Active ingredients: Deferasirox
EXJADE 125 mg dispersible tablets
EXJADE 250 mg dispersible tablets
EXJADE 500 mg dispersible tablets
Exjade package inserts are available for pack sizes: - EXJADE 125 mg dispersible tablets, EXJADE 250 mg dispersible tablets, EXJADE 500 mg dispersible tablets
- EXJADE 90 mg film-coated tablets, EXJADE 180 mg film-coated tablets, EXJADE 360 mg film-coated tablets
Why is Exjade used? What is it for?
What is EXJADE
EXJADE contains an active substance called deferasirox. It is an iron chelator that is a medicine used to remove excess iron from the body (iron overload). Deferasirox binds to excess iron and removes it by eliminating it mainly in the faeces.
What is EXJADE for
In patients with various forms of anemia (for example, thalassemia, sickle cell anemia or myelodysplastic syndromes (MDS), repeated blood transfusions may be required. These can, however, cause an excess of iron in the body. This is because the blood contains iron in the body. has no natural way to remove excess iron introduced by blood transfusions. In patients with thalassemia syndromes who are not receiving blood transfusions, iron overload can also develop over time, mainly due to increased blood pressure. Dietary iron absorption in response to low blood cell counts. Over time, excess iron can damage important organs such as the liver and heart. Medicines called iron chelators are used to eliminate iron. excess iron and reduce the risk that this can damage some organs.
EXJADE is used to treat iron overload due to frequent blood transfusions in patients with beta thalassemia major aged 6 years and older.
EXJADE is also used for the treatment of iron overload when deferoxamine therapy is contraindicated or inadequate in patients with beta thalassemia major with iron overload due to infrequent blood transfusions, in patients with other forms of anemia, and in children. aged between 2 and 5 years.
EXJADE is also used when deferoxamine therapy is contraindicated or inadequate for the treatment of patients 10 years of age and older who have iron overload associated with thalassemia syndromes but do not require blood transfusion.
Contraindications When Exjade should not be used
Do not take EXJADE
- if you are allergic to deferasirox or any of the other ingredients of this medicine. If this applies to you, tell your doctor before taking EXJADE. If you think you may be allergic, ask your doctor for advice.
- if you have moderate or severe kidney disease.
- if you are currently taking any other iron chelating medicines.
EXJADE is not recommended
- if you are in an advanced stage of myelodysplastic syndrome (MDS: decreased production of blood cells by the bone marrow) or have advanced cancer.
Precautions for use What you need to know before taking Exjade
Talk to your doctor or pharmacist before taking EXJADE:
- if you have a kidney or liver problem.
- if you have a heart problem due to iron overload.
- if you notice a marked reduction in your urine output (sign of kidney problem).
- if you have a severe skin rash, or difficulty breathing and dizziness or swelling especially of the face and throat (signs of a severe allergic reaction).
- if you have a rash, red skin, blistering of the lips, eyes or mouth, peeling of the skin, fever (signs of a severe skin reaction)
- if you experience a combination of sleepiness, pain in the right upper abdomen, yellowing or increased yellowing of the skin or eyes and dark urine (signs of liver problems).
- if you vomit blood and / or have black stools.
- if you experience frequent abdominal pain, particularly after eating or taking EXJADE.
- if you experience frequent heartburn.
- if you have low levels of platelets or white blood cells in blood tests.
- if you have blurred vision.
- if you have diarrhea or vomiting.
If any of these apply to you, tell your doctor immediately.
Monitoring of treatment with EXJADE
You will have regular blood and urine tests during your treatment. They will check the amount of iron in your body (ferritin level in your blood) to see how EXJADE is working. The tests will also check kidney function (blood creatinine level, presence of protein in the urine) and liver function (blood transaminase level). Your doctor may ask you to have a kidney biopsy if they suspect significant kidney damage. The liver may also be subjected to magnetic resonance imaging (MRI) tests to determine the amount of iron in the liver. Your doctor will evaluate these tests to decide which dose of EXJADE is most appropriate for you and will also use these tests to decide when to stop taking EXJADE.
As a precautionary measure, your sight and hearing will be examined every year during treatment.
Interactions Which drugs or foods may change the effect of Exjade
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. This applies in particular to:
- other iron chelators, which should not be taken with EXJADE,
- antacids (medicines used to treat heartburn) containing aluminum, which must not be taken at the same time of day as EXJADE,
- cyclosporine (used to prevent rejection of a transplanted organ or for other conditions such as rheumatoid arthritis or atopic dermatitis),
- simvastatin (used to lower cholesterol),
- some pain relievers or anti-inflammatory drugs (e.g. aspirin, ibuprofen, corticosteroids),
- oral bisphosphonates (used to treat osteoporosis),
- anticoagulant drugs (used to prevent or treat blood clotting),
- hormonal contraceptives (birth control drugs),
- bepridil, ergotamine (used for heart problems and migraines),
- repaglinide (used to treat diabetes),
- rifampicin (used to treat tuberculosis),
- phenytoin, phenobarbital, carbamazepine (used to treat epilepsy),
- ritonavir (used to treat HIV infection),
- paclitaxel (used in the treatment of cancer),
- theophylline (used to treat respiratory diseases such as asthma),
- clozapine (used to treat psychiatric disorders such as schizophrenia)
- tizanidine (used as a muscle relaxant),
- cholestyramine (used to lower blood cholesterol levels).
Additional tests may be needed to monitor the blood levels of some of these medicines.
Warnings It is important to know that:
Elderly (65 years of age or older)
EXJADE can be used by people aged 65 years and over at the same dose used in adults. Elderly patients may experience more side effects (especially diarrhea) than younger patients. They should be monitored closely by your doctor for side effects which may require dose adjustment.
Children and adolescents
EXJADE can be used in children and adolescents who receive regular blood transfusions aged 2 years and older and in children and adolescents who do not receive regular blood transfusions aged 10 years and older. The doctor will adjust the dose based on the patient's growth
EXJADE is not recommended for children under 2 years of age.
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.
EXJADE is not recommended during pregnancy unless strictly necessary.
If you are currently using an oral contraceptive or a contraceptive patch to prevent pregnancy, you must use an additional or different type of contraception (eg condoms), as EXJADE may reduce the effectiveness of oral and patch contraceptives.
Breastfeeding is not recommended during treatment with EXJADE.
Driving and using machines
If you feel dizzy after taking EXJADE, do not drive or use any tools or machines until you no longer feel dizzy.
EXJADE contains lactose
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Exjade: Posology
Treatment with EXJADE will be supervised by a doctor who has experience in the treatment of iron overload caused by blood transfusions.
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
How much EXJADE to take
- The dose of EXJADE is referred to body weight for all patients. Your doctor will calculate the dose you need and tell you how many tablets to take each day.
- The usual daily dose of EXJADE dispersible tablets at the start of treatment for patients receiving regular blood transfusions is 20 mg per kilogram of body weight. Your doctor may recommend a higher or lower starting dose based on the need for individual treatment.
- The usual daily dose of EXJADE dispersible tablets at the start of treatment for patients who do not receive regular blood transfusions is 10 mg per kilogram of body weight.
- Depending on how you respond to treatment, your doctor may subsequently modify your treatment by increasing or reducing the dose.
- The maximum recommended daily dose of EXJADE dispersible tablets is 40 mg per kilogram of body weight for patients receiving regular blood transfusions, 20 mg per kilogram of body weight for adult patients not receiving regular blood transfusions and 10 mg per kilogram of weight body for children and adolescents who do not receive regular blood transfusions.
Deferasirox is also available in the form of "film-coated" tablets. If you switch from the film-coated tablets to these dispersible tablets, a dose adjustment will be required.
When to take EXJADE
- Take EXJADE once a day, every day, at about the same time each day.
- Take EXJADE dispersible tablets on an empty stomach.
- So wait at least 30 minutes before eating any food. Taking EXJADE at the same time each day will also help you remember when to take your tablets.
How to take EXJADE
- Drop the tablet (s) into a glass of water, or apple or orange juice (100-200 ml).
- Mix until the tablet (s) are completely dissolved. In the glass, the liquid will appear cloudy.
- Drink all the contents of the glass. Then add some water or juice to the residue in the glass, mix and drink again.
Do not dissolve the tablets in fizzy drinks or milk. Do not chew, split or break the tablets. Do not swallow the tablets as they are.
How long to take EXJADE
Keep taking EXJADE every day for as long as your doctor tells you. This is a long-term treatment, which can last for months or years. Your disease will be checked regularly by your doctor to check that the treatment is effective (see also section 2: "Monitoring treatment with EXJADE").
If you have any questions about how long to take EXJADE, talk to your doctor.
If you forget to take EXJADE
If you forget to take a dose, take it as soon as you remember on that day. Take the next dose as planned. Do not take a double dose the following day to make up for the forgotten tablet (s).
If you stop taking EXJADE
Do not stop taking EXJADE unless your doctor tells you to. If you stop taking, the excess iron will no longer be removed from your body (see also above under "How long to take EXJADE").
Overdose What to do if you have taken too much Exjade
If you have taken too much EXJADE, or if someone else accidentally takes your tablets, contact your doctor or hospital immediately for advice. Show them the pack of tablets. You may need medical treatment.
Side Effects What are the side effects of Exjade
Like all medicines, this medicine can cause side effects, although not everybody gets them. Most side effects are mild to moderate and usually go away after a treatment period of between a few days and a few weeks.
Some side effects can be serious and require immediate medical attention.
These side effects are uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people).
- If you have a severe skin rash, or difficulty breathing and dizziness or swelling mainly of the face and throat (signs of a severe allergic reaction),
- If you have a severe rash, red skin, blistering of the lips, in the eyes or in the mouth, peeling of the skin, fever (signs of a severe skin reaction),
- If you notice a marked reduction in your urine output (sign of kidney problem),
- If you experience a combination of sleepiness, pain in the right upper abdomen, yellowing or increased yellowing of the skin or eyes and dark urine (signs of liver problems),
- If you vomit blood and / or have black stools,
- If you experience frequent abdominal pain, particularly after eating or taking EXJADE,
- If you experience frequent heartburn,
- If you experience partial loss of vision,
- If you experience severe pain in the upper abdomen (pancreatitis), stop taking this medicine and tell your doctor immediately.
Some side effects could become serious.
These side effects are uncommon.
- If you have blurred or blurred vision,
- If you have a decrease in hearing,
tell your doctor as soon as possible.
Other side effects
Very common (may affect more than 1 in 10 people)
- Changes in kidney function tests.
Common (may affect up to 1 in 10 people)
- Gastrointestinal disturbances, such as nausea, vomiting, diarrhea, abdominal pain, bloating, constipation, indigestion
- Rash
- Headache
- Abnormal liver function tests
- Itching
- Abnormal urine test (protein in urine)
If any of these affects you severely, tell your doctor.
Uncommon (may affect up to 1 in 100 people)
- Dizziness
- Fever
- Sore throat
- Swelling in the arms or legs
- Skin discolouration
- Anxiety
- Disorders of sleep
- Tiredness
If any of these effects occur severely, tell your doctor.
Frequency not known (frequency cannot be estimated from the available data).
- A reduction in the number of cells involved in blood clotting (thrombocytopenia), in the number of red blood cells (worsening of anemia), in the number of white blood cells (neutropenia) or in the number of all types of blood cells (pancytopenia)
- Hair loss
- Kidney stones
- Low urine output
- A tear in the wall of the stomach or intestines which can be painful and cause nausea
- Severe pain in the upper abdomen (pancreatitis)
- Increased acidity of the blood (metabolic acidosis).
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the blister after EXP and on the carton after EXP. The expiry date refers to the last day of that month.
- Store in the original package to protect from moisture.
- Do not use packaging that is damaged or shows signs of tampering.
- Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What EXJADE contains
The active ingredient is deferasirox.
Each dispersible tablet of EXJADE 125 mg contains 125 mg deferasirox.
Each dispersible tablet of EXJADE 250 mg contains 250 mg deferasirox.
Each dispersible tablet of EXJADE 500 mg contains 500 mg deferasirox.
The other ingredients are lactose monohydrate, crospovidone type A, povidone, sodium lauryl sulfate, microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate.
Description of what EXJADE looks like and contents of the package
EXJADE is supplied in the form of dispersible tablets. The tablets are off-white, round and flat.
- EXJADE 125 mg tablets are marked "J 125" on one side and "NVR" on the other.
- EXJADE 250 mg tablets are marked "J 250" on one side and "NVR" on the other.
- EXJADE 500 mg tablets are marked "J 500" on one side and "NVR" on the other.
EXJADE 125 mg, 250 mg and 500 mg dispersible tablets are available in unit packs containing 28, 84 or 252 dispersible tablets.
EXJADE 500 mg dispersible tablets are also available in multipacks containing 294 (3 packs of 98) dispersible tablets.
Not all pack sizes or strengths may be marketed in your country.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
EXJADE 125 MG DISPERSIBLE TABLETS
▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each dispersible tablet contains 125 mg of deferasirox.
Excipient:
Each dispersible tablet contains 136 mg of lactose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Dispersible tablet
Off-white, round, flat, bevelled-edged tablets debossed with NVR on one side and J 125 on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
EXJADE is indicated for the treatment of chronic iron overload due to frequent blood transfusions (≥7 ml / kg / month of concentrated red blood cells) in patients with beta thalassemia major aged 6 years and older.
EXJADE is also indicated for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups:
- in patients with beta thalassemia major with iron overload due to frequent blood transfusions (≥7 ml / kg / month of concentrated red blood cells) aged 2 to 5 years,
- in patients with beta thalassemia major with iron overload due to infrequent blood transfusions (
- in patients with other anemia aged 2 years and older.
EXJADE is also indicated for the treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-dependent thalassemia syndromes aged 10 years and older.
04.2 Posology and method of administration
Treatment with EXJADE should be initiated and maintained by physicians experienced in the treatment of chronic iron overload.
Posology - iron overload due to blood transfusions
It is recommended to initiate treatment after transfusion of approximately 20 units (approximately 100 ml / kg) of concentrated red blood cells or when clinical monitoring shows the presence of chronic iron overload (e.g. serum ferritin> 1,000 mcg / L ). Doses (in mg / kg) should be calculated and rounded to the nearest whole tablet.
The goals of iron chelation therapy are to eliminate the amount of iron given in transfusions and, as needed, to reduce the existing iron load.
Initial dose
The recommended starting daily dose of EXJADE is 20 mg / kg body weight.
A starting daily dose of 30 mg / kg may be considered for patients who need to reduce high body iron levels and who are also receiving more than 14 ml / kg / month of concentrated red blood cells (approximately> 4 units / month for a adult).
A starting daily dose of 10 mg / kg may be considered for patients who do not need to reduce body iron levels and who are also receiving less than 7 ml / kg / month of concentrated red blood cells (approximately
For patients already adequately treated with deferoxamine, a starting dose of EXJADE that is numerically half the dose of deferoxamine could be considered (e.g. a patient receiving 40 mg / kg / day of deferoxamine for 5 days per week (or equivalent ) could switch to a starting daily dose of 20 mg / kg / day of EXJADE). When this results in a daily dose of less than 20 mg / kg body weight, the patient's response should be monitored and, if sufficient efficacy is not achieved, an increase in dose should be considered (see section 5.1).
Dose adjustment
It is recommended to monitor serum ferritin every month and to adjust the dose of EXJADE, if necessary, every 3-6 months, based on the trend in serum ferritin values. Dose adjustments can be made in intervals between 5 and 10 mg / kg and should be adapted to the individual patient's response and therapeutic goals (maintenance or reduction of iron load) In patients inadequately controlled with doses of 30 mg / kg (e.g. serum ferritin levels persistently above 2,500 mcg / l and showing no decreasing trend over time), doses up to 40 mg / kg can be considered. The availability of long-term efficacy and safety data with EXJADE used at doses above 30 mg / kg is currently limited (264 patients followed on average for 1 year after dose escalation). If only very poor control of hemosiderosis is achieved at doses up to 30 mg / kg, a further increase (to a maximum of i 40 mg / kg) may not achieve satisfactory control, and alternative treatment options may be considered. If satisfactory control is not achieved at doses above 30 mg / kg, treatment at these doses should not be continued and alternative treatment options should be considered whenever possible. Doses above 40 mg / kg are not recommended as there is only limited experience with doses above this level.
In patients treated with doses above 30 mg / kg, dose reductions in ranges of 5 to 10 mg / kg should be considered when control has been achieved (e.g. serum ferritin levels persistently below 2,500 mcg / l and which show a decreasing trend over time). In patients whose serum ferritin level has reached the reference value (usually between 500 and 1,000 mcg / L), dose reductions in ranges of 5 to 10 mg / kg should be considered to maintain serum ferritin levels. within the reference range. If serum ferritin consistently falls below 500 mcg / L, treatment discontinuation should be considered (see section 4.4).
Posology - non-transfusion-dependent thalassemia syndromes
Chelation therapy should only be initiated when there is evidence of iron overload (liver iron concentration (LIC) ≥5 mg Fe / g / dw or serum ferritin consistently> 800 mcg / L). LIC is the best method for determining iron overload and should be used wherever it is available. Caution should be exercised in all patients during chelation therapy to minimize the risk of over-chelation.
Initial dose
In patients with non-transfusion-dependent thalassemia syndromes, the recommended starting daily dose of EXJADE is 10 mg / kg body weight.
Dose adjustment
It is recommended that serum ferritin be monitored monthly. After every 3-6 months of treatment, dose escalation in 5 to 10 mg / kg increments should be considered if the patient's LIC is ≥7 mg Fe / g dw, or if serum ferritin is consistently > 2000 mcg / l and does not show a decreasing trend, and if the patient tolerates the drug well. Doses above 20 mg / kg are not recommended because there is no experience with doses above this level in patients with non-transfusion-dependent thalassemia syndromes.
In patients in whom LIC has not been evaluated and serum ferritin is ≤2000 mcg / L, the dosage should not exceed 10 mg / kg.
For patients whose dose has been increased beyond 10 mg / kg, a dose reduction to 10 mg / kg or less is recommended when the LIC is
Discontinuation of treatment
Treatment should be stopped once a satisfactory body iron level has been reached (LIC
Particular categories of patients
Elderly patients (≥65 years old)
The dosage recommendations for elderly patients are the same as those described above. In clinical trials, elderly patients experienced a higher frequency of adverse reactions than younger patients (in particular, diarrhea) and should be monitored closely for adverse reactions that may require dose adjustment.
Pediatric population
The dosing recommendations for pediatric patients aged 2-17 years with iron overload due to blood transfusions are the same as for adult patients. Dose calculation should take into account the changes in weight of pediatric patients over time.
In children with iron overload from blood transfusions aged 2 to 5 years, the exposure is lower than in adults (see section 5.2). As a result, patients in this age group may require higher doses than required. in adults, however the starting dose should be the same as for adults, followed by individual titration.
In pediatric patients with non-transfusion-dependent thalassemia syndromes, the dosage should not exceed 10 mg / kg. In these patients, tighter control of LIC and serum ferritin is essential to avoid excessive chelation: in addition to monthly serum ferritin assessment, LIC should be checked every three months when serum ferritin is ≤800 mcg / L.
The safety and efficacy of EXJADE in infants from birth to 23 months of age have not been established. No data are available.
Patients with impaired renal function
EXJADE has not been studied in patients with renal impairment and is contraindicated in patients with estimated creatinine clearance.
Patients with impaired hepatic function
EXJADE is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the dose should be reduced considerably and followed by a progressive increase up to a limit of 50% (see sections 4.4 and 5.2), and EXJADE should be used with caution. in such patients. Hepatic function should be checked in all patients before treatment, every 2 weeks during the first month, and every month thereafter (see section 4.4).
Method of administration
For oral use.
EXJADE should be taken once daily on an empty stomach, at least 30 minutes before food, preferably at the same time each day (see sections 4.5 and 5.2).
The tablets are dissolved by mixing them in a glass of water or orange or apple juice (100-200 ml), until a fine suspension is obtained. After ingesting the suspension, any residue should be resuspended in a small amount of water or juice and swallowed. The tablets must not be chewed or swallowed whole (see also section 6.2).
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Combination with other iron chelating therapies as the safety of these combinations has not been established (see section 4.5).
Patients with estimated creatinine clearance
04.4 Special warnings and appropriate precautions for use
Kidney function:
EXJADE has only been studied in patients with baseline serum creatinine in the age-appropriate normal range.
During clinical trials, an increase of> 33% in serum creatinine on ≥2 consecutive occasions, sometimes above the upper limit of the normal range, occurred in approximately 36% of patients. This increase was dose dependent. About two-thirds of the patients who showed an increase in serum creatinine, it returned to levels below 33% without dose adjustment. In the remainder of the patients the increase in serum creatinine did not always respond to a reduction in dose or to Discontinuation of treatment Cases of acute renal failure have been reported following post-marketing use of EXJADE (see section 4.8). In some of these post-marketing cases, deterioration in renal function led to renal failure requiring temporary or permanent dialysis.
The causes of the increase in serum creatinine have not been elucidated. Therefore particular attention should be paid to monitoring serum creatinine in patients taking concomitantly renal-depressing medicinal products, and in patients receiving high doses of EXJADE and / or low frequency of blood transfusions (
It is recommended that serum creatinine be assessed twice before initiating therapy. Serum creatinine, creatinine clearance (estimated with Cockcroft-Gault formula or MDRD in adults and Schwartz formula in children) and / or plasma cystatin C levels should be monitored weekly for the first month after initiation or modification of therapy with EXJADE, and once a month thereafter. Patients with prior renal disorders and patients taking medicinal products that depress renal function may be at increased risk of complications. Care should be taken to maintain adequate hydration in patients who have diarrhea or vomiting.
Cases of metabolic acidosis have been reported during post-marketing treatment with EXJADE. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhea, or conditions in which acid-base imbalance is a known complication. In these populations the acid-base balance should be monitored as clinically indicated. Discontinuation of EXJADE transplantation should be considered in patients who develop metabolic acidosis.
For adult patients, the daily dose may be reduced by 10 mg / kg if an increase in serum creatinine of> 33% above the mean of pre-treatment values and a decrease in clearance are observed at two consecutive visits. creatinine estimated below the lower limit of the normal range (
If, after dose reduction, an increase in serum creatinine> 33% above the mean of pre-treatment values is observed in adult and pediatric patients and / or the calculated creatinine clearance falls below the lower limit of "normal range, treatment should be discontinued. Treatment may be resumed depending on individual clinical circumstances.
Proteinuria tests should be performed monthly. If necessary, other markers of renal tubular function may also be monitored (eg glycosuria in non-diabetic patients and low serum levels of potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria). Dose reduction or discontinuation of treatment may be considered if there are abnormalities in marker levels of tubular function and / or if clinically indicated. Renal tubulopathy has mainly been reported in children and adolescents with beta-thalassemia treated with EXJADE.
If, despite dose reduction or discontinuation of treatment, serum creatinine remains significantly elevated and if there is also a persistent abnormality in another marker of renal function (e.g. proteinuria, Fanconi syndrome), the patient should be referred to a nephrologist, and additional specialist tests (such as kidney biopsy) may be considered.
Liver function:
Elevation of liver function tests have been observed in patients treated with EXJADE. Post-marketing cases of hepatic failure, some with fatal outcome, have been reported in patients treated with EXJADE. Most cases of hepatic failure involved patients with significant morbidity, including pre-existing liver cirrhosis. However, the role of EXJADE as a contributing or aggravating factor cannot be excluded (see section 4.8).
It is recommended that serum transaminases, bilirubin and alkaline phosphatase be checked prior to initiation of treatment, every 2 weeks during the first month and then monthly. If there is a persistent and progressive increase in serum transaminase levels not attributable to other causes, EXJADE should Once the cause of the liver function test abnormalities has been clarified or after returning to normal levels, a cautious resumption of treatment at a lower dose, followed by a gradual increase in dose may be considered.
EXJADE is not recommended in patients with severe hepatic impairment (Child-Pugh Class C) (see section 5.2).
Summary of safety monitoring recommendations:
In patients with short life expectancy (e.g. high-risk myolodysplastic syndromes), particularly when concomitant morbidity may increase the risk of adverse events, the benefit of EXJADE may be limited and less than the risks. Consequently, treatment with EXJADE is not recommended in these patients.
Caution should be exercised in elderly patients due to a higher frequency of adverse reactions (in particular, diarrhea).
Data in children with non-transfusion-dependent thalassemia are very limited (see section 5.1). Consequently, in the pediatric population, EXJADE therapy should be monitored very closely for undesirable effects and to monitor iron load. Furthermore, before treating children with non-transfusion-dependent thalassemia and excessive iron overload with EXJADE, physicians should be aware that the consequences of long-term exposure in these patients are currently unknown.
Gastrointestinal disorders
Upper gastrointestinal ulcer and haemorrhage have been reported in patients receiving EXJADE, including children and adolescents. Multiple ulcers have been observed in some patients (see section 4.8). There have been reports of complicated ulcers with perforation of the digestive system. There have also been reports of fatal gastrointestinal bleeding, especially in elderly patients who had haematological malignancies and / or low platelet counts. Physicians and patients should be advised during therapy with EXJADE. pay attention to the onset of signs and symptoms of gastrointestinal ulceration and bleeding and promptly initiate evaluation and concomitant treatment if a serious gastrointestinal adverse reaction is suspected. Caution should be exercised in patients taking EXJADE in combination with substances that have recognized ulcerogenic potential, such as non-steroidal anti-inflammatory drugs, corticosteroids, or oral bisphosphonates, in patients on anticoagulants, and in patients with platelet counts lower than 50.000 / mm3 (50 x 109 / l) (see section 4.5).
Skin disorders
Skin rashes may appear during treatment with EXJADE. In most cases, the rashes resolve spontaneously. If treatment interruption is necessary, treatment can be resumed after the eruption has resolved, at a lower dose which can then be gradually increased. In severe cases, resumption of treatment can be done in conjunction with oral steroid administration for a short time. Cases of Stevens-Johnson syndrome (SJS) have been reported post-marketing. The risk of other more serious skin reactions [toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS)] cannot be excluded. If SJS or any other serious skin reaction is suspected, EXJADE should be discontinued immediately and should not be reintroduced.
Hypersensitivity reactions
Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving EXJADE, with the onset of the reaction occurring in the majority of cases within the first month of treatment (see section 4.8). If such reactions occur, EXJADE should be discontinued and appropriate medical intervention instituted. Due to the risk of anaphylactic shock, deferasirox should not be reintroduced in patients who have experienced a hypersensitivity reaction (see section 4.3).
Sight and hearing
Auditory (hearing loss) and ocular (lens opacity) disturbances have been reported (see section 4.8). It is recommended that auditory and ophthalmic examinations (including fundoscopy) be performed prior to initiation of treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during treatment, a dose reduction or discontinuation of treatment may be considered.
Blood disorders
In patients treated with EXJADE, there have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia (or worsening of these cytopenias) and worsening of anemia. Most of these patients had pre-existing haematological disorders which are frequently associated with insufficiency. However, a contributing or aggravating role of treatment cannot be excluded. Discontinuation of treatment should be considered in patients who develop cytopenia that is not attributable to any cause.
Other considerations
It is recommended that serum ferritin levels be monitored monthly to assess patient response to therapy (see section 4.2). If serum ferritin consistently falls below 500 mcg / l (in iron overload due to blood transfusions) or below 300 mcg / l (in non-transfusion-dependent thalassemia syndromes), the possibility of a "discontinuation of treatment" should be considered.
Results of serum creatinine, serum ferritin, and serum transaminase tests should be recorded and evaluated regularly to monitor their progress. The results should also be reported in the notebook provided to the patient.
In a clinical study, treatment with EXJADE for up to 5 years did not affect the growth and sexual development of treated pediatric patients. However, as a general precautionary measure for the management of pediatric patients with iron overload due to blood transfusions, body weight, growth and sexual development should be monitored at regular intervals (every 12 months).
Cardiac dysfunction is a known complication of severe iron overload. In patients with severe iron overload, cardiac function should be monitored during long-term treatment with EXJADE.
Each tablet contains 136 mg of lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, or severe lactase deficiency should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
The safety of EXJADE in combination with other iron chelators has not been established. Therefore it should not be combined with other iron chelating therapies (see section 4.3).
Co-administration of EXJADE with substances that have recognized ulcerogenic potential, such as non-steroidal anti-inflammatory drugs (including high-dose acetylsalicylic acid), oral corticosteroids or bisphosphonates may increase the risk of gastrointestinal toxicity (see section 4.4). Co-administration of EXJADE with anticoagulants may also increase the risk of gastrointestinal haemorrhage Close clinical monitoring is required when deferasirox is combined with these substances.
The bioavailability of deferasirox was variably increased when concomitant with food. EXJADE should therefore be taken on an empty stomach at least 30 minutes before food, preferably at the same time each day (see sections 4.2 and 5.2. ).
Deferasirox is metabolised by UGT enzymes. In a study in healthy volunteers, the concomitant administration of EXJADE (single dose of 30 mg / kg) and the potent UGT enzyme inducer rifampicin (repeated dose of 600 mg / day) resulted in a decrease in deferasirox exposure of the 44% (90% CI: 37% - 51%). Therefore, concomitant use of EXJADE with potent UGT enzyme inducers (eg rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir) may lead to decreased efficacy of EXJADE. The patient's serum ferritin should be monitored during and after. concomitant treatment and, if necessary, adjust the dose of EXJADE.
In a mechanistic study to determine the degree of enterohepatic recirculation, cholestyramine significantly reduced deferasirox exposure (see section 5.2).
In a study in healthy volunteers, the concomitant administration of EXJADE and midazolam (substrate of cytochrome CYP3A4) resulted in a decrease in midazolam exposure by 17% (90% CI: 8% - 26%). In clinical practice this effect may Therefore caution should be exercised when deferasirox is combined with drugs metabolised via CYP3A4 (eg cyclosporine, simvastatin, hormonal contraceptives, bepridil, ergotamine) given the possible reduction in their efficacy.
In a study in healthy volunteers, the concomitant administration of deferasirox as a moderate inhibitor of CYP2C8 (30 mg / kg / day) with CYP2C8 substrate repaglinide, given as a single dose of 0.5 mg, increased AUC and Cmax. repaglinide approximately 2.3 times (90% CI [2.03-2.63]) and 1.6 times (90% CI [1.42-1.84]), respectively. of repaglinide higher than 0.5 mg has not been determined, concomitant use of deferasirox with repaglinide should be avoided. Close clinical and blood glucose monitoring should be performed if the combination appears necessary (see section 4.4). An interaction between deferasirox and other CYP2C8 substrates such as paclitaxel cannot be excluded.
In a study in healthy volunteers, the concomitant administration of EXJADE as a CYP1A2 inhibitor (repeated dose of 30 mg / kg / day) and CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an increase in AUC. 84% theophylline (90% CI: 73% -95%). Single dose Cmax was not affected but, with chronic administration, an increase in theophylline Cmax is expected. Therefore, concomitant use of EXJADE and theophylline is not recommended. If EXJADE and theophylline are used concomitantly, monitoring of theophylline concentration and a reduction of theophylline dose should be considered. An interaction between EXJADE and other CYP1A2 substrates should not be considered. it can be excluded. The same recommendations regarding theophylline apply to substances which are predominantly metabolised by cytochrome CYP1A2 and which have a narrow therapeutic index (e.g. clozapine, tizanidine).
The concomitant administration of EXJADE and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, it is not recommended to take EXJADE tablets with aluminum-containing antacid preparations.
The concomitant administration of EXJADE and vitamin C has not been formally studied. Vitamin C doses of up to 200 mg per day have not been associated with adverse consequences.
No interaction was observed between EXJADE and digoxin in healthy adult volunteers.
04.6 Pregnancy and breastfeeding
Pregnancy
For deferasirox no clinical data on exposed pregnancies are available. Animal studies have shown reproductive toxicity at doses found to be maternally toxic (see section 5.3). The potential risk for humans is unknown.
As a precaution, it is recommended not to use EXJADE during pregnancy unless absolutely necessary.
EXJADE may reduce the efficacy of hormonal contraceptives (see section 4.5).
Feeding time
In animal studies, deferasirox was found to be rapidly and extensively excreted in human milk. No effects on offspring were observed. It is unknown whether deferasirox is excreted in human milk. Breastfeeding is not recommended while taking EXJADE.
Fertility
No fertility data are available for humans. In animals, no adverse effects on male or female fertility were found (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the effects of EXJADE on the ability to drive and use machines have been performed. Patients who experience dizziness, an uncommon adverse reaction, should exercise caution when driving or using machines (see paragraph 4.8).
04.8 Undesirable effects
Summary of the safety profile
The most frequent reactions reported during chronic treatment with EXJADE in adult and pediatric patients include gastrointestinal disturbances in approximately 26% of patients (mainly nausea, vomiting, diarrhea or abdominal pain) and rash in approximately 7% of patients. Diarrhea was most commonly reported in pediatric patients aged 2 to 5 years and in the elderly. These reactions are dose-dependent, mostly mild to moderate in intensity, usually transient and resolve in most cases even with continued treatment.
During clinical trials, approximately 36% of patients experienced increases in serum creatinine> 33% in two or more consecutive determinations, some times above the upper limit of the normal range. They were dose dependent. Approximately two-thirds of patients who experienced an increase in serum creatinine returned to below 33% without dose adjustment. In the remaining patients the increase in serum creatinine did not always respond to dose reduction or discontinuation of treatment. Indeed in some cases after dose reduction only stabilization of serum creatinine values was observed (see section 4.4).
In a retrospective meta-analysis of 2,102 adult and pediatric beta-thalassemia patients with transfusional iron overload (including patients with different characteristics such as transfusion intensity, dose and duration of treatment) treated in two randomized clinical trials and four open-label studies lasting up to five years, a decrease in mean creatinine clearance of 13.2% was observed in adult patients (95% CI: -14.4%, -12.1%; n = 935) and 9, 9% in pediatric patients (95% CI: -11.1%, -8.6%; n = 1,142) during the first year of treatment. In a subset of patients followed for more than one year (n = 250 up to five years) no further decrease in mean creatinine clearance levels was observed in subsequent years.
In a randomized, double-blind, placebo-controlled, one-year study in patients with non-transfusion-dependent thalassemia syndromes and iron overload, the most frequent study drug-related adverse events reported by patients treated with EXJADE 10 mg / kg / day were diarrhea (9.1%), rash (9.1%) and nausea (7.3%). Alterations in serum creatinine and creatinine clearance were reported in 5.5% and 1.8% of patients treated with EXJADE 10 mg / kg / day, respectively. Hepatic transaminase elevations greater than 2 times baseline and 5 times the upper limit of normal were reported in 1.8% of patients treated with EXJADE 10 mg / kg / day.
Table of adverse reactions
Adverse reactions are ranked below using the following convention: very common (≥1 / 10); common (≥1 / 100,
Table 1
1 Adverse reactions reported from post-marketing experience. They arise from spontaneous reports for which it is not always possible to safely establish the frequency or a causal relationship to drug exposure.
Gallstones and related biliary disorders have been reported in approximately 2% of patients.Elevation of transaminases was reported as an adverse drug reaction in 2% of patients. An increase in transaminases more than 10 times the upper limit of the normal range, indicative of hepatitis, was uncommon (0.3%). In post-marketing experience, hepatic failure, sometimes fatal, has been reported with EXJADE. , especially in patients with pre-existing liver cirrhosis (see section 4.4). Post-marketing cases of metabolic acidosis have been reported. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhea, or conditions in which acid-base imbalance is a known complication (see section 4.4). Severe acute pancreatitis can potentially present as a complication of gallstones (and related biliary disorders). As with other iron chelating treatments, high frequency hearing loss and clouding of the lens (early cataract) have been uncommonly observed in patients treated with EXJADE (see section 4.4).
Pediatric population
Diarrhea was reported more commonly in pediatric patients 2 to 5 years of age than in older patients.
Renal tubulopathy has mainly been reported in children and adolescents with beta-thalassemia treated with EXJADE.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.
04.9 Overdose
Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In one case, this led to subclinical hepatitis which resolved after a "discontinuation of treatment. Single doses of 80 mg / kg in iron-overloaded thalassemia patients caused mild nausea and diarrhea.
Acute signs of overdose may include nausea, vomiting, headache and diarrhea. Overdose can be treated by induction of emesis or gastric lavage, and with symptomatic treatment.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: iron chelating agent.
ATC code: V03AC03.
Mechanism of action
Deferasirox is an orally active chelator, highly selective for iron (III). It is a tridentate ligand that binds iron with high affinity in a 2: 1 ratio. Deferasirox promotes the excretion of iron, mainly in the faeces. Deferasirox has a low affinity for zinc and copper and does not cause a steady decrease in serum levels of these metals.
Pharmacodynamic effects
In an iron balance metabolic study in iron-overloaded adult thalassemia patients, EXJADE at daily doses of 10, 20 and 40 mg / kg induced mean net excretion of 0.119, 0.329 and 0.445 mg of Fe / kg, respectively. body weight / day.
Clinical efficacy and safety
EXJADE has been studied in 411 adult patients (age ≥16 years) and 292 pediatric patients (age 2 to sickle cell anemia and other congenital and acquired anemias (myelodysplastic syndromes, Diamond-Blackfan syndrome, aplastic anemia and other very rare anemias).
Daily treatment of frequently transfused adult and pediatric patients with beta-thalassemia at doses of 20 and 30 mg / kg for one year led to a reduction in total body iron indicators; hepatic iron concentration was reduced by approximately -0.4 and -8.9 mg Fe / g liver (dry weight from biopsy) on average, respectively, and serum ferritin was reduced by approximately -36 and -926 mcg / l, respectively on average. At these same doses the ratios of iron excretion to iron intake were 1.02 (indicating a net iron balance) and 1.67 (indicating a "net iron elimination), respectively. EXJADE induced similar responses in patients with Iron overload with other anemias. Daily doses of 10 mg / kg for one year can maintain hepatic iron and serum ferritin levels and induce a net iron balance in patients receiving infrequent transfusions or erythrocytoapheresis. Serum ferritin assessed with monthly monitoring reflected changes in hepatic iron concentration, indicating that the trend in serum ferritin can be used to monitor response to therapy. The limited clinical data (29 patients with normal cardiac function at baseline) with the use of MRI indicate that treatment with EXJADE 10-30 mg / kg / day for 1 year may also reduce iron levels in the heart (on average, the increase in MRI T2 * was from 18.3 to 23.0 milliseconds).
The main analysis of the pivotal comparison study conducted in 586 patients with beta thalassemia and iron overload due to blood transfusions did not demonstrate the non-inferiority of EXJADE to deferoxamine in the analysis of the total patient population. A post-hoc analysis of this study shows that in the subgroup of patients with hepatic iron concentration ≥7 mg Fe / g dry weight treated with EXJADE (20 and 30 mg / kg) or deferoxamine (35 to ≥50 mg / kg), the non-inferiority criteria were met. However in patients with hepatic iron concentration
Preclinical and clinical studies have shown that EXJADE can be active as deferoxamine when used in a 2: 1 dose ratio (e.g. a dose of EXJADE is numerically half the dose of deferoxamine). However, this dosing recommendation has not been prospectively evaluated in clinical trials.
In addition, in patients with hepatic iron concentration ≥7 mg Fe / g dry weight suffering from various rare anemias or sickle cell anemia, EXJADE up to 20 and 30 mg / kg causes a decrease in hepatic iron and serum ferritin concentrations comparable to as obtained in patients with beta thalassemia.
In patients with non-transfusion-dependent thalassemia syndromes and iron overload, treatment with EXJADE was evaluated in a one-year, randomized, double-blind, placebo-controlled study. The study compared the efficacy of two different deferasirox regimens (starting doses of 5 and 10 mg / kg / day, 55 patients in each arm) and corresponding placebo (56 patients). 145 adult patients and 21 pediatric patients. The primary efficacy parameter was the change in liver iron concentration (LIC) from baseline after 12 months of treatment. One of the secondary efficacy parameters was the change in serum ferritin between baseline and fourth trimester. starting dose of 10 mg / kg / day, EXJADE led to a reduction in total body iron indicators. On average, hepatic iron concentration decreased by 3.80 mg Fe / g / dry weight in patients treated with EXJADE (dose initial of 10 mg / kg / day) and increased by 0.38 mg Fe / g / dry weight in patients treated with placebo (p
The European Medicines Agency has deferred the obligation to submit the results of studies with EXJADE in one or more subsets of the pediatric population for the treatment of chronic iron overload requiring chelation therapy (see section 4.2 for information on pediatric use). .
05.2 Pharmacokinetic properties
Absorption
Deferasirox is absorbed after oral administration with a median time to maximum plasma concentration (Tmax) of approximately 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox from EXJADE tablets is approximately 70% compared to an intravenous dose. Total exposure (AUC) was approximately doubled when taken with a high-fat meal (fat content> 50% of calories) and increased by approximately 50% when taken with a standard meal. Bioavailability (AUC) deferasirox was moderately (approximately 13-25%) higher when taken 30 minutes before normal or high fat meals.
Distribution
Deferasirox is highly (99%) bound to plasma proteins, almost exclusively to serum albumin, and has a small volume of distribution of approximately 14 liters in adults.
Biotransformation
Glucuronidation is the major metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronides in the intestine and subsequent reabsorption (enterohepatic recirculation) is likely to occur: In a study in healthy volunteers, administration of cholestyramine following a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure. (AUC).
Deferasirox is mainly glucuronidated via UGT1A1 and to a lesser extent UGT1A3. The CYP450 catalysed (oxidative) metabolism of deferasirox appears to be minor in humans (approximately 8%). In vitro no inhibition of the metabolism of deferasirox by hydroxyurea was observed.
Elimination
Deferasirox and its metabolites are mainly excreted in the faeces (84% of the dose). The renal excretion of deferasirox and its metabolites is minimal (8% of the dose). The mean elimination half-life (t1 / 2) ranges from 8 to 16 hours. MRP2 and MXR transporters (BCRP) are involved in biliary excretion of deferasirox.
Linearity / Non-linearity
Under steady-state conditions, the Cmax and AUC0-24h of deferasirox increase approximately linearly with dose. With multiple dosing, exposure increases by an accumulation factor of 1.3 to 2.3.
Characteristics of patients
Pediatric patients
The overall exposure of adolescents (12 to ≤17 years) and children (2 to
Sex
Females have a moderately lower (17.5%) apparent clearance for deferasirox than males. As the dosage is adjusted on an individual basis according to the response, this is not expected to have clinical consequences.
Elderly patients
The pharmacokinetics of deferasirox have not been studied in elderly patients (aged 65 years and over).
Renal or hepatic insufficiency
The pharmacokinetics of deferasirox have not been studied in patients with renal insufficiency. The pharmacokinetics of deferasirox are unaffected by hepatic transaminase levels up to 5 times the upper limit of the normal range.
In a clinical study with single doses of 20 mg / kg deferasirox, the mean exposure increased by 16% in subjects with mild hepatic impairment (Child-Pugh Class A) and by 76% in subjects with moderate hepatic impairment. (Child-Pugh Class B) compared to subjects with normal hepatic function. In subjects with mild to moderate hepatic impairment the mean C of deferasirox increased by 22%. In subjects with severe hepatic impairment (Child -Pugh Class C) exposure increased 2.8-fold (see sections 4.2 and 4.4).
05.3 Preclinical safety data
Non-clinical data reveal no special risk for iron overload patients based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. The main findings were renal toxicity and lens opacity (cataract). Similar evidence was seen in newborn and juvenile animals. Renal toxicity is believed to be primarily due to iron loss in animals that did not have prior iron overload.
Genotoxicity tests in vitro were negative (Ames test, chromosomal aberration test) or positive (screen V79). Deferasirox caused the formation of micronuclei in vivo in the bone marrow, but not in the liver, in rats not given a load of iron at lethal doses. No such effects were observed in rats that were not given an iron load. Deferasirox was not carcinogenic when administered to rats in a 2-year study and p53 +/- transgenic heterozygous mice in a 6-month study.
The potential for reproductive toxicity was evaluated in rats and rabbits. Deferasirox was not teratogenic, but caused an increased frequency of skeletal changes and stillbirths in rats at high doses that were severely toxic to the non-iron overloaded mother. Deferasirox caused no other effects on fertility or reproduction.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Lactose monohydrate
Crospovidone type A
Microcrystalline cellulose
Povidone
Sodium lauryl sulfate
Anhydrous colloidal silica
Magnesium stearate
06.2 Incompatibility
Dispersion in carbonated drinks or milk is not recommended due to foaming and slow dispersion, respectively. The tablets should not be chewed or swallowed whole.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store in the original package to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package
PVC / PE / PVDC / Aluminum blisters.
Packs containing 28, 84 or 252 dispersible tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Europharm Limited
Frimley Business Park
Camberley GU16 7SR
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/06/356/001
037421017
EU / 1/06/356/002
037421029
EU / 1/06/356/007
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 28.08.2006
Date of latest renewal: 28.08.2011
10.0 DATE OF REVISION OF THE TEXT
D.CCE July 2015
