1. Name Of The Medicinal Product
® 125 mg dispersible tablets
® 250 mg dispersible tablets
® 500 mg dispersible tablets
2. Qualitative And Quantitative Composition
Each dispersible tablet contains 125 mg deferasirox.
Each dispersible tablet contains 250 mg deferasirox.
Each dispersible tablet contains 500 mg deferasirox.
Excipient:
Each dispersible tablet contains 136 mg lactose.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Dispersible tablet
Off-white, round, flat tablets with bevelled edges and imprints (NVR on one face and J 125 on the other).
Off-white, round, flat tablets with bevelled edges and imprints (NVR on one face and J 250 on the other).
Off-white, round, flat tablets with bevelled edges and imprints (NVR on one face and J 500 on the other).
4. Clinical Particulars
4.1 Therapeutic Indications
EXJADE is indicated for the treatment of chronic iron overload due to frequent blood transfusions (
EXJADE is also indicated for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups:
- in patients with beta thalassaemia major with iron overload due to frequent blood transfusions (
- in patients with beta thalassaemia major with iron overload due to infrequent blood transfusions (<7 ml/kg/month of packed red blood cells) aged 2 years and older,
- in patients with other anaemias aged 2 years and older.
4.2 Posology And Method Of Administration
Treatment with EXJADE should be initiated and maintained by physicians experienced in the treatment of chronic iron overload due to blood transfusions.
Posology
It is recommended that treatment 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 µg/l). Doses (in mg/kg) must be calculated and rounded to the nearest whole tablet size.
The goals of iron chelation therapy are to remove the amount of iron administered in transfusions and, as required, to reduce the existing iron burden.
Starting dose
The recommended initial daily dose of EXJADE is 20 mg/kg body weight.
An initial daily dose of 30 mg/kg may be considered for patients who require reduction of elevated body iron levels and who are also 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 who do not require reduction of body iron levels and who are also receiving less than 7 ml/kg/month of packed red blood cells (approximately <2 units/month for an adult). The patient's response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained (see section 5.1).
For patients already well managed on treatment with deferoxamine, a starting dose of EXJADE 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 EXJADE). When this results in a daily dose less than 20 mg/kg body weight, the patient's response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained (see section 5.1).
Maintenance dose
It is recommended that serum ferritin be monitored every month and that the dose of EXJADE be adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin. Dose adjustments may be made in steps of 5 to 10 mg/kg and are to be tailored to the individual patient's response and therapeutic goals (maintenance or reduction of iron burden). In patients not adequately controlled with doses of 30 mg/kg (e.g. serum ferritin levels persistently above 2,500 µg/l and not showing a decreasing trend over time), doses of up to 40 mg/kg may be considered. The availability of long-term efficacy and safety data with EXJADE used at doses above 30 mg/kg is currently limited (264 patients followed for an average of 1 year after dose escalation). If only very poor haemosiderosis control is achieved at doses up to 30 mg/kg, a further increase (to a maximum of 40 mg/kg) may not achieve satisfactory control, and alternative treatment options may be considered. If no satisfactory control is achieved at doses above 30 mg/kg, treatment at such doses should not be maintained and alternative treatment options should be considered whenever possible. Doses above 40 mg/kg are not recommended because there is only limited experience with doses above this level.
In patients treated with doses greater than 30 mg/kg, dose reductions in steps of 5 to 10 mg/kg should be considered when control has been achieved (e.g. serum ferritin levels persistently below 2,500 µg/l and showing a decreasing trend over time). In patients whose serum ferritin level has reached the target (usually between 500 and 1,000 µg/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 µg/l, an interruption of treatment should be considered (see section 4.4).
Elderly patients (
The dosing recommendations for elderly patients are the same as described above. In clinical trials, elderly patients experienced a higher frequency of adverse reactions than younger patients (in particular, diarrhoea) and should be monitored closely for adverse reactions that may require a dose adjustment.
Paediatric population
The dosing recommendations for paediatric patients aged 2 to 17 years are the same as for adult patients. Changes in weight of paediatric patients over time must be taken into account when calculating the dose.
In children aged between 2 and 5 years, exposure is lower than in adults (see section 5.2). This age group may therefore require higher doses than are necessary in adults. However, the initial dose should be the same as in adults, followed by individual titration.
The safety and efficacy of EXJADE in children from birth to 23 months of age have not yet been established. No data are available.
Patients with renal impairment
EXJADE has not been studied in patients with renal impairment and is contraindicated in patients with estimated creatinine clearance <60 ml/min (see sections 4.3 and 4.4).
Patients with hepatic impairment
EXJADE has not been studied in patients with hepatic impairment and must be used with caution in such patients. The initial dosing recommendations for patients with hepatic impairment are the same as described above. Hepatic function in all patients should be monitored before treatment, every 2 weeks during the first month and then every month (see section 4.4).
Method of administration
For oral use.
EXJADE must be taken once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day (see sections 4.5 and 5.2).
The tablets are dispersed by stirring in a glass of water or orange or apple 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 (see also section 6.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Combination with other iron chelator therapies as the safety of such combinations has not been established (see section 4.5).
Patients with estimated creatinine clearance <60 ml/min.
4.4 Special Warnings And Precautions For Use
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In patients with a short life expectancy (e.g. high-risk myelodysplastic syndromes), especially when co-morbidities could increase the risk of adverse events, the benefit of EXJADE might be limited and may be inferior to risks. As a consequence, treatment with EXJADE is not recommended in these patients.
Caution should be used in elderly patients due to a higher frequency of adverse reactions (in particular, diarrhoea).
Gastrointestinal
Upper gastrointestinal ulceration and haemorrhage have been reported in patients, including children and adolescents, receiving EXJADE. Multiple ulcers have been observed in some patients (see section 4.8). There have been reports of fatal gastrointestinal haemorrhages, especially in elderly patients who had haematological malignancies and/or low platelet counts. Physicians and patients should remain alert for signs and symptoms of gastrointestinal ulceration and haemorrhage during EXJADE therapy and promptly initiate additional evaluation and treatment if a serious gastrointestinal adverse reaction is suspected. Caution should be exercised in patients who are taking EXJADE in combination with substances that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, in patients receiving anticoagulants and in patients with platelet counts below 50,000/mm3 (50 x 109/l) (see section 4.5).
Skin disorders
Skin rashes may appear during EXJADE treatment. The rashes resolve spontaneously in most cases. When interruption of treatment may be necessary, treatment may be reintroduced after resolution of the rash, at a lower dose followed by gradual dose escalation. In severe cases this reintroduction could be conducted in combination with a short period of oral steroid administration.
Hypersensitivity reactions
Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving EXJADE, with the onset of the reaction occurring in the majority of cases within the first month of treatment (see section 4.8). If such reactions occur, EXJADE should be discontinued and appropriate medical intervention instituted.
Vision and hearing
Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported (see section 4.8). Auditory and ophthalmic testing (including fundoscopy) is recommended before the start of treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during the treatment, dose reduction or interruption may be considered.
Blood disorders
There have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia, or aggravation of these cytopenias in patients treated with EXJADE. Most of these patients had pre-existing haematological disorders that are frequently associated with bone marrow failure. However, a contributory or aggravating role cannot be excluded. Interruption of treatment should be considered in patients who develop unexplained cytopenia.
Other considerations
Monthly monitoring of serum ferritin is recommended in order to assess the patient's response to therapy (see section 4.2). If serum ferritin falls consistently below 500 µg/l, an interruption of treatment should be considered.
The results of the tests for serum creatinine, serum ferritin and serum transaminases should be recorded and regularly assessed for trends. The results should also be noted in the provided patient's booklet.
In one clinical study, growth and sexual development of paediatric patients treated with EXJADE for up to 5 years were not affected. However, as a general precautionary measure in the management of paediatric patients with transfusional iron overload, body weight, height and sexual development should be monitored at regular intervals (every 12 months).
Cardiac dysfunction is a known complication of severe iron overload. Cardiac function should be monitored in patients with severe iron overload during long-term treatment with EXJADE.
Each tablet contains 136 mg lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or severe lactase deficiency should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The safety of EXJADE in combination with other iron chelators has not been established. Therefore, it must not be combined with other iron chelator therapies (see section 4.3).
The concomitant administration of EXJADE with substances that have known ulcerogenic potential, such as NSAIDs (including acetylsalicylic acid at high dosage), corticosteroids or oral bisphosphonates may increase the risk of gastrointestinal toxicity (see section 4.4). The concomitant administration of EXJADE with anticoagulants may also increase the risk of gastrointestinal haemorrhage. Close clinical monitoring is required when deferasirox is combined with these substances.
The bioavailability of deferasirox was increased to a variable extent when taken along with food. EXJADE must therefore be taken on an empty stomach at least 30 minutes before food, preferably at the same time each day (see sections 4.2 and 5.2).
Deferasirox metabolism depends on UGT enzymes. In a healthy volunteer study, the concomitant administration of EXJADE (single dose of 30 mg/kg) and the potent 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 EXJADE with potent UGT inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir) may result in a decrease in EXJADE efficacy. The patient's serum ferritin should be monitored during and after the combination, and the dose of EXJADE adjusted if necessary.
Cholestyramine significantly reduced the deferasirox exposure in a mechanistic study to determine the degree of enterohepatic recycling (see section 5.2).
In a healthy volunteer study, the concomitant administration of EXJADE and midazolam (a CYP3A4 probe 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 substances metabolised through CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive agents, bepridil, ergotamine).
In a healthy volunteer study, the concomitant administration of deferasirox as a moderate CYP2C8 inhibitor (30 mg/kg daily), with repaglinide, a CYP2C8 substrate, given as a single dose of 0.5 mg, increased repaglinide AUC and Cmax about 2.3-fold (90% CI [2.03-2.63]) and 1.6-fold (90% CI [1.42-1.84]), respectively. Since the interaction has not been established with dosages higher than 0.5 mg for repaglinide, the concomitant use of deferasirox with repaglinide should be avoided. If the combination appears necessary, careful clinical and blood glucose monitoring should be performed (see section 4.4). An interaction between deferasirox and other CYP2C8 substrates like paclitaxel cannot be excluded.
In a healthy volunteer study, the concomitant administration of EXJADE as a CYP1A2 inhibitor (repeated dose of 30 mg/kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an increase of theophylline AUC by 84% (90% CI: 73% to 95%). The single dose Cmax was not affected, but an increase of theophylline Cmax is expected to occur with chronic dosing. Therefore, the concomitant use of EXJADE with theophylline is not recommended. If EXJADE and theophylline are used concomitantly, monitoring of theophylline concentration and theophylline dose reduction should be considered. An interaction between EXJADE and other CYP1A2 substrates cannot be excluded. For substances that are predominantly metabolised by CYP1A2 and that have a narrow therapeutic index (e.g. clozapine, tizanidine), the same recommendations apply as for theophylline.
The concomitant administration of EXJADE and aluminium-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminium than for iron, it is not recommended to take EXJADE tablets with aluminium-containing antacid preparations.
The concomitant administration of EXJADE and vitamin C has not been formally studied. Doses of vitamin C up to 200 mg per day have not been associated with adverse consequences.
No interaction was observed between EXJADE and digoxin in healthy adult volunteers.
4.6 Pregnancy And Lactation
Pregnancy
No clinical data on exposed pregnancies are available for deferasirox. Studies in animals have shown some reproductive toxicity at maternally toxic doses (see section 5.3). The potential risk for humans is unknown.
As a precaution, it is recommended that EXJADE is not used during pregnancy unless clearly necessary.
Breast-feeding
In animal studies, deferasirox was found to be rapidly and extensively secreted into maternal milk. No effect on the offspring was noted. It is not known if deferasirox is secreted into human milk. Breast-feeding while taking EXJADE is not recommended.
Fertility
No fertility data is available for humans. In animals, no adverse effects on male or female fertility were found (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects of EXJADE on the ability to drive and use machines have been performed. Patients experiencing the uncommon adverse reaction of dizziness should exercise caution when driving or operating machinery (see section 4.8).
4.8 Undesirable Effects
Summary of the safety profile
The most frequent reactions reported during chronic treatment with EXJADE in adult and paediatric patients include gastrointestinal disturbances in about 26% of patients (mainly nausea, vomiting, diarrhoea or abdominal pain) and skin rash in about 7% of patients. Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years and in the elderly. These reactions are dose-dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is continued.
During clinical trials, increases in serum creatinine of >33% on two or more consecutive occasions, sometimes above the upper limit of the normal range, occurred in about 36% of patients. These were dose-dependent. About two-thirds of the patients showing serum creatinine increase returned below the 33% level without dose adjustment. In the remaining third the serum creatinine increase did not always respond to a dose reduction or a dose interruption. Indeed, in some cases, only a stabilisation of the serum creatinine values has been observed after dose reduction (see section 4.4).
Tabulated list of adverse reactions
Adverse reactions are ranked below using the following convention: very common (
Table 1
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1 Adverse reactions reported during postmarketing experience. These are derived from spontaneous reports for which it is not always possible to reliably establish frequency or a causal relationship to exposure to the medicinal product.
Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver transaminases were reported as an adverse reaction in 2% of patients. Elevations of transaminases greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon (0.3%). During postmarketing experience, hepatic failure, sometimes fatal, has been reported with EXJADE, especially in patients with pre-existing liver cirrhosis (see section 4.4). As with other iron chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been uncommonly observed in patients treated with EXJADE (see section 4.4).
Paediatric population
Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients.
Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with EXJADE.
4.9 Overdose
Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In one case, this resulted in subclinical hepatitis which resolved after a dose interruption. Single doses of 80 mg/kg in iron-overloaded thalassaemic patients caused mild nausea and diarrhoea.
Acute signs of overdose may include nausea, vomiting, headache and diarrhoea. Overdose may be treated by induction of emesis or by gastric lavage, and by symptomatic treatment.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Iron chelating agent, ATC code: V03AC03
Mechanism of action
Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, primarily in the faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels of these metals.
Pharmacodynamic effects
In an iron-balance metabolic study in iron-overloaded adult thalassaemic patients, EXJADE at daily doses of 10, 20 and 40 mg/kg induced the mean net excretion of 0.119, 0.329 and 0.445 mg Fe/kg body weight/day, respectively.
Clinical efficacy and safety
EXJADE has been investigated in 411 adult (age
Daily treatment at doses of 20 and 30 mg/kg for one year in frequently transfused adult and paediatric patients with beta-thalassaemia led to reductions in indicators of total body iron; liver iron concentration was reduced by about -0.4 and -8.9 mg Fe/g liver (biopsy dry weight (dw)) on average, respectively, and serum ferritin was reduced by about -36 and -926 µg/l on average, respectively. At these same doses the ratios of iron excretion : iron intake were 1.02 (indicating net iron balance) and 1.67 (indicating net iron removal), respectively. EXJADE induced similar responses in iron-overloaded patients with other anaemias. Daily doses of 10 mg/kg for one year could maintain liver iron and serum ferritin levels and induce net iron balance in patients receiving infrequent transfusions or exchange transfusions. Serum ferritin assessed by monthly monitoring reflected changes in liver iron concentration indicating that trends in serum ferritin can be used to monitor response to therapy. Limited clinical data (29 patients with normal cardiac function at baseline) using MRI indicate that treatment with EXJADE 10-30 mg/kg/day for 1 year may also reduce levels of iron in the heart (on average, MRI T2* increased from 18.3 to 23.0 milliseconds).
The principal analysis of the pivotal comparative study in 586 patients suffering from beta-thalassaemia and transfusional iron overload did not demonstrate non-inferiority of EXJADE to desferrioxamine in the analysis of the total patient population. It appeared from a post-hoc analysis of this study that, in the subgroup of patients with liver iron concentration
It appeared from preclinical and clinical studies that EXJADE could be as active as desferrioxamine when used in a dose ratio of 2:1 (i.e. a dose of EXJADE that is numerically half of the desferrioxamine dose). However, this dosing recommendation was not prospectively assessed in the clinical trials.
In addition, in patients with liver iron concentration
5.2 Pharmacokinetic Properties
Absorption
Deferasirox is absorbed following oral administration with a median time to maximum plasma concentration (tmax) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox from EXJADE tablets is about 70% compared to an intravenous dose. Total exposure (AUC) was approximately doubled when taken along with a high-fat breakfast (fat content >50% of calories) and by about 50% when taken along with a standard breakfast. The bioavailability (AUC) of deferasirox was moderately (approx. 13–25%) elevated when taken 30 minutes before meals with normal or high fat content.
Distribution
Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and has a small volume of distribution of approximately 14 litres in adults.
Biotransformation
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: in a healthy volunteer study, the administration of cholestyramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC).
Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalysed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). No inhibition of deferasirox metabolism by hydroxyurea was observed in vitro.
Elimination
Deferasirox and its metabolites are primarily excreted in the faeces (84% of the dose). Renal excretion of deferasirox and its metabolites is minimal (8% of the dose). The mean elimination half-life (t1/2) ranged from 8 to 16 hours. The transporters MRP2 and MXR (BCRP) are involved in the biliary excretion of deferasirox.
Linearity / non-linearity
The Cmax and AUC0-24h of deferasirox increase approximately linearly with dose under steady-state conditions. Upon multiple dosing exposure increased by an accumulation factor of 1.3 to 2.3.
Characteristics in patients
Paediatric patients
The overall exposure of adolescents (12 to
Gender
Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males. Since dosing is individually adjusted according to response this is not expected to have clinical consequences.
Elderly patients
The pharmacokinetics of deferasirox have not been studied in elderly patients (aged 65 or older).
Renal or hepatic impairment
The pharmacokinetics of deferasirox have not been studied in patients with renal or hepatic impairment. The pharmacokinetics of deferasirox were not influenced by liver transaminase levels up to 5 times the upper limit of the normal range.
5.3 Preclinical Safety Data
Preclinical data reveal no special hazard for patients with iron overload, based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. The main findings were kidney toxicity and lens opacity (cataracts). Similar findings were observed in neonatal and juvenile animals. The kidney toxicity is considered mainly due to iron deprivation in animals that were not previously overloaded with iron.
Tests of genotoxicity in vitro were either negative (Ames test, chromosomal aberration test) or positive (V79 screen). Deferasirox caused formation of micronuclei in vivo in the bone marrow, but not liver, of non-iron-loaded rats at lethal doses. No such effects were observed in iron-preloaded rats. Deferasirox was not carcinogenic when administered to rats in a 2-year study and transgenic p53+/- heterozygous mice in a 6-month study.
The potential for toxicity to reproduction was assessed in rats and rabbits. Deferasirox was not teratogenic, 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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose monohydrate
Crospovidone type A
Cellulose, microcrystalline
Povidone
Sodium laurilsulfate
Silica, colloidal anhydrous
Magnesium stearate
6.2 Incompatibilities
Dispersion in carbonated drinks or milk is not recommended due to foaming and slow dispersion, respectively.
6.3 Shelf Life
3 years
6.4 Special Precautions For Storage
Store in the original package in order to protect from moisture.
6.5 Nature And Contents Of Container
PVC/PE/PVDC/Aluminium blisters.
Packs containing 28, 84 or 252 dispersible tablets.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8. Marketing Authorisation Number(S)
Exjade 125mg dispersible tablets:
EU/1/06/356/001
EU/1/06/356/002
EU/1/06/356/007
Exjade 250mg dispersible tablets:
EU/1/06/356/003
EU/1/06/356/004
EU/1/06/356/008
Exjade 500mg dispersible tablets:
EU/1/06/356/005
EU/1/06/356/006
EU/1/06/356/009
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 28.08.2006
Date of latest renewal: 27.07.2011
10. Date Of Revision Of The Text
27.07.2011
Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu
LEGAL CATEGORY
POM
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