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Desferal….. Deferoxamine
Exjade ... Asunra (Exjade) and Desirox (Exjade by Cipla) Deferasirox, ICL 670,
Desirox and Asurna is the same drug being marketed under different names.
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.
Exjade (Deferasirox) removes iron in stool and Deferoxamine (Desferal) which removes iron both in
stool and urine
IRON OVERLOAD
In 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 Overload
I 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 patient
II 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
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/KELFER
Dose-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 Effects
Nausea, 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 Kelfer
i) 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 THERAPY
It should be given in consultation with the referral centre.
Indications:
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.
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 COMPLICATIONS
Iron-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.
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
DIET