Dejex

Each dispersible tablet contains Deferasirox 250 mg.

Pharmacodynamics: Deferasirox is an orally active chelating agent that is selective for iron (III) with a high affinity binding ratio of 2:1. Iron excretion produced by deferasirox is primarily fecal.
Pharmacokinetics: Absorption: Time to peak, plasma ~1.5 to 4 hours.
Bioavailability: 70%.
Distribution: Volume of distribution: Adults: 14.4 ± 2.7 L.
Protein binding: ~ 99% to serum albumin.
Metabolism: Hepatic via glucuronidation by UGT1A1 (primarily) and UGT1A3; minor oxidation by CYP450 (approximately 8%); undergoes enterohepatic recirculation.
Half-life elimination: 8 to 16 hours.
Excretion: Feces (84%), urine (8%).
Moderately lower (by 17.5%) in women than in men.

Treatment of chronic iron overload caused by blood transfusions (transfusional hemosiderosis) in patients 2 years and older; Treatment of chronic iron overload in patients with non-transfusion-dependent thalassemia syndromes age 10 years and older.

Recommended Dose: Do not chew or swallow tablets whole.
Completely disperse tablets in water, orange juice, or apple juice (use 100 mL for total doses < 1 g; 200 mL for doses ≥ 1 g); stir to form a fine suspension and drink entire contents. Rinse remaining residue with more fluid and drink.
Avoid dispersion of tablets in milk due to slowed dissolution or carbonated drinks due to foaming.
Administer at same time each day on an empty stomach, at least 30 minutes before food.
Transfusional iron overload: Treatment should be initiated after the transfusion of approximately 20 units (about 100 mL/kg) of packed red blood cells or when there is evidence of clinical monitoring that chronic iron overload is present (e.g., serum ferritin consistently > 1,000 mcg/L). Dose (in mg/kg) must be calculated and rounded to the nearest whole tablet size.
Initial dose: 20 mg/kg once daily.
An initial daily dose of 30 mg/kg may be considered for patients receiving more than 14 mL/kg/month of packed red blood cells, and for whom the objective is the reduction of iron overload.
An initial daily dose of 10 mg/kg may be considered for patients receiving less than 7 mL/kg/month of packed red blood cells, and for whom the objective is the maintenance of the body iron level.
For patients already well-managed on treatment with deferoxamine, a starting dose of deferasirox that is numerically half that of the deferoxamine dose could be considered (e.g., a patient receiving 40 mg/kg/day of deferoxamine for 5 days per week (or equivalent) could be transferred to a starting daily dose of 20 mg/kg/day of deferasirox).
Dose adjustment: It is recommended that serum ferritin be monitored every month and that the dose of Dejex is adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin. Dose adjustments may be made in step of 5 to 10 mg/kg; and are to be tailored to the individual patient's response and therapeutic goals.
In patients not adequately controlled with 30 mg/kg/day, doses up to 40 mg/kg/day may be considered for serum ferritin levels persistently > 2,500 mcg/L and not decreasing over time (doses above 40 mg/kg/day are not recommended).
In patients whose serum ferritin level has reached the target (usually between 500 and 1,000 microgram/L), dose reductions in steps of 5 to 10 mg/kg should be considered to maintain serum ferritin levels within the target range. If serum ferritin falls consistently below 500 microgram/L, an interruption of treatment should be considered.
Non-transfusion-dependent thalassemia syndromes: Treatment should only be initiated with evidence of chronic iron overload (liver iron concentration (LIC) ≥ 5 mg Fe/g dry weight or serum ferritin >800 mcg/L.
In patients with no LIC assessment, caution should be taken during chelation therapy to minimize the risk of over-chelation.
Initial dose: 10 mg/kg once daily.
Dose adjustment: It is recommended that serum ferritin be monitored every month. Every 3 to 6 months of treatment, consider a dose increase in increments of 5 to 10 mg/kg if the patient's LIC is ≥ 7 mg Fe/g dry weight, or serum ferritin is consistently >2,000 microgram/L and not showing a downward trend, and the patient is tolerating 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.
Consider dose adjustment to not exceed 10 mg/kg, if the patient's LIC is < 7 mg Fe/g dry weight, or serum ferritin is < 2,000 microgram/L.
In patients in whom LIC was not assessed and serum ferritin is ≤ 2,000 microgram/L, dosing should not exceed 10 mg/kg.
Once a satisfactory body iron level has been achieved (LIC < 3 mg Fe/g dry weight or serum ferritin < 300 mcg/L), treatment should be interrupted. Treatment should be re-initiated when there is evidence from clinical monitoring that chronic iron overload is present.
Special population: Pediatric patients: The dosing recommendations for pediatric patients are the same as for adult patients. Changes in weight of pediatric patients over time must be taken into account when calculating the dose.
Elderly patients: The dosing recommendations for elderly patients are the same as for adult patients. Elderly patients experienced a higher frequency of adverse reactions than younger patients and should be monitored closely for adverse reactions that may require a dose adjustment.
Renal impairment: Deferasirox must be used with caution in patients with serum creatinine levels above the age-appropriate upper limit of the normal range (ULN). Caution should especially be used in patients with creatinine clearance between 40 and less than 60 mL/min, particularly in case where there are additional risk factors that may impair renal function such as concomitant medications, dehydration, or severe infections. The initial dosing recommendations for patients with renal impairment are the same as described previously.
Serum creatinine should be monitored monthly in all patients and if necessary daily doses can be reduced by 10 mg/kg (see Precautions).
In patients in whom creatinine clearance < 40 mL/min or serum creatinine > 2 times the age-appropriate upper limit of the normal range (ULN), the use is contraindicated.
Hepatic impairment: Hepatic function in all patients should be monitored before the initiation of treatment, every 2 weeks during the first month and monthly thereafter (see Precautions).
Moderate impairment ( Child - Pugh class B): Initial: Reduce dose by 50%;
Severe impairment (Child - Pugh class C): Avoid use.

Hepatitis was reported in one patient who received 2 to 3 times the prescribed dose of deferasirox over a period of several weeks. In iron overloaded thalassemic patients, single doses up to 80 mg/kg have been tolerated with nausea and diarrhea noted. Single doses up to 40 mg/kg were tolerated in healthy volunteers.
Acute signs of overdose may include nausea, vomiting, headache, and diarrhea. Overdose may be treated by induction of emesis or by gastric lavage and by symptomatic treatment.

Known hypersensitivity to deferasirox or any component of the formulation.
Crcl < 40 mL/minute or serum creatinine > 2 times the age-appropriate ULN;
High-risk myelodysplastic syndromes (MDS) patients and patients with other hematological and non-hematological malignancies who are not expected to benefit from chelation therapy due to the rapid progression of their disease.

The decision to remove accumulated iron should be individualized based on anticipated clinical benefit and risk of chelation therapy (see Recommended dose under Dosage & Administration).
Caution should be used in elderly patients due to a higher frequency of adverse reactions.
Renal impairment: Non-progressive rises in serum creatinine have been noted, usually within the normal range. Cases of acute renal failure have been reported. There have been rare cases of acute renal failure requiring dialysis.
It is recommended that serum creatinine and/or creatinine clearance be assessed in duplicate before initiating therapy and monitored monthly thereafter.
Patients with pre-existing renal conditions, or patients who are receiving medicinal products that may depress renal function may be more at risk of complications and weekly monitoring of serum creatinine and/or creatinine clearance is recommended in the first month after initiation or modification of therapy, and monthly thereafter. Caution should be used in patients with creatinine clearance between 40 - 60 mL/min, particularly in cases where there are additional risk factors that may impair renal function such as concomitant medications, dehydration, or severe infections.
Renal tubulopathy has been reported. Most of these patients were children and adolescents with beta-thalassemia and serum ferritin levels < 1,500 mcg/L.
Tests for proteinuria should be performed monthly.
Care should be taken to maintain adequate hydration in patients who develop diarrhea or vomiting.
For adult patients, the daily dose may 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 seen at two consecutive visits and cannot be attributed to other causes.
For pediatric patients, the dose may be reduced by 10 mg/kg if serum creatinine levels rise above the age-appropriate upper limit of normal at two consecutive visits.
If there is a progressive increase in serum creatinine beyond the upper limit of normal, treatment should be interrupted. Re-initiation is depending on the individual clinical circumstances.
Hepatic impairment: Deferasirox is not recommended in patients with severe hepatic impairment (Child - Pugh class C).
Most reports of hepatic failure involved patients with significant co-morbidities including liver cirrhosis and multi-organ failure; fatal outcomes were reported in some of these patients.
It is recommended that serum transaminases, bilirubin and alkaline phosphatase be monitored before the initiation of treatment, every 2 weeks during the first month and monthly thereafter. If there is a persistent and progressive increase in serum transaminase levels that cannot be attributed to other causes, treatment should be interrupted. Once the cause of the abnormalities has been clarified or after return to normal levels, cautious re-initiation of treatment at a lower dose followed by gradual dose escalation may be considered.
Blood disorders: There have been reports of cytopenia in patients treated with deferasirox. Most of these patients had pre-existing hematologic disorders that are frequently associated with bone marrow failure. The relationship of these episodes to treatment with deferasirox is uncertain. Blood counts should be monitored regularly. Dose interruption of treatment with deferasirox should be considered in patients who develop unexplained cytopenia.
Gastrointestinal disorders: Gastrointestinal irritation may occur during treatment. Upper gastrointestinal ulceration and hemorrhage have been reported. There have been rare reports of fatal GI hemorrhages, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts.
Physicians and patients should remain alert for signs and symptoms of GI ulceration and hemorrhage during deferasirox therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected There have been reports of ulcers complicated with gastrointestinal perforation (including fatal outcome).
Caution should be exercised in patients who are taking deferasirox in combination with drugs that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, in patients receiving anticoagulant (see Interactions) and in patients with platelet counts < 50 x 10⁹/L.
Hypersensitivity reactions: Rare cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported, the onset of the reaction occurring in the most of cases within the first month of treatment. If reactions are severe, deferasirox should be discontinued and appropriate medical intervention instituted.
Skin disorders: Cases of Stevens-Johnson syndrome (SJS) have been reported. If SJS is suspected deferasirox should be discontinued immediately and should not be re-introduced.
Rare cases of erythema multiforme have been reported during deferasirox treatment.
Skin rashes may appear during deferasirox treatment. For rashes of mild to moderate severity, may be continued without dose adjustment, since the rash often resolves spontaneously. For more severe rash, where interruption of treatment may be necessary, may be re-introduced after resolution of the rash, at a lower dose followed by gradual dose escalation.
Vision and hearing: Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported. Auditory and ophthalmic testing is recommended before the start of deferasirox treatment and at regular intervals thereafter (every 12 months). If disturbances are noted, dose reduction or interruption may be considered.
Other considerations: As with other iron chelator treatment, the risk of toxicity of deferasirox may be increased when inappropriately high doses are given in patients with a low iron burden or with serum ferritin levels that are only slightly elevated.
Deferasirox must not be combined with other iron chelator therapies as the safety of such combinations has not been established.
The tablets contain lactose. This medicine is not recommended for patients with rare hereditary problems of galactose intolerance, of severe lactase deficiency or of glucose-galactose malabsorption.
Driving and using machines: No studies on the effects of deferasirox on the ability to drive and use machines have been performed. Patients experiencing the uncommon adverse effect of dizziness should exercise caution when driving or operating machinery.
Use in Children: Deferasirox has not been associated with growth retardation in children followed for up to 5 years in clinical trials. However, as a general precautionary measure, body weight and longitudinal growth in pediatric patients can be monitored at regular interval (every 12 months).

Animal studies showed that deferasirox was not teratogenic in rat or rabbits but caused increased frequency of skeletal variations and stillborn pups in rats at high doses that were severely toxic to the non-iron-overloaded mother. Deferasirox did not cause other effects on fertility or reproduction. The potential risk for humans is unknown.
No clinical data on exposed pregnancies are available for deferasirox. Studies in animals have shown some reproductive toxicity at maternally toxic doses. The potential risk for humans is unknown. As a precaution, it is recommended that deferasirox not be used during pregnancy unless clearly necessary.
It is not known if deferasirox is secreted into human milk. Deferasirox was found to be rapidly and extensively secreted into maternal milk. No effects on the offspring were noted at maternally non-toxic doses of deferasirox. Breast-feeding while taking deferasirox is not recommended.

Adverse reactions are ranked as follows using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥1/10,000, < 1/1,000); very rare (< 1/10,000).
Psychiatric disorders: Uncommon: anxiety, sleep disorder.
Nervous system disorders: Common: headache.
Uncommon: dizziness.
Eye disorders: Uncommon: early cataract, maculopathy.
Rare: optic neuritis.
Ear disorders: Uncommon: hearing loss.
Respiratory, thoracic, and mediastinal disorders: Uncommon: pharyngolaryngeal pain.
Gastrointestinal disorder: Common: diarrhea, constipation, vomiting, nausea, abdominal pain, abdominal distension, dyspepsia.
Uncommon: gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, gastritis.
Rare: esophagitis.
Unspecified: gastrointestinal perforation.
Hepatobiliary disorders: Common: transaminases increased.
Uncommon: hepatitis, cholelithiasis.
Unspecified: hepatic failure.
Skin and subcutaneous tissue disorders: Common: rash, pruritus.
Uncommon: pigmentation disorder.
Rare: erythema multiforme.
Unspecified: Stevens-Johnson syndrome, leukocytoclastic vasculitis, urticaria, alopecia.
Renal and urinary disorders: Very common: blood creatinine increased.
Common: proteinuria.
Uncommon: renal tubulopathy (Fanconi's syndrome).
Unspecified: renal tubular necrosis, acute renal failure (serum creatinine in duplicate at baseline prior to initiation and in general will return to normal when discontinuation), interstitial nephritis.
Immune system disorders: Unspecified: hypersensitivity reactions (including anaphylaxis and angioedema).

Agents that may decrease deferasirox systemic exposure: Deferasirox is UDP-glucuronosyltransferase (UGP) substrate, the concomitant administration of deferasirox and the potent UGT inducer (such as rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in deferasirox efficacy. If deferasirox and a potent UGT inducer are used concomitantly, increases in the dose of deferasirox should be considered based on clinical response to therapy.
Agents that may affected by deferasirox: Interaction with agents metabolized by CYP3A4: The concomitant administration of deferasirox and midazolam (a CYP3A4 substrate) resulted in a decrease of midazolam exposure. Therefore, due to a possible decrease in efficacy, caution should be exercised when deferasirox is combined with substances metabolized through CYP3A4 (e.g., ciclosporin, simvastatin, hormonal contraceptive agents).
Interaction with agents metabolized by CYP2C8: The concomitant administration of deferasirox and the CYP2C8 substrate repaglinide resulted in an increase in repaglinide AUC and Cmax. An interaction between deferasirox and other CYP2C8 substrates like paclitaxel cannot be excluded.
Interaction with agents metabolized by CYP1A2: The concomitant administration of deferasirox and the CYP1A2 substrate theophylline resulted in an increase in theophylline AUC. An interaction between deferasirox and other CYP1A2 substrates may be possible.
Anticipated interactions resulting in a concomitant use not recommended: Concurrent use of aluminum oxide and deferasirox may result in decreased deferasirox effectiveness.
Concomitant administration of deferasirox with drugs that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, and use of deferasirox in patients receiving anticoagulants may increase the risk of gastrointestinal irritation.

Store below 30 °C.

Antidotes & Detoxifying Agents

V03AC03 - deferasirox ; Belongs to the class of iron chelating agents. Used in the management of chronic iron overload associated with blood transfusion.

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