Adenuric, 120 mg 28 pcs

Chronic hyperuricaemia in conditions accompanied by deposition of urate crystals (in the presence of tophi and/or gouty arthritis, including a history).

The treatment and prevention of hyperuricaemia in adult patients undergoing cytostatic therapy for hemoblastosis with a moderate to high risk of tumor decay syndrome (120 mg dosage only).

The drug Adenuric® is intended for use in adults.

Active ingredient

Febuxostat

Composition

Core:

Active ingredient:

febuxostat – 120.0 mg.

Associates:

Lactose monohydrate – 114.75 mg,

hyprolose – 18.00 mg, <

Microcrystalline cellulose (Avicel PH 101) – 193.50 mg,

Microcrystalline cellulose (Avicel PH 102) – 258.75 mg,

croscarmellose sodium – 37.50 mg,

magnesium stearate – 3.75 mg,

colloidal silica aqueous – 3.75 mg.

Film coating: Opadray® II Yellow 85F42129 consisting of: polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, iron oxide yellow dye (E 172) – 19.23 mg.

How to take, the dosage

Ingestion. The drug Adenuric® is taken once a day, regardless of meals.

Podagra

The recommended starting dose is 80 mg of Febuxostat once daily.

After 2-4 weeks, serum uric acid concentrations should be monitored; if greater than 6 mg/dL (357 µmol/L), the dose of the drug may be increased to 120 mg once daily.

The decrease of uric acid concentration in serum against the background of Adenuric® use is fast, in connection with which the control of uric acid concentration can be carried out after two weeks from the beginning of the drug administration. The goal of the treatment is decrease and maintenance of uric acid concentration in serum less than 6 mg/dl (357 µmol/l).

Prevention of the development of acute attacks of gout is recommended for at least 6 months.

Tumor decay syndrome

The recommended dose is 120 mg of febuxostat once daily regardless of meals. The drug Adenuric® should be started two days before the start of cytostatic therapy. The duration of Adenuric® use should be at least 7 days. Depending on the duration of chemotherapy the duration of Adenuric® use may be increased up to 9 days.

Elderly patients

There is no need to adjust the dose of the drug.

Patients with hepatic impairment

Phodagra

In patients with mild hepatic impairment (Child-Pugh grade A: 5-6 points), the recommended dose of the drug is 80 mg once daily. The experience of using the drug in mild hepatic insufficiency is limited.

Tumor decay syndrome

In the FLORENCE study, no dose adjustment of febuxostat was required depending on liver function (patients with severe hepatic impairment were not included in the study).

There have been no studies of efficacy and safety of febuxostat in patients with severe hepatic insufficiency (Child-Pugh grade C: 10-15 points).

Patients with renal impairment

In patients with mild to moderate renal impairment no dose adjustment is required.

In patients with severe renal impairment (creatinine clearance < 30 ml/min), the efficacy and safety of the drug have not been adequately studied.

Interaction

Mercaptopurine/azathioprine

Concomitant use with mercaptopurine, azathioprine is not recommended because inhibition of xanthine oxidase by febuxostat may lead to increased plasma concentration of mercaptopurine, azathioprine and increase their toxic effects. No studies have been conducted to study the interaction of febuxostat and substances metabolized with xanthine oxidase.

Cytostatics

There have been no studies of drug interactions between febuxostat and cytostatic drugs. In the FLORENCE study, febuxostat at a dose of 120 mg was used for tumor decay syndrome in patients who had undergone different types of cytostatic therapy (including monoclonal antibody therapy). However, since there have been no studies of drug interactions between febuxostat and cytotoxic drugs, potential interactions between febuxostat and concomitantly used cytotoxic chemotherapeutics cannot be excluded.

Rosiglitazone/substrates of CYP2C8 isoenzyme

In vitro data, febuxostat is a weak inhibitor of CYP2C8 isoenzyme. No changes in pharmacokinetic parameters of rosiglitazone and its metabolite N-dismethyl rosiglitazone were observed in healthy volunteers when concomitant use of 120 mg of febuxostat once daily and a single dose of 4 mg of rosiglitazone, which indicates that febuxostat does not have CYP2C8 isoenzyme inhibitor properties in vivo. No dose adjustment is required when concomitant use of febuxostat and rosiglitazone (or other CYP2C8 isoenzyme substrates).

Theophylline

When using other xanthine oxidase inhibitors concomitantly with theophylline, an increase in plasma concentration of theophylline was noted. In concomitant usage in healthy volunteers of febuxostat in dose of 80 mg once per day and single dose of theophylline 400 mg no changes in pharmacokinetic parameters or tolerability of theophylline were observed, thus in concomitant usage of febuxostat in dose of 80 mg and theophylline no special measures of caution are required. Studies of concomitant use of febuxostat in a dose of 120 mg and theophylline have not been conducted.

Naproxen and other glucuronidation inhibitors

The metabolism of febuxostat depends on the activity of the enzyme uridine diphosphate glucuronyl transferase (UDFGT). Drugs that inhibit the glucuronidation process, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and probenicid, may theoretically affect the excretion of Febuxostat. In healthy volunteers, concomitant use of febuxostat and naproxen at a dose of 250 mg 2 times per day showed a 28% increase in Cmax of febuxostat, 41% increase in AUC and 26% increase in T1/2. In clinical trials concomitant use of febuxostat and naproxen or other NSAIDs/COG-2 inhibitors was not accompanied by clinically significant increase in the frequency of side effects. No dose adjustment is required with concomitant use of febuxostat and naproxen.

Glucuronidation inducers

Concomitant use of febuxostat with strong glucuronidation inducers may increase its metabolism and decrease its effectiveness. With concomitant use it is necessary to control serum uric acid concentration 1-2 weeks after the start of therapy. If glucuronidation inducer is withdrawn, Cmax increase of febuxostat is possible. Colchicine/indomethacin/hydrochlorthiazide/warfarin

Febuxostat can be used simultaneously with colchicine or indomethacin without dose adjustment.

There is also no need for dose adjustment of febuxostat when used concomitantly with hydrochlorthiazide.

The concomitant use of febuxostat (80 mg or 120 mg once daily) with warfarin has no effect on warfarin pharmacokinetics, INR (international normalized ratio) and factor VII activity in healthy volunteers. When concomitant use of febuxostat with warfarin, no dose adjustment of warfarin is required.

Desipramine/substrates of CYP2D6 isoenzyme

According to in vitro data, febuxostat is a weak inhibitor of CYP2D6 isoenzyme. In the study in healthy volunteers during the use of febuxostat at a dose of 120 mg once a day there was a 22% increase in AUC of desipramine (CYP2D6 isoenzyme substrate), that indicates a weak inhibitory effect of febuxostat on CYP2D6 isoenzyme in vivo. Thus, no dose adjustment is required when concomitant use of febuxostat and CYP2D6 isoenzyme substrates.

Antacids

When concomitant use with antacids containing magnesium hydroxide or aluminum hydroxide, there was decreased absorption of febuxostat (approximately by 1 hour) and decreased Cmax by 32%, but AUC of febuxostat was not significantly changed. Thus, febuxostat can be taken simultaneously with antacids.

Special Instructions

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Contraindications

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Side effects

Given the different course of gout and tumor decay syndrome, the side effects of febuxostat in these nosologies are presented separately.

Gout

The most frequent side effects in patients with gout when using febuxostat according to the results of clinical studies (4072 patients taking febuxostat in doses from 10 mg to 300 mg) and according to post-marketing surveillance data were: gout attack, liver dysfunction, diarrhea, headache, nausea, skin rash and edema.

In the majority of cases the above phenomena were characterized by a mild to moderate degree of severity. Rare cases of hypersensitivity reactions to febuxostat, accompanied in some cases by systemic symptoms, were reported during post-marketing follow-up.

Possible adverse effects are listed below according to the World Health Organization’s top-down frequency of occurrence: very frequently (≥1/10); frequently (≥1/100,< 1/10), infrequently (≥1/1000,< 1/100), rarely (≥1/10000,< 1/1000), very rarely (< 1/10000), including individual reports.

The frequency of side effects is based on data from clinical trials and post-marketing experience with febuxostat.

Blood and lymphatic system

Rarely: pancytopenia, thrombocytopenia.

In immune system disorders

Rare: anaphylactic reactions*, hypersensitivity reactions*.

Nervous system disorders

Often: headache;

Infrequently: Dizziness, paresthesia, hemiparesis, somnolence, altered sense of taste, hyposthesia, hyposmia (impaired sense of smell).

Endocrine system disorders

Infrequent: increased concentration of thyroid hormone (TSH) in plasma.

Metabolism and nutrition disorders

Often: gout attacks***;

Infrequently: Diabetes mellitus, hyperlipidemia, decreased appetite, increased body weight;

Rarely: decreased body weight, increased appetite, anorexia.

Mental side

Infrequent: decreased libido, insomnia;

Rarely: nervousness.

Sight

Rarely: blurred vision.

Hearing organ and labyrinth disorders

Rarely: tinnitus.

Cardiac disorders

Infrequent: atrial fibrillation, palpitations, ECG changes, left bundle of Gis block (see section “Tumor decay syndrome”), sinus tachycardia (see section “Tumor decay syndrome”).

Vascular disorders

Infrequent: increase in blood pressure, “rushes” of blood to the face, a feeling of fever, hemorrhages (see section “Tumor decay syndrome”).

Respiratory system, chest and mediastinal organs

Infrequent: dyspnea, bronchitis, upper respiratory tract infections, cough, chest pain, feeling of discomfort in the chest.

Gastrointestinal tract

Often: diarrhea**, nausea;

Infrequently: Abdominal pain, bloating, gastroesophageal reflux disease, vomiting, dry oral mucosa, dyspeptic phenomena, constipation, frequent stools, flatulence, abdominal discomfort;

Rarely: pancreatitis, ulcerative stomatitis.

Hepatic and biliary tract disorders

Often: Impaired liver function**;

Infrequent: cholelithiasis;

Rarely: hepatitis, jaundice*, liver damage*.

Skin and subcutaneous tissue

Often: skin rash (including various types of rash mentioned below with lower frequency);

Infrequent: Dermatitis, urticaria, pruritus, skin discoloration, skin lesions, petechiae, macular rash, maculopapular rash, papular rash;

Rarely: toxicodermal necrolysis*, Stevens-Johnson syndrome*, angioedema*, drug reaction with eosinophilia and systemic symptoms* (see (see section “Special indications”), severe forms of generalized rash*, erythema, exfoliative rash, follicular rash, vesicular rash, pustular rash, pruritic rash*, erythematous rash, crust-like rash, alopecia, hyperhidrosis.

Musculoskeletal system

Infrequent: Arthralgia, arthritis, myalgia, skeletal muscle pain, muscle weakness, muscle spasm, muscle tension, bursitis;

Rarely: rhabdomyolysis*, joint stiffness, muscle stiffness.

Renal and urinary tract disorders

Infrequent: Renal failure, nephrolithiasis, hematuria, pollakiuria, proteinuria;

Rarely: tubulointerstitial nephritis*, imperative urge to urinate.

Reproductive system disorders

Infrequent: erectile dysfunction.

General disorders

Often: edema;

Infrequently: increased fatigue;

Rarely: thirst.

Influence on laboratory and instrumental findings

Infrequent: increased plasma amylase activity, decreased platelet count, decreased white blood cell count, decreased lymphocyte count, increased plasma creatine and creatinine, decreased hemoglobin, increased plasma urea concentration, increased plasma triglyceride concentration, increased plasma cholesterol concentration, decreased hematocrit, increased plasma lactate dehydrogenase activity, increased plasma potassium concentration.

Rarely: increased plasma glucose concentration, prolongation of activated partial thromboplastin time, decreased number of red blood cells, increased plasma alkaline phosphatase activity.

* Side effects observed during post-marketing surveillance.

** Non-infectious diarrhea and liver disorders observed in phase III studies were more common with concomitant use of colchicine.

*** Additional information regarding the development of acute gout attacks is in the section “Special Indications”.

Description of Individual Adverse Effects

During post-marketing use there have been rare reports of severe allergic reactions (hypersensitivity reactions), including Stevens-Johnson syndrome, toxicodermal necrolysis, anaphylactic reactions and shock.

Stevens-Johnson syndrome and toxicodermal necrolysis are characterized by the development of a progressive skin rash accompanied by bullous lesions of the skin or mucosa, and eye irritation.

Hypersensitivity reactions to febuxostat may also manifest with the following symptoms: skin reactions characterized by infiltrative maculopapular rashes; generalized or exfoliative rash, as well as skin lesions, facial edema, fever, disorders of the blood forming organs, such as thrombocytopenia and eosinophilia, and involvement of one or more organs (liver and kidneys, including tubulointerstitial nephritis).

Gout attacks usually occur soon after the start of Adenuric® and during the first months of therapy. Later the frequency of attacks decreases. It is recommended to prevent development of acute attacks of gout.

Tumor decay syndrome

In the FLORENCE study, side effects were noted in 22 patients (6.4%). In both groups (febuxostat group and allopurinol group), the incidence of adverse events was similar (11 patients each, 6.4%). In most cases, the adverse events were characterized by mild to moderate severity. Overall, with the exception of the three side effects listed below from the FLORENCE study, no features of the safety profile of febuxostat in addition to that of gout were noted.

Cardiac side

Infrequent: left bundle branch block, sinus tachycardia.

vascular side

Infrequent: hemorrhages

Overdose

In case of overdose of the drug, symptomatic and supportive therapy is indicated.

Symptoms:worsening of side effects.

Similarities

Azurix, Febuxostat NW