Siroxtrin 125 mg/250 mg/500 mg Dispersible Tablets

SIROXTRIN is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional haemosiderosis) in adult and paediatric patients (aged 2 years and over). SIROXTRIN is also indicated for the treatment of chronic iron overload in patients with non-transfusion-dependent thalassemia syndromes aged 10 years and older. SIROXTRIN therapy should only be initiated when there is evidence of iron overload (liver iron concentration (LIC) u2265 5 mg Fe/g dry weight (dw) or serum ferritin consistently > 800 microgram/L).

Posology

Transfusional iron overload

Dosage

It is recommended that therapy with SIROXTRIN be started after the transfusion of approximately 20 units (about 100 ml/kg) of packed red blood cells or when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum ferritin > 1 000 microgram/L). Doses (in mg/kg) must be calculated and rounded to the nearest whole tablet size. SIROXTRIN is available in three tablet strengths (125 mg, 250 mg and 500 mg). The decision to remove accumulated iron should be individualised based on anticipated clinical benefit and risks of chelation therapy.

Starting dose

The starting dose is determined by the frequency of blood transfusions. The recommended initial daily dose of SIROXTRIN is 20 mg/kg body weight. 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 (approximately > 4 units/month for an adult). 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 (approximately < 2 units/month for an adult). For patients already well-managed on treatment with deferoxamine, a starting dose of SIROXTRIN that is numerical 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 SIROXTRIN).

Non-transfusion-dependent thalassaemia syndrome

Dosage

SIROXTRIN therapy should only be initiated when there is evidence of iron overload (liver iron concentration (LIC) u2265 5 mg Fe/g dry weight (dw) or serum ferritin consistently > 800 microgram/L). In patients with no LIC assessment, caution should be taken during chelation therapy to minimise the risk of over-chelation.

Starting dose

The recommended initial daily dose of SIROXTRIN is 10 mg/kg body weight.

Dose adjustment

It is recommended that serum ferritin be monitored every month to assess the patientsu2019 response to therapy and to minimize the risk of overchelation (see section 4.3). Every 3 to 6 months of treatment, consider a dose increase in increments of 5 to 10 mg/kg if the patientu2019s LIC is u2265 7 mg Fe/g dw, or serum ferritin is consistently > 2 000 microgram/L and not showing a downward trend, and the patient is tolerating the medicine 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 thalassaemia syndromes. In patients in whom LIC was not assessed and serum ferritin is u2264 2 000 microgram/L, dosing should not exceed 10 mg/kg. For patients in whom the dose was increased to > 10 mg/kg, dose reduction is recommended to 10 mg/kg or less when LIC is < 7 mg Fe/g dw or serum ferritin is u2264 2 000 microgram/L. Once a satisfactory body iron level has been achieved (LIC < 3 mg Fe/g dw or serum ferritin < 300 microgram/L), treatment should be interrupted. Treatment should be re-initiated when there is evidence from clinical monitoring that chronic iron overload is present.

Special populations

Elderly patients

The dosing recommendations for elderly patients are the same as described above. Elderly patients experienced a higher frequency of adverse reactions than younger patients and elderly patients should be monitored closely for adverse reactions that may require a dose adjustment.

Patients with renal impairment

SIROXTRIN treatment must be used with caution in patients with serum creatinine levels above the age-appropriate upper limit of the normal range (see section 4.3). SIROXTRIN should not be used by patients with CrCl below 60 ml/min. (see section 4.3). The initial dosing recommendations for patients with renal impairment are the same as described above. Serum creatinine should be monitored monthly in all patients and if necessary daily doses can be reduced by 10 mg/kg (see section 4.4). For adult patients, the daily dose of SIROXTRIN 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 paediatric 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, SIROXTRIN should be interrupted. Therapy with SIROXTRIN may be reinitiated depending on the individual clinical circumstances.

Patients with hepatic impairment

For patients with moderate hepatic impairment (Child-Pugh B), the starting dose should be reduced by approximately 50 %. SIROXTRIN should not be used in patients with severe hepatic impairment (Child-Pugh C) (see section 4.3). Hepatic function in all patients should be monitored before the initiation of treatment, every 2 weeks during the first month and monthly thereafter (see section 4.4).

Paediatric population

The dosing recommendations for paediatric patients are the same as for adult patients. It is recommended that serum ferritin be monitored every month to assess the patientu2019s response to therapy and to minimize the risk of overchelation (see section 4.4). Changes in weight of paediatric patients over time must be taken into account when calculating the dose.

Method of administration

SIROXTRIN must be taken once daily on an 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 u2013 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 (see section 4.5). Dispersion in carbonated drinks or milk is not recommended due to foaming and slow dispersion, respectively.

• Hypersensitivity to deferasirox or to any of the other excipients (see section 6.1).
• Creatinine clearance < 60 ml/min.
• Repaglinide (see section 4.5).
• High risk myelodysplastic syndrome (MDS) patients and patients with other haematological and nonhaematological malignancies with limited expected survival (< 1 year) who are not expected to benefit from chelation therapy due to the rapid progression of their disease.
• Severe hepatic impairment (Child-Pugh C).
• Pregnancy and lactation (see section 4.6).

Concomitant administration of SIROXTRIN with medicine that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, and use of SIROXTRIN in patients receiving anticoagulants may increase the risk of gastrointestinal complications such as ulceration and haemorrhage.

There have been post marketing reports of hepatic failure in patients treated with deferasirox (as in SIROXTRIN). Most reports of hepatic failure involved patients with significant comorbidities including liver cirrhosis and multi-organ failure; fatal outcomes were reported in some of these patients. The decision to remove accumulated iron should be individualised based on anticipated clinical benefit and risks of chelation therapy. 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 in patients treated with SIROXTRIN, usually within the normal range. Cases of acute renal failure have been reported (see section 4.8). Although causal relationship with SIROXTRIN could not be established, there have been cases of acute renal failure requiring dialysis or with fatal outcome. 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 other medicines 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 (including switching formulation) and monthly thereafter. SIROXTRIN should not be used in patients with creatinine clearance less than 60 mL/min (see section 4.3). Renal tubulopathy has been reported in patients treated with deferasirox (as in SIROXTRIN). The majority of these patients were children and adolescents with beta-thalassaemia and serum ferritin levels < 1 500 microgram/L. Dose reduction or interruption may be considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated.

Tests for proteinuria should be performed monthly. Care should be taken to maintain adequate hydration in patients who develop diarrhoea or vomiting.

For adult patients, the daily dose of SIROXTRIN 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 (see section 4.2). The recommendations for renal function monitoring are summarized in the Table 1.

Table 1: Recommendations for renal function monitoring

Serum creatinine

Creatinine clearance

Before initiation of therapy

Twice (2x) and/or

Twice (2x)

Contraindicated

> 2 times age appropriate ULN* or < 40 mL/min

Monitoring

Monthly and/or

Monthly

For patients with pre-existing renal conditions, or patients who are receiving medicines that may depress the renal function as they may be more at risk of complications in the first month after initiation, or modification of therapy (including switching formulation), monitoring should be:

Weekly and/or

Weekly

Reduction of daily dose by 10 mg/kg/day if following renal parameters are observed on two consecutive visits and cannot be attributed to other causes:

Adult patients

> 33 % above pre-treatment average (non-progressive rise)

Paediatric patients

> age-appropriate ULN*

After dose reduction, interrupt treatment, if:

Adult and paediatric patients

Progressive increase in serum creatinine beyond the upper limit of normal

*ULN: upper limit of the normal range

Hepatic

SIROXTRIN is not recommended in patients with severe hepatic impairment (Child-Pugh C) (see section 4.3). Deferasirox is principally eliminated by glucuronidation and is minimally (about 8 %) metabolised by oxidative cytochrome P450 enzymes. Although uncommon (0,3 %), elevations of transaminases greater than 10 times the upper limit of the normal range, suggestive of hepatitis, have been observed. There have been post marketing reports of hepatic failure in patients treated with deferasirox (as in SIROXTRIN). Most reports of hepatic failure involved patients with significant comorbidities 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, SIROXTRIN should be interrupted. Once the cause of the liver function test abnormalities has been clarified or after return to normal levels, cautious re-initiation of SIROXTRIN treatment at a lower dose followed by gradual dose escalation may be considered.

Anticipated interactions resulting in a concomitant use not recommended

The concomitant administration of SIROXTRIN and aluminium-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminium than for iron, SIROXTRIN tablets must not be taken with aluminium-containing antacid preparations. Concomitant administration of SIROXTRIN with medicine that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, and use of SIROXTRIN in patients receiving anticoagulants may increase the risk of gastrointestinal complications such as ulceration and haemorrhage.

Interaction with midazolam and other medicines metabolised by CYP3A4

In a healthy volunteer study, the concomitant administration of deferasirox (as in SIROXTRIN) and midazolam (a CYP3A4 substrate) resulted in a decrease of midazolam exposure by 17 % (90 % CI: 8 % - 26 %). In the clinical setting, this effect may be more pronounced. Therefore, due to a possible decrease in efficacy, caution should be exercised when deferasirox is combined with medicines metabolised through CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive medicines).

Medicines that may decrease SIROXTRIN systemic exposure

In a healthy volunteer study, the concomitant administration of deferasirox (as in SIROXTRIN) (single dose of 30 mg/kg) and the potent UDP-glucuronosyltransferase (UGT) inducer rifampicin (repeated dose of 600 mg/day) resulted in a decrease of deferasirox exposure by 44 % (90 % CI: 37 % - 51 %). Therefore, the concomitant use of SIROXTRIN with potent UGT inducers (e.g. rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in SIROXTRIN efficacy. If SIROXTRIN and a potent UGT inducer are used concomitantly, increases in the dose of SIROXTRIN should be considered based on clinical response to therapy.

Interaction with repaglinide and other medicines metabolised by CYP2C8

In a healthy volunteer study, the concomitant administration of deferasirox (as in SIROXTRIN) (repeated dose of 30 mg/kg/day) and the CYP2C8 substrate repaglinide (single dose of 0,5 mg) resulted in an increase in repaglinide AUC and C max by 131 % (90 % CI: 103 % - 164 %) and 62 % (90 % CI: 42 % - 84 %), respectively. An interaction between SIROXTRIN and other CYP2C8 substrates like paclitaxel cannot be excluded.

Interaction with theophylline and other medicines metabolized by CYP1A2

In a healthy volunteer study, the concomitant administration of deferasirox (as in SIROXTRIN) (repeated dose of 30 mg/kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an increase in theophylline AUC by 84 % (90 % CI: 73 % to 95 %). The single dose C max was not affected, but an increase of theophylline C max is expected to occur with chronic dosing.

Interaction with busulfan

Based on literature reports, concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC). The AUC increase ranged approximately 40 to 150 %. The mechanism of the interaction remains unclear. Caution should be exercised when deferasirox is combined with busulfan and the patientu2019s plasma concentrations of busulfan should be monitored.

When deferasirox (as in SIROXTRIN) and theophylline are used concomitantly, monitoring of theophylline concentration and possible theophylline dose reduction should be considered. An interaction between SIROXTRIN and other CYP1A2 substrates may be possible.

Interaction with food

The bioavailability of deferasirox (as in SIROXTRIN) was increased to a variable extent when taken along with food. SIROXTRIN must therefore be taken on an empty stomach at least 30 minutes before food, preferably at the same time each day (see section 4.2). Information on dispersion of SIROXTRIN in fruit juices other than orange and apple is not available.

Other information

No interaction was observed between deferasirox (as in SIROXTRIN) and digoxin in healthy volunteers. The concomitant administration of deferasirox (as in SIROXTRIN) and vitamin C has not been formally studied. Doses of vitamin C up to 200 mg/day have not been associated with adverse consequences. The safety profile of deferasirox in combination with other iron chelators (deferoxamine, deferiprone) observed in clinical trials, post-marketing experience or published literature (as applicable) was consistent with that characterized for monotherapy.

Pregnancy

Safety in pregnancy and lactation has not been established. Studies in animals have shown some reproductive toxicity at maternally toxic doses. The potential risk for humans is unknown. SIROXTRIN should not be used during pregnancy (see section 4.3).

Breastfeeding

In animal studies, deferasirox (as in SIROXTRIN) was found to be rapidly and extensively secreted into maternal milk. It is not known if SIROXTRIN is secreted into human milk. Breastfeeding while taking SIROXTRIN is not recommended.

Fertility

No fertility data is available for humans. In animals, no adverse effects on male or female fertility were found.

No studies on the effects of SIROXTRIN on the ability to drive and use machines have been performed. Patients experiencing dizziness should exercise caution when driving or operating machinery (see section 4.8).

a. Summary of the safety profile

The most frequent reactions reported during chronic treatment with deferasirox (as in SIROXTRIN) in adult and paediatric patients included gastrointestinal disturbances (mainly nausea, vomiting, diarrhoea, or abdominal pain), and skin rash. Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years and in the elderly. These reactions are dose dependent. Mild, non-progressive increases in serum creatinine, mostly within the normal range, occur in 36 % of patients. These reactions are dose-dependent, often resolve spontaneously and can sometimes be alleviated by reducing the dose (see section 4.4).

b. Tabulated summary of adverse reactions

The frequency of adverse reactions listed below is defined using the following convention: frequent; less frequent or frequency unknown (cannot be estimated from the available data).

System organ class

Frequency

Adverse reactions

Blood and lymphatic system disorders

Frequency unknown

Pancytopenia, thrombocytopenia, neutropenia, aggravated anaemia

Immune system disorders

Frequency unknown

Hypersensitivity reactions (including anaphylaxis and angioedema)

Metabolism and nutrition disorders

Frequency unknown

Metabolic acidosis

Psychiatric disorders

Less frequent

Anxiety, sleep disorder

Nervous system disorders

Frequent

Headache

Less frequent

Dizziness

Eye disorders

Less frequent

Early cataract, maculopathy, optic neuritis

Ear and labyrinth disorders

Less frequent

Hearing loss

Respiratory, thoracic and mediastinal disorders

Less frequent

Pharyngolaryngeal pain

Gastrointestinal disorders

Frequent

Diarrhoea, constipation, vomiting, nausea, abdominal pain, abdominal distension, dyspepsia

Less frequent

Gastritis, gastrointestinal haemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, oesophagitis

Frequency unknown

Gastrointestinal perforation, acute pancreatitis

Hepato-biliary disorders

Frequent

Increased transaminases

Less frequent

Hepatitis, cholelithiasis

Frequency unknown

Hepatic failure

Skin and subcutaneous tissue disorders

Frequent

Rash, pruritis

Less frequent

Pigmentation disorder, drug reaction with eosinophilia and systemic symptoms (DRESS)

Frequency unknown

Stevens-Johnson syndrome, leukocytoclastic vasculitis, hypersensitivity vasculitis, urticaria, erythema multiforme, alopecia, toxic epidermal necrolysis (TEN)

Renal and urinary disorders

Frequent

Increased blood creatinine, proteinuria

Less frequent

Glycosuria, renal tubulopathy (Fanconiu2019s syndrome)

Frequency unknown

Nephrolithiasis, renal tubular necrosis, acute renal failure (serum creatinine increases > 2 x upper limit of normal), tubulointerstitial nephritis

General disorders and administration site conditions

Less frequent

Pyrexia, oedema, fatigue

c. Paediatric population

Renal tubulopathy has been reported in patients treated with deferasirox (as in SIROXTRIN). The majority of these patients were children and adolescents with beta-thalassaemia and serum ferritin levels < 1 500 microgram/L. In a 5-year observational study in which 267 children aged 2 to 33 % and above the upper limit of normal (ULN) on u2265 2 consecutive occasions were observed in 3,1 % of children and elevation of alanine aminotransferase (ALT) greater than 5 times the ULN was reported in 4,3 % of children. The most frequently observed AEs with reported suspected relationship to study medicine were increase in ALT (21,1 %), increase in aspartate aminotransferase (AST, 11,9 %), vomiting (5,4 %), rash (5,0 %), increase in blood creatinine (3,8 %), abdominal pain (3,1 %) and diarrhoea (1,9 %). Overall growth and development were not affected in this paediatric population.

Single doses up to 40 mg/kg in normal participants have been well tolerated. Early sign of acute overdose are digestive effects such as abdominal pain, diarrhoea, nausea and vomiting. Hepatic and renal disorders have been reported, including cases of liver enzyme and creatinine increased with recovery after treatment discontinuation. An erroneously administered single dose of 90 mg/kg led to Fanconi syndrome with resolved after treatment.

There is no specific antidote for deferasirox. Symptomatic and supportive treatment should be initiated as appropriate to the patientu2019s clinical status. Symptomatic treatment, as medically appropriate.