IRON CHELATON MEDICINE

Desferal….. Deferoxamine

Kelfer ... L1, Deferiprone, DFP, ferriprox

Exjade ... Asunra (Exjade) and Desirox (Exjade by Cipla) Deferasirox, ICL 670,

Desirox and Asurna is the same drug being marketed under different names.

Desirox and Asurna by Cipla and Novartis respectively

Exjade is being released in India Cipla and Novartis. EXJADE is named ASUNRA in INDIA & Is by NOVARTIS.

Cipla is marketing the drug under the marketing name of Desirox in 250mg and 500mg packaging.

Serrum Ferritin, Serrum Creatinine, LFT, and Protein Urea so to know how the drug is working.

Kidney (which is reflected in the creatinine levels).

Exjade (Deferasirox) removes iron in stool and Deferoxamine (Desferal) which removes iron both in stool and urine

IRON OVERLOADIn thalassemia major, due to increased activity of bone marrow, body absorbs increased quantities of iron, as much as 3-4 mg/day depending upon severity of anemia. Absorption depends upon iron content in food & it may increase up to 10 mg/day if iron tonics are given.On an average each unit of blood contains 200-250 mg of iron. A patient receiving 15-30 unit of blood/year receives between 3-6gm of iron i.e. about 3-6 times the normal annual iron requirement of 1gm.There is a tremendous range of variability in end organ toxicity among patients who seemingly have the same amount of tissue iron i.e. end organ function, as well as tissue iron concentration, must be serially monitored during the management of chronic iron overload. Iron loading of the liver can be detected after about six months of monthly transfusions, while cardiac loading takes about eight to ten years. The liver loads linearly with time, whereas the heart remains devoid of iron for years. However, once it starts, iron loading of the heart is very rapid. Evidence of liver dam*age can occur after about four years of transfusions. Evaluation of Iron OverloadI Serum Ferritin: Serum iron & TIBC are of no value to know iron overload. Serum ferritin reflects iron stores in the body tissues and is a good indicator of iron storage status. Serum ferritin levels are disproportionately increased in fever, infections, chronic liver disease, arthritis etc. and decreased in vitamin C deficiency. It is a convenient way to monitor iron over*load. The change in ferritin is a reasonable predictor of change in total body iron. While there is about a 70 percent correlation of ferritin with LIC (liver Iron concentration) in population studies, there is tremendous scatter in the relation, so fer*ritin is a poor marker of absolute iron content in an individual patientII Liver biopsy: Liver biopsy & quantitative measurement of liver iron, is highly reliable though it is invasive and entails elevated risk. It should be reserved only for special indications. The LIC is reported in wet weight and dry weight. The LIC in patients with thalassemia should always be maintained below 7,000 µg/g dry weight and 1,100 µg/g wet weight in order to avoid iron-induced organ damage

III MRI T2*MRI has enabled to measure the amount of iron in the organs and tissue-specific factors. The onset of cardiac dysfunction is more complex and less well understood. A cardiac T2* greater than 20 ms is not associated with iron-induced cardiac dysfunction. A car*diac T2* between 10 and 20 ms indicates excess iron in the heart and represents a warning for potential cardiac dysfunction. If the T2* is less than 10 ms, the risk of cardiac dysfunction is high, and treatment should be considered emergent. Under full chelation with desferioxamine, about 50 per*cent of liver iron can be removed in four to six months. It takes about 17 months to remove half of the heart iron. IV SQUID - Superconducting QUantum Interference Device (Ferritometer)It is non-invasive, sensitive, and accurate, works on high-power magnetic field. Iron interferes with the field and changes in the field are detected. It is an effective way to non-invasively monitor LIC. This device is not easily available. Only 4 machines are available worldwideIRON CHELATIONWhen to start Chelation? Serum ferritin levels should be assessed after 12-15 transfusions. Chelation therapy should be initiated when serum ferritin is above 1000ng/ml.1. DESFERAL (Desferioxamine)Dose 25-50 mg/kg/day subcutaneous with the help of infusion pump over 8-12 hours. Ten percent Desferal solution is prepared in water for injection i.e. one vial of Desferal is dissolved in 5ml water for injection. If more than one vial is to be administered 2.5 to 5 ml of water for injection can be added per vial of Desferal. Desferal solution should not be stored for more than 24 hours. Subcutaneous Desferal can be given in the abdomen at 1” away from umbilicus, antero-medial thighs and in adolescents/adults also at triceps. It should be given subcutaneous over 8-12 hours.Infusion pumps and special 27G short needle, long tubing scalp vein sets are available with Thalassemia

Societies at subsidized cost.Desferal should never be added in blood bag. However, it can be given along with blood transfusion with the help of infusion pump in the same i v canula. If the pump is not available then Desferal solution can be further diluted in 50-100ml of 5% Dextrose or Normal saline and given by separate line with help of 3 way canola together with blood transfusion alongwith diureticsIf patient is incapable of using subcutaneous Desferal due to local drug reactions like pain, tenderness or swelling, intravenous Desferal can be given. But intravenous Desferal should be initiated only in consultation with referral center.

General Desferal dose recommendationsS.Ferritin < 2000 ng/L 25mg/Kg/dayS.Ferritin 2000-3000 ng/L 35mg/kg/dayS.Ferritin >3000 ng/L 50mg/kg/dayVitamin C - 50-150 mg should be given after setting the pump on. Desferal with high dose of Vitamin C (500 mg) may cause cardiac impairment. However, this side effect is reversible on withdrawal of Vitamin C.High-dose, continuous Desferal An aggressive chelation regimen is recommended when liver iron is greater than 20 mg/g dry weight or cardiac T2* is less than 20. Deferoxamine at 60 mg/kg per day, 24 hours per day, 7 days per week may be indicated with patients with severe iron over load and vital organ dysfunction. Patients with a T2* less than 10 ms or a liver iron greater than 30 mg/g dry weight are candidates for this therapy. If the patient has cardiac dys*function, this therapy is mandatory and must be emer*gently started. Other indications are:-A) patient is highly overloaded and had not used any chelation for long,B) Patient is preparing for BMT,C) Patient is planning for pregnancy with high serum ferritin,Desferal can be administered intra*venously using a central line. The intravenous therapeu*tic dose is 60 mg/kg per day. Continuous intravenous infusion can remove large quantities of iron and is very effective in reversing the cardiac complications. Intravenous infusions of Desferal are given very slowly. Rapid intravenous infusion may lead to collapse.

Undesirable effects: 1. Frequent pain, swelling, burning, itching, and rashes at site of injection/infusion occasionally

accompanied by fever, chills and lethargy. 2. High doses of Desferal especially in patients with low S. ferritin may lead to the visual & hearing

side effects. 3. Desferal increases susceptibility to Yersinia enterocolitica & Yersinia pseudotuberculosis

infection. 4. Concurrent treatment with prochlorperazine (Stemetil) may lead to temporary impairment of

consciousness. 5. Use of Desferrioxamine should be avoided during pregnancy if serum ferritin level is between

1000-2000 ng/ml. However in patients with higher serum ferritin levels Desferal can be given safely after Ist Trimester.

L1/DEFERIPRONE/KELFERDose-75-100 mg/Kg/day in two or three divided oral doses. It is available in 250 and 500 mg capsules. When child cannot swallow capsules, the capsule can be opened and medicine can be mixed with honey or sweetening agent and be given. Adverse EffectsNausea, vomiting, diarrhea, abdominal pain & distension (5%) All these symptoms are mild and subside on continuation of treatment. Addition of anti acids, anti vomiting drugs help in reducing these symptoms. Pain in joints is observed in 10-20% of cases. Incidence decreases with reduction of dose (upto 50mg/kg/day) or on withdrawal of drug. Pain killers along with Glucosamine help in relieving the symptoms. If not, the drug should be temporarily withdrawn. It may be restarted again after some time. Absence removal destruction

Deficiency or elimination of white cells, neutrophils or platelets has been observed in 1-2% of cases. It is reversible on discontinuation of therapy. Monitoring of Patients on Kelferi) Hb, TLC, DLC & platelet count every 3-4 weekly interval or whenever there is any sign of infection.In case of infection, Deferiprone should be stopped immediately and get CBC (Hb, TLC, DLC, Platelet) done. Kelfer should be stopped if TLC is below 3,000 cu mm or absolute neutrophil count <1,000 cumm or platelet count < 1, 00,000 cu mm. It may be re-started after counts return to normal under close supervision of the doctor. However in case of recurrent loss of neutrophils, leucocytes or platelets the Kelfer should not be re-started. If the neutrophil count drops to <500 cu mm or severe infection the child should be referred to a referral center. (Kelfar should not be restarted if the above side effects are noted because of this drug)

COMBINATION THERAPYIt should be given in consultation with the referral centre.Indications:

If serum ferritin level is high (>5000 ng/ml) In presence of cardiac or endocrine dysfunction Patients who can not afford Desferal Patients who are intolerant to full dose of Kelfer

Dose It should be individualized based upon the patient’s condition and several other factors

DEFRASIROX/ICL670C/EXJADE“ASUNRA/DESIROX” Itis a new once daily oral iron chelator. It should be taken empty stomach at least 30 minutes before food, preferably at the same time each day. The tablets are dispersed by stirring in a glass of water or apple or orange juice (100 to 200 mL) until a fine suspension is obtained. After the suspension has been swallowed, any residue must be resuspended in a small volume of water or juice and swallowed. The tablets must not be chewed or swallowed whole.Dosage

The recommended initial daily dose of Defrasirox is 20-30 mg/kg body weight. 20 mg/kg body weight for patients well-managed with Desferal or Kelfer, 30 mg/kg for those whose S. ferritin is high (>2000 ng/ml) or their blood transfusion requirement

is high. 10 mg/kg for thalassaemia intermedia, if transfusions are required occasionally and S. ferritin is

not high. In India, many patients will require 30 mg/kg as their initial S. ferritin may be quite high due to

lack of adequate iron chelation in the past. Above 30 mg/kg not recommended since there is no experience with doses above this level. Ferritin level consistently below 500 ng/ml requires an interruption of treatment

S. ferritin be monitored every month, the dose of Defrasirox be adjusted based on the S. ferritin and tailored to the individual patient’s response and therapeutic goals. Adverse (toxic) effects:20% of patients may complain nausea, vomiting, diarrhea, or abdominal pain. Maintain adequate hydration in patients who develop diarrhea or vomiting.

Skin rash are found in about 5% of patients. For mild to moderate skin rashes, defrasirox may be continued without dose adjustment, since the rash often resolves spontaneously. For more severe rashes, interruption of treatment may be necessary.

Mild, increases in serum creatinine level, may occur in about 35% of patients. It is recommended that serum creatinine be assessed before starting defrasirox and monitored regularly thereafter. Defrasirox be reduced by 10 mg/kg if a non-progressive rise in serum creatinine by >33% above the average of the pre-treatment measurements is observed.

Urine albumin should also be performed monthly.

Elevations of SGOT, SGPT & alkaline phosphatase were reported in about 2% of patients. Liver function be monitored every month. If there is a persistent and progressive increase in liver enzymes defrasirox should be interrupted.

Deficiency or elimination of white cells, neutrophils or platelets has been observed in 1-2% of cases. It is reversible on discontinuation of therapy. Hb, TLC, DLC & platelet count should be done intermittently and defrasirox should be discontinued for those having unexplained reduction of blood cells.

Hearing loss and early cataracts have been very rarely observed in patients. Hearing & Eye testing (including fundoscopy) is recommended before the start of treatment and every year. If disturbances are noted, dose is reduced or interruption may be considered.

Most of these reactions are dose-dependent, generally transient and mostly resolve even if defrasirox is continued or by reducing the dose. Defrasirox has not been used in patients with kidney or liver disorders and must be used with caution in such patients. No growth retardation has been noticed. However body weight and longitudinal growth should be monitored at regular intervals. Defrasirox must not be combined with other iron chelator (Desferal or Kelfer) therapies as the safety of such combinations has not been established.

EVALUATION OF IRON OVERLOADSerum ferritin is a convenient way to monitor iron over*load. Since fer*ritin is a poor marker of absolute iron content in any patient, it is important to have 3 to 5 fer*ritin measurements in a year to determine the direction of change in iron. Because of the sensitivity of ferritin levels to inflammation, vitamin C, and iron, changes between two consecutive measures can be very misleading. A patient can almost completely empty the liver of iron and reduce ferritin to very low levels even though significant amounts of iron may remain in the heart.Heart involvement is the most life-threatening of the iron-related complications. The heart often remains iron-free for many years. Once iron loading starts in heart, it pro*gresses very rapidly. Removal of iron from the heart progresses very slowly with a half-life of approximately 17 months. The heart often does not unload until the liver iron drops to very low levels. The foundation of effective treatment of iron in heart problems is continuous exposure to chelation. This can reduce dysfunction even before the heart begins to unload iron.SPLENECTOMYInadequately transfused thalassemia major and thalassemia intermedia patients invariably develop splenomegaly (enlargement of spleen). It results in increased blood requirement, increased iron load & enhanced risk of blood transfusion transmitted infections. Children may develop deficiency or of white cells, neutrophils or platelets and it become difficult to maintain pre-transfusion Hb near 10gm/dl. Some children may also have protruded abdomen

Indications of Splenectomy (surgical removal of spleen)* Enlargement of spleen with fall in mean annual Hb concentration* Increase of annual blood requirement by 50% or more over initial requirement.* Packed red cell consumption of more than 250 ml/kg/year.* Deficiency or of white cells, neutrophils or platelets.* Reduced red cell survival of 15 days or less by Chromium studies.* Splenomegaly resulting in abdominal discomfort.Frequent blood transfusions at early intervals may help in avoiding splenectomy in early stages.Splenectomy, preferably be postponed to after 5th year of age. Patient should be immunized against Pneumococcal, Meningococcal A & C and Haemophilus influenza B (HiB) at least 4 weeks prior to operation.

Care after SplenectomyPenicillin tablets or injection Benzethine Penicillin every 3 weeks life long or at least till 25 years of age. It

is advisable to give Aspirin 50-100mg/day if platelet count exceeds 8,00,000/mm3. After removal of spleen infections should be dealt with broad-spectrum antibiotics immediately without waiting for laboratory reports and patient should be referred to major center.ENDOCRINE COMPLICATIONSGrowth Impairment Delayed Puberty HypothyroidismHypoparathyroidism OsteoporosisDiabetes Mellitus

Growth Growth parameters should be recorded twice a year. Weight: It should be measured before breakfast with minimum clothing.Length while lying down: It is recorded until 2 years of age.Standing height is recorded after 2 years of age. Sitting height: is measured from top of head to buttocks while the child is sitting.All these measurements should preferably be recorded on the growth charts for proper monitoring and early detection of growth retardation.Delayed puberty: Complete lack of pubertal development in girls by the age of 13 years and in boys by 14 years. Hypogonadism: Testicular size (less than 4 ml) and the absence of breast development by the age of 16 years. Arrested puberty: Lack of pubertal progression over a year or longer. If there is any endocrine complication the patient should be referred to a referral centre for detailed investigation, diagnosis and treatment.

CARDIAC COMPLICATIONSIron-induced damage to heart muscles results in heart failure, other complications and sudden death in thalassemics. The average age of presenting cardiac symptoms in a non-chelated thalassemic is 11 years with the range 6-18 years. Over 60% of these develop heart failure by 16 years of age with the range of 6-25 years, 50% of those who develop cardiac failure die within one year if left untreated. Patients should be referred to a referral centre for proper diagnosis and treatment.

Cardiac Examination: - 12 lead ECGTread Mill TestX-Ray- ChestEchocardiogramHOLTERMUGA SCAN

1. ECG shows changes in T waves and ST segments of anterior chest leads. Sometimes R & S waves are also affected suggesting bilateral enlargement. Conduction disturbance in the form of bundle branch block may be seen.

2. 24 hour Holter ECG analysis is the standard method for detecting the cardiac arrhythmia. 3. Tread Mill Test (TMT) is of value for identifying patients at risk for cardiac arrhythmias or

ventricular dysfunction. 4. Echocardiography: Echocardiography reveals functioning of various heart chambers along with

reduction in ejection fraction. 5. Doppler analysis of intracardiac flows may give the best insight into abnormalities of diastolic

function.

Treatment plan 1. Asymptomatic patients with normal heart condition 2. No restrictions to physical activity and body exercise.

3. Asymptomatic patients with moderate cardiac impairment 4. No restriction to physical activity 5. Medication 6. Symptomatic patients with severe cardiac impairment 7. Restriction of physical activity 8. Slow blood transfusion with diuretics 9. Management of cardiac complications should be under the guidance of referral centre.

D I E T 1. High calorie, high protein nutritious diet 2. Foods rich in iron should be avoided e.g. meat, liver, kidney, egg yolk, green vegetables, jaggery

etc. 3. Food should not be cooked in iron pots. 4. Meals should include bread, cereals, milk, moong dal, soya bean etc. to reduce the iron absorption 5. Vitamin C rich fruits e.g. citrus fruits should be avoided along with meals. 6. Strong tea be taken along with meals. 7. Milk and milk products should be frequently taken.

LIFE EXPECTANCY AND QUALITY OF LIFEIt depends on the treatment. Overall survival is given below:No Diagnosis/No Treatment 1-5 years. Only Blood Transfusion & No Chelation 8-18 years Repeated blood transfusion to maintain Hb10 gm along withIron chelation to maintain S.Ferritin 1000mg NORMALHowever transfusion transmitted infections like Hepatitis B, C and HIV does affect the quality of life & total life span. With the current management the Thalassemics live a normal healthy life. They attend school, play sports, and take part in all sorts of social activities. In countries where ideal treatment is available many Thalassemics are now touching sixty. They are doctors, engineers, professors, executives, self-employed, married and have their own “Normal” children. Even in India many Thalassemics have crossed thirty, highly educated, employed, living happy married life with normal children