Adenuric · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-094704 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The most commonly reported adverse reactions in clinical trials (4,072 subjects treated at least with a dose from 10 mg to 300 mg), post-authorisation safety studies (FAST study: 3001 subjects treated at least with a dose from 80 mg to 120 mg) and post-marketing experience are gout flares, liver function abnormalities, diarrhoea, nausea, headache, dizziness, dyspnoea, rash, pruritus,arthralgia, myalgia, pain in extremity, oedema and fatigue. These adverse reactions were mostly mild or moderate in severity. Rare serious hypersensitivity reactions to febuxostat, some of which were associated to systemic symptoms, and rare events of sudden cardiac death, have occurred in the post-marketing experience. Tabulated list of adverse reactions Common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000) adverse reactions occurring in patients treated with febuxostat are listed below. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1: Adverse reactions in combined phase 3, long-term extension studies, post-authorisation safety studies and post-marketing experience Blood and lymphatic system Rare disorders Pancytopenia, thrombocytopenia, agranulocytosis*, anaemia# Immune system disorders Rare Anaphylactic reaction*, drug hypersensitivity* Endocrine disorders Uncommon Blood thyroid stimulating hormone increased, hypothyroidism# Eye disorders Uncommon Blurred vision Rare Retinal artery occlusion# 6 Metabolism and nutrition Common*** disorders Gout flares Uncommon Diabetes mellitus, hyperlipidemia, decrease appetite, weight increase Rare Weight decrease, increase appetite, anorexia Psychiatric disorders Uncommon Libido decreased, insomnia Rare Nervousness, depressed mood#, sleep disorder# Nervous system disorders Common

Auszug; vollständigen Abschnitt im Original lesen.

HOS-094710 · has-adverse-reaction-information · PDF-Seite 22

Summary of the safety profile The most commonly reported adverse reactions in clinical trials (4,072 subjects treated at least with a dose from 10 mg to 300 mg), post-authorisation safety studies (FAST study: 3001 subjects treated at least with a dose from 80 mg to 120 mg) and post-marketing experience in gout patients are gout flares, liver function abnormalities, diarrhoea, nausea, headache, dizziness, dyspnoea, rash, pruritus,arthralgia, myalgia, pain in extremity, oedema and fatigue. These adverse reactions were mostly mild or moderate in severity. Rare serious hypersensitivity reactions to febuxostat, some of 22 which were associated to systemic symptoms, and rare events of sudden cardiac death, have occurred in the post-marketing experience. Tabulated list of adverse reactions Common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000) adverse reactions occurring in patients treated with febuxostat are listed below. The frequencies are based on studies and post-marketing experience in gout patients. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1: Adverse reactions in combined phase 3, long-term extension studies, post-authorisation safety studies and post-marketing experience in gout patients Blood and lymphatic system Rare disorders Pancytopenia, thrombocytopenia, agranulocytosis*, anaemia# Immune system disorders Rare Anaphylactic reaction*, drug hypersensitivity* Endocrine disorders Uncommon Blood thyroid stimulating hormone increased, hypothyroidism# Eye disorders Uncommon Blurred vision Rare Retinal artery occlusion# Metabolism and nutrition Common*** disorders Gout flares Uncommon Diabetes mellitus, hyperlipidemia, decrease appetite, weight increase Rare Weight decrease, increase appetite, anorexia Psychiatric disorders Uncommon Libido decreased, insomnia

Auszug; vollständigen Abschnitt im Original lesen.

HOS-094706 · has-contraindication-information · PDF-Seite 19

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see also section 4.8).

HOS-094700 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see also section 4.8).

HOS-094699 · has-indication-information · PDF-Seite 2

Treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history, or presence of, tophus and/or gouty arthritis). ADENURIC is indicated in adults.

HOS-094705 · has-indication-information · PDF-Seite 18

ADENURIC is indicated for the treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history, or presence of, tophus and/or gouty arthritis). ADENURIC is indicated for the prevention and treatment of hyperuricaemia in adult patients undergoing chemotherapy for haematologic malignancies at intermediate to high risk of Tumor Lysis Syndrome (TLS). ADENURIC is indicated in adults.

HOS-094708 · has-interaction-information · PDF-Seite 21

Mercaptopurine/azathioprine On the basis of the mechanism of action of febuxostat on XO inhibition concomitant use is not recommended. Inhibition of XO by febuxostat may cause increased plasma concentrations of these drugs leading to myelotoxicity. In case of concomitant administration with febuxostat, the dose of mercaptopurine/azathioprine should be reduced to the 20% or less of the previously prescribed dose (see sections 4.4 and 5.3). The adequacy of the proposed dose adjustment, which was based on a modelling and simulation analysis from preclinical data in rats, was confirmed by the results of a clinical drug-drug interaction study in healthy volunteers, receiving azathioprine 100 mg alone and a reduced dose of azathioprine (25 mg) in combination with febuxostat (40 or 120 mg). Drug interaction studies of febuxostat with other cytotoxic chemotherapy have not been conducted. In the Tumor Lysis Syndrome pivotal trial febuxostat 120 mg daily was administered to patients undergoing several chemotherapy regimens, including monoclonal antibodies. However, drug-drug and drug-disease interactions were not explored during this study. Therefore, possible interactions with any concomitantly administered cytotoxic drug cannot be ruled out. Rosiglitazone/CYP2C8 substrates Febuxostat was shown to be a weak inhibitor of CYP2C8 in vitro. In a study in healthy subjects, coadministration of 120 mg febuxostat QD with a single 4 mg oral dose of rosiglitazone had no effect on the pharmacokinetics of rosiglitazone and its metabolite N-desmethyl rosiglitazone, indicating that febuxostat is not a CYP2C8 enzyme inhibitor in vivo. Thus, co-administration of febuxostat with rosiglitazone or other CYP2C8 substrates is not expected to require any dose adjustment for those compounds. Theophylline An interaction study in healthy subjects has been performed with febuxostat to evaluate whether the inhibition of XO may cause an increase in the theophylline circulating levels as reported with other XO inhibitors. The results of the study showed that the co-administration of febuxostat 80 mg QD with theophylline 400 mg single dose has no effect on the pharmacokinetics or safety of theophylline. Therefore no special caution is advised when febuxostat 80 mg and theophylline are given concomitantly. No data is available for febuxostat 120 mg. Naproxen and other inhibitors of glucuronidation Febuxostat metabolism depends on Uridine Glucuronosyl Transferase (UGT) enzymes. Medicinal prod

Auszug; vollständigen Abschnitt im Original lesen.

HOS-094702 · has-interaction-information · PDF-Seite 4

Mercaptopurine/azathioprine On the basis of the mechanism of action of febuxostat on XO inhibition concomitant use is not recommended. Inhibition of XO by febuxostat may cause increased plasma concentrations of these drugs leading to myelotoxicity. In case of concomitant administration with febuxostat, the dose of mercaptopurine/azathioprine should be reduced to 20% or less of the previously prescribed dose (see sections 4.4 and 5.3) The adequacy of the proposed dose adjustment, which was based on a modelling and simulation analysis from preclinical data in rats, was confirmed by the results of a clinical drug-drug interaction study in healthy volunteers, receiving azathioprine 100 mg alone and a reduced dose of azathioprine (25 mg) in combination with febuxostat (40 or 120 mg). 4 Drug interaction studies of febuxostat with other cytotoxic chemotherapy have not been conducted. No data is available regarding the safety of febuxostat during other cytotoxic therapy. Rosiglitazone/CYP2C8 substrates Febuxostat was shown to be a weak inhibitor of CYP2C8 in vitro. In a study in healthy subjects, coadministration of 120 mg febuxostat QD with a single 4 mg oral dose of rosiglitazone had no effect on the pharmacokinetics of rosiglitazone and its metabolite N-desmethyl rosiglitazone, indicating that febuxostat is not a CYP2C8 enzyme inhibitor in vivo. Thus, co-administration of febuxostat with rosiglitazone or other CYP2C8 substrates is not expected to require any dose adjustment for those compounds. Theophylline An interaction study in healthy subjects has been performed with febuxostat to evaluate whether the inhibition of XO may cause an increase in the theophylline circulating levels as reported with other XO inhibitors. The results of the study showed that the co-administration of febuxostat 80 mg QD with theophylline 400 mg single dose has no effect on the pharmacokinetics or safety of theophylline. Therefore no special caution is advised when febuxostat 80 mg and theophylline are given concomitantly. No data is available for febuxostat 120 mg. Naproxen and other inhibitors of glucuronidation Febuxostat metabolism depends on Uridine Glucuronosyl Transferase (UGT) enzymes. Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, could in theory affect the elimination of febuxostat. In healthy subjects concomitant use of febuxostat and naproxen 250 mg twice daily was associated with

Auszug; vollständigen Abschnitt im Original lesen.

HOS-094709 · has-pregnancy-information · PDF-Seite 22

Pregnancy Data on a very limited number of exposed pregnancies have not indicated any adverse effects of febuxostat on pregnancy or on the health of the foetus/new born child. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development or parturition (see section 5.3). The potential risk for human is unknown. Febuxostat should not be used during pregnancy. Breastfeeding It is unknown whether febuxostat is excreted in human breast milk. Animal studies have shown excretion of this active substance in breast milk and an impaired development of suckling pups. A risk to a suckling infant cannot be excluded. Febuxostat should not be used while breastfeeding. Fertility In animals, reproduction studies up to 48 mg/kg/day showed no dose-dependent adverse effects on fertility (see section 5.3). The effect of ADENURIC on human fertility is unknown.

HOS-094703 · has-pregnancy-information · PDF-Seite 6

Pregnancy Data on a very limited number of exposed pregnancies have not indicated any adverse effects of febuxostat on pregnancy or on the health of the foetus/new born child. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development or parturition (see section 5.3). The potential risk for human is unknown. Febuxostat should not be used during pregnancy. Breastfeeding It is unknown whether febuxostat is excreted in human breast milk. Animal studies have shown excretion of this active substance in breast milk and an impaired development of suckling pups. A risk to a suckling infant cannot be excluded. Febuxostat should not be used while breastfeeding. Fertility In animals, reproduction studies up to 48 mg/kg/day showed no dose-dependent adverse effects on fertility (see section 5.3). The effect of ADENURIC on human fertility is unknown.

HOS-094707 · has-warning-information · PDF-Seite 19

Cardio-vascular disorders Treatment of chronic hyperuricaemia In patients with pre-existing major cardiovascular diseases (e.g. myocardial infarction, stroke or unstable angina), during the development of the product and in one post registrational study (CARES), a higher number of fatal cardiovascular events were observed with febuxostat when compared to allopurinol. However, in a subsequent post registrational study (FAST), febuxostat was not inferior to allopurinol in the incidence of both fatal and non-fatal cardiovascular events. Treatment of this patient group should be exercised cautiously and they should be monitored regularly. For further details on cardiovascular safety of febuxostat refer to section 4.8 and section 5.1. Prevention and treatment of hyperuricaemia in patients at risk of TLS Patients undergoing chemotherapy for haematologic malignancies at intermediate to high risk of Tumor Lysis Syndrome treated with ADENURIC should be under cardiac monitoring as clinically appropriate. Medicinal product allergy / hypersensitivity Rare reports of serious allergic/hypersensitivity reactions, including life-threatening Stevens-Johnson Syndrome, Toxic epidermal necrolysis and acute anaphylactic reaction/shock, have been collected in the post-marketing experience. In most cases, these reactions occurred during the first month of therapy with febuxostat. Some, but not all of these patients reported renal impairment and/or previous hypersensitivity to allopurinol. Severe hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) were associated with fever, haematological, renal or hepatic involvement in some cases. Patients should be advised of the signs and symptoms and monitored closely for symptoms of allergic/hypersensitivity reactions (see section 4.8). Febuxostat treatment should be immediately stopped if serious allergic/hypersensitivity reactions, including Stevens-Johnson Syndrome, occur since early withdrawal is associated with a better prognosis. If patient has developed 19 allergic/hypersensitivity reactions including Stevens-Johnson Syndrome and acute anaphylactic reaction/shock, febuxostat must not be re-started in this patient at any time. Acute gouty attacks (gout flare) Febuxostat treatment should not be started until an acute attack of gout has completely subsided. Gout flares may occur during initiation of treatment due to changing serum u

Auszug; vollständigen Abschnitt im Original lesen.

HOS-094701 · has-warning-information · PDF-Seite 3

Cardio-vascular disorders In patients with pre-existing major cardiovascular diseases (e.g. myocardial infarction, stroke or unstable angina), during the development of the product and in one post registrational study (CARES), a higher number of fatal cardiovascular events were observed with febuxostat when compared to allopurinol. However, in a subsequent post registrational study (FAST), febuxostat was not inferior to allopurinol in the incidence of both fatal and non-fatal cardiovascular events. Treatment of this patient group should be exercised cautiously and they should be monitored regularly. For further details on cardiovascular safety of febuxostat refer to section 4.8 and section 5.1. Medicinal product allergy / hypersensitivity Rare reports of serious allergic/hypersensitivity reactions, including life-threatening Stevens-Johnson Syndrome, Toxic epidermal necrolysis and acute anaphylactic reaction/shock, have been collected in the post-marketing experience. In most cases, these reactions occurred during the first month of therapy with febuxostat. Some, but not all of these patients reported renal impairment and/or previous hypersensitivity to allopurinol. Severe hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) were associated with fever, haematological, renal or hepatic involvement in some cases. Patients should be advised of the signs and symptoms and monitored closely for symptoms of allergic/hypersensitivity reactions (see section 4.8). Febuxostat treatment should be immediately stopped if serious allergic/hypersensitivity reactions, including Stevens-Johnson Syndrome, occur since early withdrawal is associated with a better prognosis. If patient has developed allergic/hypersensitivity reactions including Stevens-Johnson Syndrome and acute anaphylactic reaction/shock, febuxostat must not be re-started in this patient at any time. Acute gouty attacks (gout flare) Febuxostat treatment should not be started until an acute attack of gout has completely subsided. Gout flares may occur during initiation of treatment due to changing serum uric acid levels resulting in mobilization of urate from tissue deposits (see section 4.8 and 5.1). At treatment initiation with febuxostat flare prophylaxis for at least 6 months with an NSAID or colchicine is recommended (see section 4.2). If a gout flare occurs during febuxostat treatment, it should not be discontinued. The gout flare should be managed concurr

Auszug; vollständigen Abschnitt im Original lesen.