blood in the stools. This may be a sign of bleeding in the stomach or gut (common).
• Difficultly with moving, speaking or understanding or seeing; sudden severe headache, seizure, numbness or weakness in any part of the body. These may be signs of bleeding inside your head (common).
• Difficulty breathing, swelling of the lips, itching or rash: This may be due to an allergic (hypersensitivity) reaction (common).
• Serious immune reaction (differentiation syndrome) that may cause fever, cough, difficulty breathing, rash, decreased urine, hypotension (low blood pressure), swelling of the arms or legs and rapid weight gain (not known).

2        QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipients with known effect

Each vial contains 0.5 mmol potassium (E340) and 0.29 mmol sodium (E524).

4.4     Special warnings and precautions for use

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving decitabine. Differentiation syndrome may be fatal (see section 4.8). Treatment with high-dose IV corticosteroids and haemodynamic monitoring should be considered at first onset of symptoms or signs suggestive of differentiation syndrome. Temporary discontinuation of Dacogen should be considered until resolution of symptoms and if resumed, caution is advised.

4.8     Undesirable effects

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving decitabine. Differentiation syndrome may be fatal and symptoms and clinical findings include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary oedema, peripheral oedema, rapid weight gain, pleural effusions, pericardial effusions, hypotension and renal dysfunction. Differentiation syndrome may occur with or without concomitant leucocytosis. Capillary leak syndrome and coagulopathy can also occur (see section 4.4).

4.8     Undesirable effects

System Organ Class

5        PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Dacogen‑treated subjects (11%, 24/223) experienced worsening of hyperglycaemia compared with subjects in the TC arm (6%, 13/212).

4.4     Special warnings and precautions for use

Cardiac disease

Patients with a history of severe congestive heart failure or clinically unstable cardiac disease were excluded from clinical studies and therefore the safety and efficacy of Dacogen in these patients has not been established. Cases of cardiomyopathy with cardiac decompensation, in some cases reversible after treatment discontinuation, dose reduction or corrective treatment, have been reported in the postmarketing setting. Patients, especially those with cardiac disease history, should be monitored for signs and symptoms of heart failure

4.8     Undesirable effects

4.2     Posology and method of administration

Paediatric population

The safety and efficacy of Dacogen in children aged < 18 years have not yet been established. No data are availableDacogen should not be used in children with AML aged < 18 years, because efficacy was not established. Currently available data are described in sections 4.8, 5.1, and 5.2.

4.4     Special warnings and precautions for use

Excipients

This medicine contains 0.5 mmol potassium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicine contains less than 1 mmol (39 mg) of potassium per dose, i.e. essentially ‘potassium- free’.

This medicine contains 0.29 mmol (6.67 mg) sodium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicine contains between 13.8 mg‑138 mg (0.6‑6 mmol) sodium per dose (depending on the infusion fluid for dilution), equivalent to 0.7‑7% of the WHO recommended maximum daily intake of 2 g sodium for an adult. To be taken into consideration by patients on a controlled sodium diet.

4.8     Undesirable effects

Paediatric population

The safety assessment in paediatric patients is based on the limited safety data from a Phase I/II study to evaluate pharmacokinetics, safety and efficacy of Dacogen in paediatric patients (aged 1 to 14 years) with relapsed or refractory AML (n = 17) (see section 5.1). No new safety signal was observed in this paediatric study.

4.2     Posology and method of administration

Paediatric population

The safety and efficacy of Dacogen in children aged < 18 years have not yet been established. No data are availableDacogen should not be used in children with AML aged < 18 years, because efficacy was not established. Currently available data are described in sections 4.8, 5.1, and 5.2.

4.4     Special warnings and precautions for use

Excipients

This medicine contains 0.5 mmol potassium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicine contains less than 1 mmol (39 mg) of potassium per dose, i.e. essentially ‘potassium- free’.

This medicine contains 0.29 mmol (6.67 mg) sodium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicine contains between 13.8 mg‑138 mg (0.6‑6 mmol) sodium per dose (depending on the infusion fluid for dilution), equivalent to 0.7‑7% of the WHO recommended maximum daily intake of 2 g sodium for an adult. To be taken into consideration by patients on a controlled sodium diet.

4.8     Undesirable effects

Paediatric population

The safety assessment in paediatric patients is based on the limited safety data from a Phase I/II study to evaluate pharmacokinetics, safety and efficacy of Dacogen in paediatric patients (aged 1 to 14 years) with relapsed or refractory AML (n = 17) (see section 5.1). No new safety signal was observed in this paediatric study.

4.4     Special warnings and precautions for use

Hepatic impairment

Use in patients with hepatic impairment has not been established. Caution should be exercised in the administration of Dacogen to patients with hepatic impairment and patients should be monitored closely and in patients who develop signs or symptoms of hepatic impairment. Liver function tests should be performed prior to initiation of therapy and prior to each treatment cycle, and as clinically indicated (see sections 4.2 and 5.2).

Renal impairment

Use in patients with severe renal impairment has not been studied. Caution should be exercised in the administration of Dacogen to patients with severe renal impairment (Creatinine Clearance [CrCl] < 30 ml/min) and these patients should be monitored closely. Renal function tests should be performed prior to initiation of therapy and prior to each treatment cycle, and as clinically indicated (see section 4.2).

4.8     Undesirable effects

6.6          Special precautions for disposal and other handling

Reconstitution procedure

The powder should be aseptically reconstituted with 10 ml of water for injections. Upon reconstitution, each ml contains approximately 5 mg of decitabine at pH 6.7 to 7.3. Within 15 minutes of reconstitution, the solution must be further diluted with cold infusion fluids (sodium chloride 9 mg/ml [0.9%] solution for injection or 5% glucose solution for injection) to a final concentration of 0.15 to 1.0 mg/ml. For the shelf-life and the precaution for storage after reconstitution, see section 6.3.

Removal of black triangle statement.

Administrative chnages to sections 4.2, 4.3, 4.5, 4.6, 4.7, 4.8,  6.5, 6.6,  9 and 10

2          QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of powder for concentrate for solution for infusion contains 50 mg decitabine.

4.4       Special warnings and precautions for use

Excipients

This medicine contains 0.5 mmol potassium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicine contains less than 1 mmol (39 mg) of potassium per dose, i.e. essentially ‘potassium- free’.between 1-10 mmol potassium per dose depending on the infusion fluid for dilution. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

.4         Special warnings and precautions for use

Respiratory, thoracic and mediastinal disorders

Cases of interstitial lung disease (ILD) (including pulmonary infiltrates, oganising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving decitabine. Careful assessment of patients with an acute onset or unexplained worsening of pulmonary symptoms should be performed to exclude ILD. If ILD is confirmed, appropriate treatment should be initiated (see section 4.8).

4.8       Undesirable effects

Respiratory, thoracic and mediastinal disorders

Cases of interstitial lung disease (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving decitabine.

4.1     Therapeutic indications

Dacogen is indicated for the treatment of adult patients aged 65 years and above with newly diagnosed de novo or secondary acute myeloid leukaemia (AML), according to the World Health Organisation (WHO) classification, who are not candidates for standard induction chemotherapy.

Reconstituted and diluted solution

Within 15 minutes of reconstitution, Tthe concentrate (in 10 ml of sterile water for injections) must be further diluted within 15 minutes using infusion fluids after reconstitution. The prepared diluted solution for intravenous infusion can be stored at room temperature (20°C - 25°C) for up to a maximum of 2 hours before administration.

If administration of the diluted solution for intravenous infusion is not intended to start within 2 hours, the concentrate must be diluted within 15 minutes of reconstitution using pre-cooled with cold (2°C - 8°C) infusion fluids. This prepared diluted solution for intravenous infusion mustcan be stored refrigerated at 2°C - 8°C for up to a maximum of 73 hours, and can then be stored followed by up to 1 hour at room temperature (20°C - 25°C) for up to 2 hours before administration.

From a microbiological point of view, the product should be used within the time period recommended above. It is the responsibility of the user to follow the recommended storage times and conditions and ensure that reconstitution has taken place in aseptic conditions.

6.6     Special precautions for disposal and other handling

Reconstitution procedure

The powder should be aseptically reconstituted with 10 ml of water for injections. Upon reconstitution, each ml contains approximately 5 mg of decitabine at pH 6.7 to 7.3. Immediately afterWithin 15 minutes of reconstitution, the solution shouldmust be further diluted with cold infusion fluids [sodium chloride 9 mg/ml (0.9%) solution for injection or, 5% glucose solution for injection], or Lactated Ringer’s solution for injection to a final concentration of 0.1 to 1.0 mg/ml. For the shelf-life and the precaution for storage after reconstitution, see section 6.3.

Section 4.8

IMB name changed to HPRA

Addition of enterocolitis, including neutropaenic colitis and caecitis as 'not known' ADRs

4.4     Special warnings and precautions for use

Myelosuppression

Myelosuppression and complications of myelosuppression, including infections and bleeding that occur in patients with AML may be exacerbated with Dacogen treatment. Therefore patients are at increased risk for severe infections (due to any pathogen such as bacterial, fungal and viral), with potentially fatal outcome (see section 4.8). Patients should be monitored for signs and symptoms of infection and treated promptly.

In clinical studies, the majority of patients had baseline Grade 3/4 myelosuppression. In patients with baseline Grade 2 abnormalities, worsening of myelosuppression was seen in most patients and more frequently than in patients with baseline Grade 1 or 0 abnormalities. Myelosuppression caused by Dacogen is reversible. Complete blood and platelet counts should be performed regularly, as clinically indicated and prior to each treatment cycle. In the presence of myelosuppression or its complications, treatment with Dacogen may be interrupted and/or supportive measures instituted (see sections 4.2 and 4.8).

4.8     Undesirable effects

^b     Excluding pneumonia, urinary tract infection, sepsis, septic shock and sinusitis.

^c     The most frequently reported "other infections" in study DACO-016 were: oral herpes, oral candidiasis, pharyngitis, upper respiratory tract infection, cellulitis, bronchitis, nasopharyngitis.

Description of selected adverse drug reactions

Haematologic adverse drug reactions

The most commonly reported haematologic adverse drug reactions associated with Dacogen treatment included febrile neutropenia, thrombocytopenia, neutropenia, anaemia and leukopenia.

Serious bleeding-related adverse drug reactions, some of which lead to a fatal outcome, such as central nervous system (CNS) haemorrhage (2%) and gastrointestinal (GI) haemorrhage (2%), in the context of severe thrombocytopenia, were reported in patients receiving Dacogen.

Haematological adverse drug reactions should be managed by routine monitoring of complete blood counts and early administration of supportive treatments as required. Supportive treatments include, administration of prophylactic antibiotics and/or growth factor support (e.g., G-CSF) for neutropenia and transfusions for anaemia or thrombocytopenia according to institutional guidelines. For situations where decitabine administration should be delayed, see section 4.2.

Infections and infestations adverse drug reactions

Serious infection-related adverse drug reactions, with potentially fatal outcome, such as septic shock, sepsis, pneumonia, and other infections (viral, bacterial and fungal) were reported in patients receiving Dacogen.