Exsirox

Deferasirox.

Each tablet contains Deferasirox 250 mg.

Pharmacology: Pharmacodynamics: Deferasirox selectively binds iron, forming a complex that is excreted primarily through the feces.
Pharmacokinetics: Absorption: Deferasirox is well absorbed following oral administration, with peak plasma concentrations usually attained within 1.5 - 4 hours. The absolute oral bioavailability of the drug is 70%. Food variably increases the bioavailability of Deferasirox.
Distribution: Deferasirox volume distribution in adults is 14.4 ± 2.7 Liters. Protein binding is approximately 99% to serum albumin.
Metabolism: Deferasirox is metabolized principally in the liver via glucuronidation by uridine diphosphate-glucuronosyltransferase (UGT1A1) and to a lesser extent by UGT1A3. Deferasirox is minimally metabolized (8%) by oxidative cytochrome P-450 (CYP) enzymes. Deferasirox undergoes enterohepatic recirculation.
Excretion: Deferasirox and its metabolites are eliminated principally in feces via bile (84%) and to a lesser extent in urine (8%). The half-life of Deferasirox is 7-16 hours.

Chronic iron overload due to transfusions – Treatment of chronic iron overload caused by blood transfusion (transfusional hemosiderosis) in patients 2 years and older.
Chronic iron overload in non-transfusions-dependent thalassemia syndromes – Treatment of chronic iron overload in patients 10 years and older.

EXSIROX (250 mg) is administered orally once daily on an empty stomach (at least 30 minutes before eating), preferably at the same time each day. EXSIROX tablets for oral suspension should not be chewed or swallowed whole. The tablets for oral suspension should be completely dispersed by stirring in water, orange juice or apple juice. Doses of less than 1 g should be dispersed in 105 ml (3.5 oz.) and doses of 1 g or more should be dispersed in 210 ml (7 oz.) of liquid. The EXSIROX suspension should be used immediately following preparation. Following administration, any residue should be re-suspended in a small volume of liquid and swallowed.
Adult: Chronic iron overload due to transfusions: Maximum dose 40 mg/kg/day.
Initial dosage 20 mg/kg once daily.
Dosage adjustment – After commencing therapy, monitor serum ferritin monthly and adjust the dosage of EXSIROX if necessary every 3 to 6 months, based on serum ferritin trends. Make dosage adjustments in increments of 5 to 10 mg/kg and tailor adjustments to the individual patient’s response and therapeutic goals. In patients not adequately controlled with doses of 30 mg/kg (eg, serum ferritin levels persistently above 2,500 mcg/L and not showing a decreasing trend over time), doses of up to 40 mg/kg may be considered. Doses higher than 40 mg/kg are not recommended. If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with EXSIROX.
Discontinuation of therapy – Discontinue therapy for serum creatinine greater than 2 times the age-appropriate upper limit of normal (ULN) or for CrCl less than 40 mL/min.
Chronic iron overload in non-transfusions-dependent thalassemia syndromes: Maximum dose 20 mg/kg/day.
Initial dosage 10 mg/kg once daily.
Dosage adjustment – After commencing therapy, monitor serum ferritin monthly. Monitor LIC every 6 months. If the base line LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 20 mg/kg/day after 4 weeks. After 6 months, if the LIC greater than 7 mg Fe/g dw, increase the dose of EXSIROX to a maximum of 20 mg/kg daily.
If after 6 months of therapy, the LIC is 3 to 7 mg Fe/g dw, continue treatment with EXSIROX at no more than 10 mg/kg daily.
Discontinuation of therapy – Interrupt therapy when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw. If the LIC is less than 3 mg Fe/g dw, interrupt treatment and continue to monitor LIC. Restart treatment when the LIC rise again to more than 5 mg Fe/g dw.
Pediatric: Chronic iron overload due to transfusions: 2 years and older: See Adult for dosing.
Chronic iron overload in non-transfusions-dependent thalassemia syndromes: 10 years and older: See Adult for dosing.
Renal function impairment: Renal impairment at treatment initiation: CrCl 40 to 60 mL/minute: Reduce initial dose by 50%.
CrCl less than 40 mL/minute or serum creatinine more than 2 times age-appropriate ULN: Use is contraindicated.
Renal toxic during treatment: Chronic iron overload due to transfusions: Adults and adolescents 16 years and older – For increase in serum creatinine by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 10 mg/kg.
Children 2 to 15 years of age – For increase in serum creatinine more than 33% above the average baseline level and above the age-appropriate ULN: Reduce daily dose by 10 mg/kg.
Chronic iron overload in non-transfusions-dependent thalassemia syndromes: Adults and adolescents 16 years and older – For increase in serum creatinine by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, interrupt therapy if the dose is 5 mg/kg or reduce by 50% if the dose is 10 or 20 mg/kg.
Children 2 to 15 years of age – For increase in serum creatinine more than 33% above the average baseline level and above the age-appropriate ULN: Reduce daily dose by 5 mg/kg.
Hepatic function impairment: Hepatic function impairment at treatment initiation: Moderate hepatic impairment (Child-Pugh class B): Reduce the starting dose by 50%.
Severe hepatic impairment (Child-Pugh class C): Avoid use.
Hepatic toxicity during treatment: Severe or persistent increase in transaminase/bilirubin: Reduce dose or temporarily interrupt treatment.

Adult: Chronic iron overload due to transfusions: Maximum dose 40 mg/kg/day.
Chronic iron overload in non-transfusions-dependent thalassemia syndromes: Maximum dose 20 mg/kg/day.
Pediatric: Chronic iron overload due to transfusions: 2 years and older: Maximum dose 40 mg/kg/day.
Chronic iron overload in non-transfusions-dependent thalassemia syndromes: 10 years and older: Maximum dose 20 mg/kg/day.
Symptoms: Overdose data are limited. Signs and symptoms of an acute overdose are anticipated to be similar to excessive pharmacologic adverse events. 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 beta-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.
Treatment: MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment is symptomatic and supportive. MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. Severe anaphylaxis should be treated with antihistamines, corticosteroids, and epinephrine. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg; filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding.

EXSIROX (250 mg) is contraindicated in: Patients with known hypersensitivity to Deferasirox or any component of this formulation.
Patients with creatinine clearance < 40 ml/min or serum creatinine > 2 times the age-appropriate ULN.
Patients with poor performance status.
Patients with high-risk myelodysplastic syndromes.
Patients with advanced malignancies.
Patients with platelet counts < 50,000/mm³.

Renal failure: Acute renal failure (including fatalities and case requiring dialysis) may occur; observed more frequently in patients with comorbid conditions and advanced hematologic malignancies. Obtain serum creatinine and calculate CrCl in duplicate at baseline prior to initiation and monitor at least monthly thereafter; in patients with underlying renal dysfunction or at risk for acute renal failure, monitor creatinine weekly during the first month and then at least monthly thereafter. Dose reduction, interruption or discontinuation should be considered for serum creatinine elevations. Monitor serum creatinine and/or CrCl more frequently if creatinine levels are increasing. May cause proteinuria; monitor monthly although the clinical significance of proteinuria is unknown. Renal tubular damage, including Fanconi syndrome, has also been reported, primarily in pediatric/adolescent patients with beta-thalassemia and serum ferritin level less than 1,500 mcg/L.
Hepatic failure: Hepatic injury and failure (including fatalities) may occur. Monitor transaminases and bilirubin at baseline, every 2 weeks for 1 month, then at least monthly thereafter. Hepatitis and elevated transaminases have also been reported. Hepatotoxicity is more common in patients older than 55 years and in patients with significant comorbidities (eg, cirrhosis, multiorgan failure). Reduce dose or temporarily interrupt treatment for severe or persistent increases in transaminases/bilirubin.
Heart failure: The Canadian labeling recommends against use in patients with acute heart failure associated with iron overload (has not been studied).
Gastrointestinal events: GI hemorrhage (including fatalities) may occur; observed more frequently in elderly patients with advanced hematologic malignancies and/or low platelet counts; discontinue treatment for suspected GI hemorrhage or ulceration. Other GI effects including irritation and ulceration (sometimes complicated with GI perforation, including fatalities) have been reported. Use caution with concurrent medications that may increase risk of adverse GI effects (eg, NSAIDs, corticosteroids, anticoagulants, oral bisphosphonates). Monitor patients closely for signs/symptoms of GI ulceration/bleeding.
Bone marrow suppression: Cytopenias (including agranulocytosis, neutropenia, thrombocytopenia and worsening anemia) have been reported (some fatal); risk may be increased in patients with preexisting hematologic disorders; monitor blood cell counts regularly. Interrupt treatment in patients who develop cytopenias; may reinitiate once cause of cytopenia has been determined; use is contraindicated if platelet count less than 50,000/mm³.
Dermatologic toxicity: May cause skin rash (dose related); mild to moderate rashes may resolve without treatment interruption; for severe rash, interrupt and consider restarting at a lower dose with dose escalation and oral steroids. Severe skin reactions, including Stevens-Johnson and erythema multiforme, have also been reported; if suspected, discontinue immediately and evaluate. Do not reintroduce therapy.
Auditory disturbances: Decreased hearing and high frequency hearing loss have been reported (rare) with use; perform auditory testing prior to initiation and regularly (every 12 months) during use. If abnormalities develop monitor more closely and consider dose reduction or treatment interruption.
Ocular disturbances: Lens cataracts, intraocular pressure elevation and retinal disorders have been reported (rare) use; perform ophthalmic testing prior to initiation and regularly (every 12 months) during use. If abnormalities develop, monitor more closely and consider dose reduction or treatment interruption.
Other minerals: Deferasirox has a low affinity for binding with zinc and copper, may cause variable of disease in the serum concentration of these trace minerals.
Hypersensitivity reactions: Hypersensitivity reactions, including severe reactions (anaphylaxis and angioedema) have been reported; onset is usually within the first month of treatment. Discontinue if severe.
Renal function impairment: Use with caution in patients with renal impairment. Dosage modification or treatment discontinuation may be required; reductions in initial dose are recommended for patients with CrCl 40 to 60 ml/minute; use is contraindicated in patients with a CrCl less than 40 mL/minute or serum creatinine more than 2 times age-appropriate ULN.
Hepatic function impairment: Avoid use in patients with severe (Child-Pugh class C) hepatic impairment; a dose reduction is required in patients with moderate (Child-Pugh class B) hepatic impairment. Monitor patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) impairment closely for efficacy and for adverse reactions requiring dosage reduction.
Monitoring: Serum ferritin (baseline, monthly thereafter), iron levels (baseline), CBC with differential, serum creatinine and CrCl (2 baseline assessments then monthly thereafter; in patients who are at increased risk of complications [eg, preexisting renal conditions, elderly, comorbid conditions or receiving other potentially nephrotoxic medications]: weekly for the first month then at least monthly thereafter); liver iron concentration (non-transfusion-dependent thalassemia; baseline, every 6 months); urine protein (monthly); monitor serum creatinine and/or CrCl more frequently if creatinine levels are increasing; serum transaminases (ALT/AST) and bilirubin (baseline every 2 weeks for the first month, then monthly); baseline and annual auditory and ophthalmic examination (including slit-lamp examinations and dilated fundoscopy): performance status (in patients with hematologic malignancies); signs/symptoms of GI ulcers or hemorrhage; cumulative number of RBC units receive.
Use in Elderly: Use with caution due to the higher incidence of toxicity (eg, hepatotoxicity) and fatal events during use; monitor elderly patients closely.

Pregnancy: Category C. Adverse events were observed in animal reproduction studies. Information related to the use of EXSIROX in pregnant women is limited. The Canadian labeling recommends that Deferasirox not be used during pregnancy.
Lactation: It is not known if EXSIROX is excreted in breast milk. Due to the potential for serious adverse reactions in the breast-feeding infant, the manufacturer recommends a decision made to discontinue breastfeeding or the drug, taking into account the importance of treatment to the mother.

Dermatologic: Skin rash.
Gastrointestinal: Abdominal pain, diarrhea, nausea, vomiting.
Genitourinary: Proteinuria.
Renal: Increase serum creatinine.
Central nervous system: Fatigue.
Hepatic: Increase serum ALT.
Respiratory: Pharyngolaryngeal pain, respiratory tract infection.

Metabolism/Transport effects: Substrate of UGT1A1; Inhibits CYP1A2 (moderate), CYP2C8 (moderate).
Agomelatine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Agomelatine. Monitor therapy.
Aluminum hydroxide: Aluminum hydroxide may diminish the therapeutic effect of EXSIROX. Avoid combination.
Anticoagulants: Anticoagulants may enhance the adverse/toxic effect of EXSIROX. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy.
Bile acid sequestrants: Bile acid sequestrants may decrease the serum concentration of EXSIROX. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial EXSIROX dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification.
Bisphosphonate Derivatives: Bisphosphonate derivatives may enhance the adverse/toxic effect of EXSIROX. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy.
Corticosteroids: Corticosteroids may enhance the adverse/toxic effect of EXSIROX. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Exceptions: Beclomethasone (Nasal); Desonide; Dexamethasone (Ophthalmic); Difluprednate; Flunisolide (Nasal); Loteprednol; Mometasone (Nasal); Prednisolone (Ophthalmic); Triamcinolone (Nasal); Triamcinolone (Ophthalmic). Monitor therapy.
Corticosteroids (Systemic): Corticosteroids (Systemic) may enhance the adverse/toxic effect of EXSIROX. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy.
CYP1A2 Substrates: EXSIROX may increase the serum concentration of CYP1A2 Substrates. Monitor therapy.
CYP2C8 Substrates: EXSIROX may increase the serum concentration of CYP2C8 Substrates. Monitor therapy.
CYP3A4 Substrates: EXSIROX may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy.
Fosphenytoin: Fosphenytoin may decrease the serum concentration of EXSIROX. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial EXSIROX dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification.
Nonsteroidal Anti-Inflammatory: Nonsteroidal Anti-Inflammatory may enhance the adverse/toxic effect of EXSIROX. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy.
Phenobarbital: Phenobarbital may decrease the serum concentration of EXSIROX. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial EXSIROX dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification.
Phenytoin: Phenytoin may decrease the serum concentration of EXSIROX. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial EXSIROX dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification.
Pirfenidone: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Pirfenidone. Management: Use any such combination with caution and close monitoring for Pirfenidone toxicity. Avoid the use of Pirfenidone with moderate CYP1A2 inhibitors whenever CYP2C9, 2C19, 2C6 or 2E1 is also inhibited (either by the CYP1A2 inhibitor or by a third drug). Consider therapy modification.
Repaglinide: EXSIROX may increase in the serum concentration of Repaglinide. Monitor therapy.
Rifampin: Rifampin may decrease the serum concentration of EXSIROX. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial EXSIROX dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification.
Ritonavir: Ritonavir may decrease the serum concentration of EXSIROX. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial EXSIROX dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification.
Theophylline: EXSIROX may increase in the serum concentration of Theophylline. Avoid combination.
Tizanidine: CYP1A2 Inhibitors (Moderate) may increase the serum concentration of Tizanidine. Management: If combined use cannot be avoided, initiate Tizanidine in adult at 2mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of Tizanidine, including adverse reaction. Avoid combination.

Store at temperature not exceeding 30°C. Store in original package in order to protect from moisture.

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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