VI.2 Elements for a public summary VI.2.1 Overview of disease epidemiology Deferasirox is a medicine used to treat chronic iron overload (an excess of iron in the body). Chronic iron overload is a condition that occurs due to the inability to actively eliminate iron from the body. Chronic iron accumulation is most commonly due to either too much absorbed in the intestines (hemochromatosis) or too much iron administered by repeated transfusions (iron contained in red blood cells). Repeated transfusions can be necessary in patients with chronic anaemias, a condition of having less than the normal number of red blood cells or less than normal quantity of haemoglobin in the blood (e.g. thalassemia, sickle cell disease, myelodysplastic syndrome [a group of diseases and conditions that affect how blood is made], and a small portion of patients that have less severe clinical course that fall into the category of non-transfusion-dependent thalassemia NTDT). Chronic iron overload is a serious condition. Complications are related to iron deposits in tissues which can cause organ failure. This condition is life-threatening when the heart or the liver is affected. Chronic iron overload requiring therapy affects less than 5 in 10,000 people in the EU. Because the number of patients with chronic iron overload is low, the disease is considered rare. VI.2.2 Summary of treatment benefits Deferasirox is an Iron chelator. It attaches to excess iron in the body to form a compound called a chelate that can be excreted by the body, mainly in the stool. This helps to correct the iron overload and prevent damage to organs such as the heart or liver due to excess iron. In chronic iron overload due to blood transfusions, deferasirox was investigated in one main study comparing deferasirox with deferoxamine (another medicine used to treat iron overload) in 591 patients with beta-thalassemia major (an inherited blood disorder in which patients do not have enough haemoglobin in the blood). About half of the patients were under the age of 16, and 56 were less than six years old. The doctor and patients knew which medicine they were using because deferasirox is given by mouth but deferoxamine is given by subcutaneous infusion (very slow injection under the skin) overnight. The effectiveness was measured by looking at the level of iron contained in the liver before and after one year of treatment with the medicines. An additional study looked at the effectiveness of deferasirox in 184 patients who could not be treated with deferoxamine, including REG0197154 Version 4.0 Approved Page 41 of 113
patients with beta-thalassemia major and with other types of anaemia (low levels of haemoglobin in the blood). At the end of the main study in chronic iron overload due to blood transfusions, 53% of the patients receiving deferasirox had shown a sufficient response to treatment, compared with 66% of the patients receiving deferoxamine. This indicates that deferasirox may not have been as effective as deferoxamine. However, when looking at the 381 patients who had particularly high levels of iron in their liver at the beginning of the study and who received comparable amounts of deferasirox or deferoxamine, the two medicines were as effective as each other. There were too few patients in this study aged below six years to determine the safety and effectiveness of deferasirox in this age group. In the additional study, more than half of the patients who could not be treated with deferoxamine had responded to treatment with deferasirox after a year, including patients aged between two and five years. Deferasirox was also investigated in one main study involving 166 patients (including 21 patients aged from 10 to 18 years) from 10 years of age with non-transfusion-dependent thalassemia syndromes and iron overload. In this study, deferasirox was compared with placebo (a dummy treatment) and the main measure of effectiveness was the change in iron levels in the liver after 12 months of treatment. In this study, deferasirox was shown to be more effective than placebo at reducing iron levels in the liver: in patients treated with deferasirox (at a starting dose of 10 mg/kg/day) liver iron levels decreased on average by 3.8 mg per gram of liver compared with an average increase of 0.4 mg per gram of liver in patients treated with placebo. VI.2.3 Unknowns relating to treatment benefits Deferasirox has not been studied in pregnant women. As a precaution, it is recommended that deferasirox is not used during pregnancy unless clearly necessary. Fewer children than adults with transfusional iron overload have been studied. The understanding of the safety profile in these children is therefore considered limited. VI.2.4 Summary of safety concerns The most common side effect with deferasirox (seen in more than 1 patient in 10) is increased blood creatinine (a marker of kidney problems). For the full list of all side effects reported with deferasirox, see the package leaflet. Deferasirox must not be used in people who are hypersensitive (allergic) to deferasirox or any of the other ingredients, or in people whose creatinine clearance (a measure of the ability of the kidney to remove creatinine from the blood) is below 60 ml per minute. It must not be used in combination with other iron chelators. It is very important that the patient's kidneys and liver are checked with blood tests before treatment with deferasirox is started, and regularly during treatment. The dose should be reduced or treatment interrupted if a patient develops kidney or liver problems. Deferasirox is not recommended for patients with severe liver problems. If a severe skin reaction occurs or an allergic reaction is suspected, deferasirox should be discontinued. REG0197154 Version 4.0 Approved Page 42 of 113
Important identified risks Risk What is known Preventability Kidney disorders (Renal disorders) During clinical trials, increases in blood levels of creatinine (more precisely: serum creatinine) of greater than 33% (one-third) on at least 2 consecutive occasions, sometimes above the upper limit of the normal range, occurred in about 36% (36 out of 100) of patients. These were dosedependent. About two-third of the patients showing serum creatinine increase returned below the 33% level without dose adjustment. In the remaining third the serum creatinine increase did not always respond to a dose reduction or a dose interruption. Renal tubulopathy (sometimes called acquired Fanconi's syndrome) is a kidney disease where glucose (sugar), amino acids, uric acid, phosphate and bicarbonate pass into the urine instead of being reabsorbed back into the bloodstream. Regular blood and urine tests to monitor kidney function (blood level of creatinine, presence of protein in the urine, decrease in urine output). If diarrhoea and/or vomiting occur, adequate hydration needs to be maintained e.g. by drinking a lot. Increased liver enzymes (Increased liver transaminases) Renal tubulopathy is considered an uncommon adverse event (reported in between less than 1 out of 100 (1/100) and 1 out of 1,000 (1/1,000) patients. It has been mainly reported in children and adolescents with beta-thalassemia treated with deferasirox. Cases of acute kidney failure have been reported following the post-marketing use of deferasirox. There have been rare cases of acute kidney failure requiring dialysis. Liver function test abnormalities have been observed in approximately 2% of patients treated with deferasirox. Regular blood tests to monitor liver function. Monitoring for the following signs of liver problems: drowsiness, upper right abdominal pain, yellowing or increased yellowing of skin or eyes and dark urine. If there is persistent or progressive change, deferasirox may by interrupted or stopped. REG0197154 Version 4.0 Approved Page 43 of 113
Risk What is known Preventability Gastrointestinal bleeding and ulcers; inflammation of the oesophagus (oesophagitis) Hearing loss Eye disorders: clouding of the lens (lens opacities), retinal changes and inflammation of the optic nerve (optic neuritis) Stevens-Johnson syndrome and toxic epidermal necrolysis (a severe skin reaction) Upper gastrointestinal ulceration and bleeding have been reported in patients, including children and adolescents, receiving deferasirox. Multiple ulcers have been observed in some patients. There have been reports of fatal gastrointestinal bleeding, (resulting in death) especially in elderly patients who had blood cancers and/or low platelet counts. Physicians and patients should remain alert for signs and symptoms of gastrointestinal ulceration and haemorrhage during deferasirox therapy and promptly initiate additional evaluation and treatment if a serious gastrointestinal adverse reaction is suspected. Caution should be exercised in patients who are taking deferasirox in combination with substances that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, in patients receiving anticoagulants and in patients with platelet counts below 50000/mm 3 (50 x 10 9 /1) Auditory (decreased hearing) disturbances have been reported. Disorders of the eye and vision disturbances have been reported. Stevens-Johnson syndrome, a severe skin disorder, has been reported. Among cases reported as toxic epidermal necrolysis in the post-marketing setting, one case was diagnostically well established and associated with deferasirox. Patients should inform their doctor if low level of platelets are found in blood tests, or it they have recently taken any of the following: Certain painkillers, anti-inflammatory medicines (non-steroidal antiinflammatory drugs (NSAIDs)), like aspirin, ibuprofen, corticosteroids, oral bisphosphonates (used to treat osteoporosis), or anti-coagulant medicines. Auditory (hearing) testing is recommended before the start of treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during the treatment, dose reduction or interruption of deferasirox may be considered Eye tests are recommended before the start of treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during the treatment, dose reduction or interruption of deferasirox may be considered. Patients should inform their doctor immediately if they develop a rash, skin reddening, blistering of lips, eyes or mouth, skin peeling, sore throat (signs of severe skin reaction). Deferasirox should be discontinued in case of any severe skin or hypersensitivity reaction, including Stevens- Johnson syndrome and should not be reintroduced. REG0197154 Version 4.0 Approved Page 44 of 113
Risk What is known Preventability Liver failure (hepatic failure) Concomitant use of food Interaction with antacids (medicines used to treat heartburn) containing aluminium Effect of deferasirox on drugs that are metabolised by CYP3A4 (Induction of CYP3A4) Hepatic (liver) failure, sometimes fatal (resulting in death), have been reported in patients treated with deferasirox. Most reports of hepatic failure involved patients with significant illnesses including preexisting liver cirrhosis. The bioavailability (concentration in the blood) of deferasirox was increased to a variable extent when taken along with food. Deferasirox has significant affinity for aluminium therefore there is a potential to decrease the absorption of deferasirox from the intestines. Enzyme CYP3A may be inducted by chronic deferasirox treatment. The concomitant administration of deferasirox and midazolam (medicine that is metabolised by CYP3A4) resulted in a decrease of midazolam exposure. A slight reduction in blood levels for drugs metabolized by the CYP3A4 pathway could result in a decreased efficacy with drugs with a narrow therapeutic window. Deferasirox is not recommended in patients with severe liver disorders. In patients with moderate impairment of the liver, deferasirox must be used with caution. immediately if they experience a combination of drowsiness, upper right abdominal pain, yellowing or increased yellowing of your skin or eyes and dark urine (signs of liver problems). Liver function tests should be monitored before treatment, every 2 weeks during the first month and then every month Deferasirox must be taken on an empty stomach. At least 30 minutes must pass before eating any food. recently taken or might take antacids containing aluminium. Antacids containing aluminium should NOT be taken at the same time of day as deferasirox. recently taken or might take: - ciclosporin (used to prevent the body rejecting a transplanted organ or for other conditions, such as rheumatoid arthritis or atopic dermatitis), - simvastatin (used to lower cholesterol), - hormonal contraceptive agents (birth control medicines), - bepridil, ergotamine (used for heart problems and migraines). Caution should be exercised when deferasirox is combined with substances metabolised through CYP3A4 REG0197154 Version 4.0 Approved Page 45 of 113
Risk What is known Preventability Effect of deferasirox on drugs that are metabolised by CYP1A2 (Inhibition of CYP1A2) Interaction with medicines known to be UGT inducers (medicines like rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir that induce UGT enzymes responsible for metabolism of deferasirox) Deferasirox is an inhibitor of enzyme CYP1A2 that is involved in metabolism of certain drugs like theophylline. Concomitant use of deferasirox and theophylline increased theophylline concentration in the blood with long term dosing. An interaction between deferasirox and other CYP1A2 substrates like clozapine, tizanidine cannot be excluded. Deferasirox metabolism depends on UGT enzymes. Concomitant use of rifampicin, medicine known to induce UGT enzymes, resulted in decreased exposure to deferasirox. Decreased exposure to deferasirox may result with a decrease in deferasirox efficacy recently taken or might take: - theophylline (used to treat respiratory diseases such as asthma), - clozapine (used to treat psychiatric disorders such as schizophrenia), - tizanidine (used as a muscle relaxant). The concomitant use of deferasirox with theophylline is not recommended. If deferasirox and theophylline are used concomitantly, monitoring of theophylline concentration and theophylline dose reduction should be considered. For substances that are predominantly metabolised by CYP1A2 and that have a narrow therapeutic index (e.g. clozapine, tizanidine), the same recommendations apply as for theophylline. recently taken or might take: - rifampicin (used to treat tuberculosis) - phenytoin, phenobarbital, carbamazepine (used to treat epilepsy), - ritonavir (used in the treatment of HIV infection), The patient s serum ferritin should be monitored during and after the combination, and the dose of deferasirox adjusted if necessary. REG0197154 Version 4.0 Approved Page 46 of 113
Risk What is known Preventability Effect of deferasirox on drugs that are metabolised by CYP2C8 (Inhibition of CYP2C8) Interaction with cholestyramine (drug used to lower cholesterol levels in the blood) Deferasirox is moderate inhibitor of enzyme CYP2C8 that is involved in metabolism of certain drugs like repaglinide or paclitaxel. Concomitant use of deferasirox and repaglinide increased repaglinide concentration in the blood. An interaction between deferasirox and other CYP2C8 substrates like paclitaxel cannot be excluded. Cholestyramine reduces the absorption of deferasirox from the intestines. recently taken or might take: -repaglinide (used to treat diabetes), -paclitaxel (used in cancer treatment). Concomitant use of repaglinide should be avoided. If the combination appears necessary, careful clinical and blood glucose monitoring should be performed. recently taken or might take cholestyramine. Concomitant use of cholestyramine should be avoided. Important potential risks Risk Low blood counts (peripheral blood cytopenias) Non- compliance with posology and biological monitoring Medication errors Severe skin reactions (Drug reaction with eosinophilia and systemic symptoms, DRESS) What is known (Including reason why it is considered a potential risk) There have been post-marketing reports of leukopenia (low white blood cell count), thrombocytopenia (low platelet count) or pancytopenia (low red and white cell and platelet counts) (or worsening of these) and of worsening anaemia (low red blood cell count) in patients treated with deferasirox. Most of these patients had pre-existing blood disorders that are frequently associated with bone marrow failure. However, a contributory or aggravating role cannot be excluded. Interruption of treatment should be considered in patients who develop unexplained blood disorders The results of the blood and urine tests to monitor kidney and liver function, and hearing and eye examinations should be recorded and regularly assessed for trends Healthcare professionals and patients need to be aware of the risk of medication errors due to different formulations. A few cases DRESS have been reported, but the diagnosis has not been clearly confirmed. Currently, there is insufficient evidence that deferasirox causes these reactions. REG0197154 Version 4.0 Approved Page 47 of 113
Missing information Risk Long term safety in paediatric NTDT patients aged 10 to 17 years Safety in pregnant women What is known Fewer children than adults with transfusional iron overload have been studied. The understanding of the safety profile in these children is therefore considered limited. Deferasirox has not been studied in pregnant women. The potential risk is unknown. As a precaution, it is recommended that deferasirox is not used during pregnancy unless clearly necessary. VI.2.5 Summary of risk minimisation measures by safety concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the Patient Information Leaflet (PIL). The measures in these documents are known as routine risk minimisation measures. In addition, this medicine has special conditions and restrictions for its safe and effective use (additional risk minimisation measures). How they are implemented in each country will depend upon agreement between the manufacturer and the national authorities. These additional risk minimisation measures are for the following risks: Potential safety risk of non-compliance with posology and biological monitoring Medication errors Educational materials for physicians and patients Objective and rationale: To inform patients and caregivers about the risks of non-compliance with the posology and biological monitoring that needs to be performed before and during the treatment with deferasirox. To inform patients and caregivers about the risk of medication errors due to different formulations available on the market. To inform patients and caregivers about appropriate management of the risks to minimise its occurrence and its severity. REG0197154 Version 4.0 Approved Page 48 of 113
Educational materials for physicians and patients Summary description of main additional risk minimisation measures: The physician educational material should contain: The Summary of Product Characteristics Guide for healthcare professionals The Guide for healthcare professionals shall contain the following key elements: Description of available deferasirox formulations The recommended doses and the rules for starting treatment The need to monitor serum ferritin monthly That deferasirox causes rises in serum creatinine in some patients The importance of measuring creatinine clearance Brief overview of methods of measuring creatinine clearance That rises in serum transaminases may occur in patients treated with deferasirox The need for annual auditory and ophthalmic testing The need for a guidance table highlighting pre-treatment measurements of serum creatinine, creatinine clearance, proteinuria, hepatic enzymes, ferritin. Recommendations for treatment of non-transfusion-dependent thalassaemia (NTDT) syndromes. The patient information pack should contain: Patient information leaflet Patient guide Patient guide should contain the following key elements: Information on the need for regular monitoring, and when it should be carried out, of serum creatinine, creatinine clearance, proteinuria, hepatic enzymes, ferritin Information that renal biopsy may be considered if significant renal abnormalities occur Availability of several oral formulations and the main differences associated with these formulations (i.e., different posology regimen, different conditions of administration notably with food) Proposed action: Implementation (i.e. active or non-active) should be agreed on national basis, acknowledging that individual member states may have different market experiences and clinical practices. Exact format and content and way of distribution are to be discussed locally with the individual authorities prior to the launch, and can therefore be different from the text as described in Annex 10. VI.2.6 Planned post-authorisation development plan Not applicable. VI.2.7 Summary of changes to the risk management plan over time Not applicable for pre-approval versions. REG0197154 Version 4.0 Approved Page 49 of 113