Deferasirox GPO

Deferasirox GPO

deferasirox

Manufacturer:

GPO

Distributor:

GPO
Full Prescribing Info
Contents
Deferasirox.
Description
Deferasirox GPO: Each dispersible tablet contains 250 mg of deferasirox.
Excipients/Inactive Ingredients: Lactose, crospovidone, croscarmellose sodium, povidone, sodium lauryl sulfate, silicified microcrystalline cellulose, colloidal silicon dioxide, talcum, sodium stearyl fumarate.
Action
Pharmacology: Pharmacodynamics: Mechanism of action: Deferasirox is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper, there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.
Dose/concentration/time-pharmacodynamic response relationship: Data is not available.
Mechanism of toxicity: Data is not available.
Pharmacokinetics: Absorption: Deferasirox is absorbed following oral administration with median times to maximum plasma concentration (Tmax) of approximately 1.5-4 hours. The absolute bioavailability of deferasirox tablets for oral suspension is 70% compared with an intravenous dose. The bioavailability of deferasirox is variably increased when taken with a meal.
Distribution: Deferasirox is highly protein bound (approximately 99%), almost exclusively to serum albumin. The volume of distribution at steady state of deferasirox is 14.37±2.69 L in adults.
Metabolism: Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UDP-glucuronosyltransferase 1A1 (UGT1A1) and to a lesser extent UGT1A3. Cytochrome P450 (CYP-450)-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (approximately 8%).
Elimination: Deferasirox and metabolites are primarily excreted in the feces (84% of the dose). Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose). The mean terminal half-life ranged from 8-16 hours following oral administration.
Linearity/non-linearity pharmacokinetics: The maximum plasma concentration (Cmax) and area under the curve (AUC) of deferasirox increase approximately linearly with the dose after single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3-2.3 after multiple doses.
Special populations: Hepatic function impairment: Deferasirox exposure in patients with varying degrees of hepatic impairment was increased compared with patients with normal hepatic function. The average total (free and bound) AUC of deferasirox increased 16% in mild (Child-Pugh class A) hepatic impairment and 76% in moderate (Child-Pugh class B) hepatic impairment compared with normal hepatic function.
Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox is less than in adults. In children younger than 6 years of age, systemic exposure is approximately 50% lower than in adults.
Gender: Women have a moderately lower apparent clearance (by 17.5%) of deferasirox compared with men.
Indications/Uses
Deferasirox GPO is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in adult and pediatric patients (aged 2 years and over).
Deferasirox GPO is also indicated for the treatment of chronic iron overload in patients with non-transfusion-dependent thalassemia syndromes aged 10 years and older.
Dosage/Direction for Use
General dosing consideration: Prior to starting therapy, obtain a liver iron concentration (LIC) by liver biopsy for identifying patients for treatment with deferasirox therapy (nontransfusion-dependent thalassemia syndrome only); serum ferritin level (on at least 2 measurements 1 month apart [nontransfusion-dependent thalassemia syndrome only]); baseline serum creatinine in duplicate (due to variation in measurements) and determine the creatinine clearance (CrCl) (Cockcroft-Gault method); serum transaminases and bilirubin; and baseline auditory and ophthalmic examinations.
The safety and efficacy of deferasirox when administered with other iron chelation therapy have not been established.
Consider therapy only when a patient has evidence of chronic iron overload, transfusional. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg patient or more in patients weighing more than 40 kg) and a serum ferritin level consistently greater than 1,000 mcg/L.
Deferasirox therapy should only be considered when a patient with a chronic iron overload in nontransfusion-dependent thalassemia syndrome has a LIC of at least 5 mg of iron per gram of liver dry weight (mg Fe/g dw) and a serum ferritin greater than 300 mcg/L.
Doses (mg/kg/day) should be calculated to the nearest whole tablet.
Chronic iron overload in nontransfusion-dependent thalassemia syndromes: Adults and children (10 years of age and older): Maximum dose: 20 mg/kg daily.
Initial dosage: 10 mg/kg daily.
Dosage adjustment: After commencing therapy, monitor serum ferritin monthly. Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain a LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw. Monitor LIC every 6 months. If the baseline 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 remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 20 mg/kg daily. If after 6 months of therapy, the LIC is 3-7 mg Fe/g dw, continue treatment with deferasirox at no more than 10 mg/kg daily.
Discontinuation of therapy: Interrupt therapy when serum ferritin is less than 300 mcg/L and obtain a 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 rises again to more than 5 mg Fe/g dw.
Chronic iron overload, transfusional: Adults and children (2 years and older): Maximum dose: 40 mg/kg daily.
Initial dosage: 20 mg/kg daily.
Dosage adjustment: After commencing therapy, monitor serum ferritin monthly and adjust the dosage of deferasirox if necessary every 3 to 6 months based on serum ferritin trends. Make dose adjustments in increments of 5 or 10 mg/kg and tailor adjustment 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 deferasirox.
Discontinuation of therapy: Discontinue therapy for serum creatinine greater than 2 times of the age-appropriate upper limit of normal (ULN) or for CrCl less than 40 mL/min.
Special populations: Renal function impairment: For patients with renal impairment (CrCl 40-60 mL/min), reduce the starting dose by 50%. Use is contraindicated in patients with serum creatinine greater than 2 times the ULN or with CrCl less than 40 mL/min.
Chronic iron overload in nontransfusion-dependent thalassemia syndromes: Adults and adolescents 16 years and older: If the serum creatinine increases by 33% or more above the average baseline measurements, 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 10-15 years of age: Reduce the dose by 5 mg/kg if serum creatinine increases to more than 33% above the average baseline measurement and greater than the age-appropriate ULN.
Chronic iron overload, transfusional: Adults and adolescents 16 years and older: If the serum creatinine increases by 33% or more above the average baseline measurements, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 10 mg/kg.
Children 2-15 years of age: Reduce the dose by 10 mg/kg if serum creatinine increases to more than 33% above the average baseline measurement and greater than the age-appropriate ULN.
Hepatic function impairment: Moderate hepatic impairment (Child-Pugh class B): Reduce the starting dose by 50%.
Severe hepatic impairment (Child-Pugh class C): Avoid use.
Concomitant therapy: Avoid the concomitant use of bile acid sequestrants (eg, cholestyramine, colesevelam, colestipol) or potent UGT inducers (e.g., rifampicin, phenobarbital, phenytoin, ritonavir) with deferasirox. If these agents must be coadministered together, consider increasing the initial dose of deferasirox by 50%, and monitor serum ferritin levels and clinical responses for further dose modification.
Deferasirox should not be taken with aluminum-containing antacid products.
Mode of administration: Deferasirox should be taken once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day. Tablets should not be chewed or swallowed whole.
Completely disperse tablets by stirring in water, orange juice, or apple juice until a fine suspension is obtained. Disperse doses of less than 1 g in 105 ml of liquid and doses of 1 g or more in 210 ml of liquid. After swallowing the suspension, resuspend any residue in a small volume of liquid and swallow.
Overdosage
Symptoms: Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. This results in hepatitis, which resolved without long-term consequences after a dose interruption. Single doses of up to 80 mg/kg in patients with iron-overloaded beta-thalassemia have been tolerated, with nausea and diarrhea noted. In healthy volunteers, single dosages of up to 40 mg/kg/day were tolerated.
Treatment: There is no specific antidote for deferasirox. In case of overdose, employ gastric lavage.
Contraindications
Deferasirox is contraindicated to patients with the following conditions: CrCl less than 40 mL/min or serum creatinine greater than 2 times the age-appropriate ULN, Poor performance status, High-risk myelodysplastic syndromes, Advanced malignancies, Platelet counts less than 50 x 109/L, Known hypersensitivity to deferasirox or any component of deferasirox.
Special Precautions
Renal failure: Deferasirox can cause acute renal failure and death, particularly in patient with comorbidities and those who are in the advanced stages of their hematologic disorders. Measure serum creatinine and determine CrCl in duplicate prior to initiation of therapy and monitor renal function at least monthly thereafter. For patients with baseline renal impairment or at increased risk of acute renal failure, monitor creatinine weekly for the first month, then at least monthly thereafter. Consider dose reduction, interruption, or discontinuation based on increases in serum creatinine.
Hepatic failure: Deferasirox can cause hepatic injury, including hepatic failure and death. Measure serum transaminases and bilirubin in all patients prior to initiating treatment, every 2 weeks during the first month, and at least monthly thereafter. Avoid use of deferasirox in patients with severe (Child-Pugh class C) hepatic impairment and reduce the dose in patients with moderate (Child-Pugh class B) hepatic impairment.
Gastrointestinal (GI) hemorrhage: Deferasirox can cause GI hemorrhage, which may be fatal, especially in elderly patients who have advanced hematologic malignancies and/or low platelet counts. Monitor patients and discontinue deferasirox for suspected GI ulceration or hemorrhage. Renal effects: Deferasirox can cause acute renal failure, fatal in some patients and requiring dialysis in others. Most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematologic disorders.
Measure serum creatinine in duplicate (because of variations in measurements) and determine the CrCl before initiating therapy in all patients to establish a reliable pretreatment baseline. Monitor serum creatinine and/or CrCl at least monthly thereafter or more frequently for increases. Monitor serum creatinine weekly during the first month after initiation or modification of therapy, and at least monthly thereafter. Dose reduction, interruption, or discontinuation based on increases in serum creatinine may be necessary.
Renal tubular damage, including Fanconi syndrome, has been reported in patients treated with deferasirox, most commonly in children and adolescents with beta-thalassemia and serum ferritin levels less than 1,500 mcg/L.
Hepatic effects: Deferasirox can cause hepatic injury, which is fatal in some patients. Hepatic toxicity appears to be more common in patients older than 55 years. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure. Monitor serum transaminases (ALT and AST) and bilirubin in all patients before the initiation of treatment, every 2 weeks during the first month, and at least monthly thereafter. Consider dosage modifications or interruption of treatment for severe or persistent elevations.
Gastrointestinal (GI) effects: Fatal GI hemorrhages, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts, have been reported. Nonfatal upper GI irritation, ulceration, and hemorrhage have been reported in patients, including children and adolescents, receiving deferasirox. Monitor signs and symptoms of GI ulceration and hemorrhage during deferasirox therapy, and promptly initiate additional evaluation and treatment if a serious GI adverse reaction is suspected. The risk of GI hemorrhage may be increased when administering deferasirox in combination with drugs that have ulcerogenic or hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants.
Bone marrow suppression: Agranulocytosis, neutropenia, thrombocytopenia, and worsening anemia, including fatal events, have been reported in patients treated with deferasirox. Preexisting hematologic disorders may increase this risk. Monitor blood cell counts in all patients. Interrupt treatment with deferasirox in patients who develop cytopenias until the cause of cytopenia has been determined.
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 syndrome and erythema multiforme, have also been reported; discontinue and evaluate if suspected.
Special senses: Auditory disturbances (eg, high-frequency hearing loss, decreased hearing) and ocular disturbances (eg, lens opacities, cataracts, elevations in intraocular pressure, retinal disorders) have been reported. Perform auditory and ophthalmic testing before starting deferasirox and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more closely and consider dose reduction or interruption of therapy.
Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients receiving deferasirox, with the onset of the reaction usually occurring within the first month of treatment. If reactions are severe, discontinue deferasirox and institute appropriate medical intervention.
Effect on ability to drive and use machine: Data is not available.
Use in Children: Safety and effectiveness have not been established in pediatric patients with chronic iron overload due to blood transfusions who are younger than 2 years or pediatric patients with chronic iron overload and nontransfusion-dependent thalassemia who are younger than 10 years.
Use in Elderly: Elderly patients experienced a higher frequency of adverse reactions than younger patients. Closely monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at an increased risk for deferasirox toxicity because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Deferasirox has been associated with serious and fatal adverse reactions in elderly patients. Monitor elderly patients more frequently for toxicity.
Use In Pregnancy & Lactation
Pregnancy: US Pregnancy category C: Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
There are no adequate and well-controlled studies with deferasirox in pregnant women. It is not known if deferasirox crosses the human placenta. The molecular weight (about 373) and long elimination half-life suggest that exposure of the embryo and/or fetus will occur, but the very high protein binding should limit the exposure. Administration of deferasirox to animals during pregnancy resulted in decreased offspring viability and an increase in renal anomalies in male offspring at exposures that were less than the recommended human exposure.
Labor and delivery: Data is not available.
Lactation: It is not known whether deferasirox is excreted in human milk. The molecular weight (about 373) and long elimination half-life (8-16 hours) suggest that the drug also will be excreted into breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breast-feeding infants from deferasirox and its metabolites, decide whether to discontinue the breast-feeding or the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
Very common adverse reactions: Abdominal pain, diarrhea, nausea, vomiting, increase in serum creatinine, rash.
Uncommon adverse reactions: Anxiety, dizziness, fatigue, sleep disorder, pigmentation disorder, cholelithiasis, duodenal ulcer, gastritis, gastric ulcer (including multiple ulcers), GI hemorrhage, early cataract, hearing loss, maculopathy, edema, pharyngolaryngeal pain, pyrexia, renal tubulopathy (Fanconi syndrome).
Rare adverse reactions: Erythema multiforme, esophagitis, optic neuritis.
Drug Interactions
Metabolism/Transport effects: Deferasirox is a substrate of UGT1A1, inhibits CYP1A2 (moderate) and CYP2C8 (moderate) and induces CYP3A4 (weak/moderate).
Agomelatine: Effect: CYP1A2 inhibitor (moderate) may increase the serum concentration of agomelatine.
Management: Monitor therapy.
Aluminum hydroxide: Effect: May diminish the therapeutic effect of deferasirox.
Management: Avoid combination.
Anticoagulants: Effect: May enhance the adverse/toxic effect of deferasirox. Specifically, the risk of GI ulceration/irritation or GI bleeding may be increased.
Management: Monitor therapy.
Aripiprazole: Effect: CYP3A4 inducers may decrease the serum concentration of aripiprazole.
Management: Double the oral aripiprazole dose and closely monitor clinical response. Reduce the oral aripiprazole dose to 10-15 mg/day if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification.
Axitinib: Effect: CYP3A4 inducers (weakly to moderately effective) may decrease the serum concentration of axitinib.
Management: Avoid combination.
Bile acid sequestrants: Effect: May decrease the serum concentration of deferasirox.
Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing.
Bisphosphonates derivatives: Effect: May enhance the adverse/toxic effect of deferasirox. Specifically, the risk of GI ulceration/irritation or GI bleeding may be increased.
Management: Monitor therapy.
Corticosteroids: Effect: May enhance the adverse/toxic effect of deferasirox. Specifically, the risk of GI ulceration/irritation or GI bleeding may be increased.
Exceptions: beclomethasone (nasal) budesonide (nasal); ciclesonide (nasal); desonide; dexamethasone (ophthalmic); difluprednate; flunisolide (nasal); fluocinolone (ophthalmic); fluticasone (nasal); loteprednol; mometasone (nasal); prednisolone (ophthalmic); triamcinolone (nasal); triamcinolone (ophthalmic).
Management: Monitor therapy.
Corticosteroids (systemic): Effect: May enhance the adverse/toxic effect of deferasirox. Specifically, the risk of GI ulceration/irritation or GI bleeding may be increased.
Management: Monitor therapy.
CYP1A2, CYP2C8 substrates: Effect: Deferasirox may increase the serum concentration of CYP1A2 and CYP2C8 substrates.
Management: Monitor therapy.
CYP3A4 substrates: Effect: Deferasirox may decrease the serum concentration of CYP3A4 substrates.
Management: Monitor therapy.
Fosphenytoin, phenobarbital, phenytoin, rifampin, ritonavir: Effect: May decrease the serum concentration of deferasirox.
Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing. Consider therapy modification.
Ibrutinib: Effect: CYP3A4 inducers (weakly to moderately effective) may decrease the serum concentration of ibrutinib.
Management: Consider therapy modification.
Nonsteroidal anti-inflammatory drugs (NSAIDs): Effect: May enhance the adverse/toxic effect of deferasirox. Specifically, the risk of GI ulceration/irritation or GI bleeding may be increased.
Management: Monitor therapy.
Pirfenidone: Effect: CYP1A2 inhibitor (moderate) may increase the serum concentration of pirfenidone.
Management: This combination may be used with caution only if the moderate CYP1A2 inhibitor does not significantly inhibit other CYP enzymes and the patient is not taking any other drugs that do significantly inhibit other specific CYP enzymes. Avoid combination.
Repaglinide: Effect: Deferasirox may increase the serum concentration of repaglinide.
Management: Monitor therapy.
Saxagliptin: Effect: CYP3A4 inducers may decrease the serum concentration of saxagliptin.
Management: Monitor therapy.
Simeprevir: Effect: CYP3A4 inducers (weakly to moderately effective) may decrease the serum concentration of simeprevir.
Management: Avoid combination.
Theophylline: Effect: Deferasirox may increase the serum concentration of theophylline.
Management: Avoid combination.
Food: Effect: Bioavailability is variably increased when taken with food.
Management: Taken on an empty stomach at the same time each day at least 30 minutes before food. Maintain adequate hydration unless instructed to restrict fluid intake.
Storage
Do not store above 30°C. Store in the original container.
ATC Classification
V03AC03 - deferasirox ; Belongs to the class of iron chelating agents. Used in the management of chronic iron overload associated with blood transfusion.
Presentation/Packing
Orodispersible tab 250 mg (off white, flat, round, compressed tablets, one side debossed with "D250" and the other side debossed with "GPO") x 3 x 10's.
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