Adenuric (Febuxostat)

Nucleus:

Active substance: 

febuxostat - 120.0 mg.

Excipients: 

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, 

silicon dioxide colloidal aqueous - 3.75 mg.

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

Treatment and prevention of hyperuricemia in adult patients during cytostatic therapy of hemoblastoses with a risk of developing a moderate to high tumor decay syndrome (only for a dosage of 120 mg).

The drug Adenurik® intended for use in adults.

Taking into account the different nature of the course of gout and tumor decay syndrome, side effects when using febuxostat with these nosologies of action are presented separately.

Gout

The most common side effects in patients with gout when using febuxostat according to clinical results (4072 patients taking  febuxostat  at a dose of 10 mg to 300 mg) and according to post-marketing observation were: gout attack, impaired liver function, diarrhea, headache, nausea skin rash and swelling.

In most cases, these phenomena were characterized by mild or moderate severity. In the post-marketing monitoring period, rare cases of the development of hypersensitivity reactions to febuxostat were observed  , accompanied in some cases by systemic symptoms.

Possible side effects are listed below in accordance with the classification of the World Health Organization in descending incidence: very often (≥1 / 10); often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, <1/1000), very rarely (<1/10000), including some messages.

The incidence of side effects is based on clinical studies and post-marketing experience with febuxostat.

From the blood and lymphatic system

Rarely: pancytopenia, thrombocytopenia.

From the immune system

Rarely: anaphylactic reactions *, hypersensitivity reactions *.

From the nervous system

Often: headache;

Infrequently: dizziness, paresthesia, hemiparesis, drowsiness, change in taste perception, hyposthesia, hyposmia (weakening of smell).

Endocrine system

Infrequently: an increase in the concentration of thyroid-stimulating hormone (TSH) in blood plasma.

On the part of metabolism and nutrition

Often: attacks of gout ***;

Infrequently: diabetes mellitus, hyperlipidemia, decreased appetite, weight gain;

Rarely: weight loss, increased appetite, anorexia.

From the psyche

Infrequently: decreased libido, insomnia;

Rarely: nervousness.

On the part of the organ of vision

Rarely: blurred vision.

Hearing organ and labyrinthine disorders

Rarely: tinnitus.

From the heart

Infrequently: atrial fibrillation, palpitations, ECG changes, left bundle branch block (see the section "Tumor decay syndrome"), sinus tachycardia (see the section "Tumor decay syndrome").

From the vessels

Infrequently: increased blood pressure, flushing of the face, sensation of fever, hemorrhage (see the section "Tumor decomposition syndrome").

From the respiratory system, chest and mediastinal organs

Infrequently: dyspnea, bronchitis, upper respiratory tract infection, cough, chest pain, discomfort in the chest area.

From the digestive tract

Often: diarrhea **, nausea;

Infrequently: abdominal pain, bloating, gastroesophageal reflux disease, vomiting, dry oral mucosa, dyspeptic symptoms, constipation, rapid stool, flatulence, abdominal discomfort;

Rarely: pancreatitis, ulcerative stomatitis.

On the part of the liver and biliary tract

Often: impaired liver function **;

Infrequently: cholelithiasis;

Rarely: hepatitis, jaundice *, liver damage *.

On the part of the skin and subcutaneous tissue

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

Infrequently: 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 section "Special Instructions"), severe forms of generalized rash *, erythema, exfoliative rash, follicular rash, vesicular rash , pustular rash, itchy rash *, erythematous rash, measles-like rash, alopecia, hyperhidrosis.

From the musculoskeletal system

Infrequently: arthralgia, arthritis, myalgia, musculoskeletal pain, muscle weakness, muscle spasm, muscle tension, bursitis;

Rarely: rhabdomyolysis *, stiffness of joints, stiffness of muscles.

Disorders of the kidneys and urinary tract

Infrequently: renal failure, nephrolithiasis, hematuria, pollakiuria, proteinuria;

Rarely: tubulointerstitial nephritis *, peremptory urination.

From the reproductive system

Infrequently: erectile dysfunction.

General disorders

Often: edema;

Infrequently: increased fatigue;

Rarely: thirst.

Influence on the results of laboratory and instrumental studies

Infrequently: an increase in plasma amylase activity, a decrease in platelet count, a decrease in the number of leukocytes, a decrease in the number of lymphocytes, an increase in the content of creatine and creatinine in the blood plasma, a decrease in hemoglobin, an increase in the concentration of urea in the blood plasma, an increase in the concentration of triglycerides in the blood plasma, an increase in the concentration of cholesterol in blood plasma, decreased hematocrit, increased activity of lactate dehydrogenase in blood plasma, increased potassium content in blood plasma.

Rarely: an increase in plasma glucose concentration, lengthening of activated partial thromboplastin time, a decrease in the number of red blood cells, an increase in the activity of alkaline phosphatase in blood plasma.

* Side effects observed during the period of post-marketing observation.

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

*** Additional information regarding the development of acute attacks of gout in the section "Special instructions".

Description of individual side 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 occurrence of progressive skin rash in combination with bullous damage to the skin or mucous membranes, as well as eye irritation.

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

Gout attacks are usually observed shortly after the start of the use of Adenuric® and during the first months of therapy. Subsequently, the frequency of seizures decreases. It is recommended to prevent the development of acute attacks of gout.

Tumor Decay Syndrome

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

From the heart

Infrequently: blockade of the left bundle branch block, sinus tachycardia.

From the vessels

Infrequently: hemorrhages

Mercaptopurine / azathioprine

Concomitant use with mercaptopurine, azathioprine is not recommended, because inhibition of xanthine oxidase by febuxostat can lead to an increase in the concentration of mercaptopurine, azathioprine in the blood plasma and an increase in their toxic effect. Studies on the interaction of febuxostat and substances metabolized with xanthine oxidase have not been conducted.

Cytostatics

Studies on the drug interaction of febuxostat and cytostatic drugs have not been conducted. In the FLORENCE study, febuxostat in a dose of 120 mg was used for tumor decay syndrome in patients who underwent various types of cytostatic therapy (including monoclonal antibody therapy). Nevertheless, since studies on the drug interaction of febuxostat with cytotoxic drugs have not been conducted, the potential interaction of febuxostat with the simultaneously used cytotoxic chemotherapy cannot be ruled out.

Rosiglitazone / substrates of the CYP2C8 isoenzyme

According to in vitro data, febuxostat is a weak inhibitor of the CYP2C8 isoenzyme. In healthy volunteers with the simultaneous use of 120 mg of febuxostat 1 time per day and a single dose of 4 mg of rosiglitazone, there were no changes in the pharmacokinetic parameters of rosiglitazone and its metabolite N-dysmethyl rosiglitazone, which indicates the absence of the properties of the inhibitor of febuxostat inhibitor of the isoenzyme CYP2C8 in vivo. With the simultaneous use of febuxostat and rosiglitazone (or other substrates of the CYP2C8 isoenzyme), dose adjustment is not required.

Theophylline

With the use of other xanthioxidase inhibitors simultaneously with theophylline, an increase in theophylline concentration in blood plasma was noted. With the simultaneous use of febuxostat at a dose of 80 mg once a day in healthy volunteers and a single dose of theophylline 400 mg, there were no changes in the pharmacokinetic parameters or tolerance of theophylline, thus, with the simultaneous use of febuxostat at a dose of 80 mg and theophylline, special precautions are not required. A study of the simultaneous use of febuxostat at a dose of 120 mg and theophylline has not been conducted.

Naproxen and other glucuronidation inhibitors

The metabolism of febuxostat depends on the activity of the enzyme uridine diphosphate glucuronyl transferase (UDFGT). Medicines that inhibit the glucuronidation process, for example, non-steroidal anti-inflammatory drugs (NSAIDs) and probenicide, can potentially affect the excretion of febuxostat. In healthy volunteers with the simultaneous use of febuxostat and naproxen at a dose of 250 mg 2 times a day, there was an increase in Cmax of febuxostat by 28%, AUC by 41% and T1 / 2 by 26%. In clinical studies, the simultaneous use of febuxostat and naproxen or other NSAIDs / COX-2 inhibitors was not accompanied by a clinically significant increase in the incidence of side effects. Dose adjustment with the simultaneous use of febuxostat and naproxen is not required.

Glucuronidation inducers

With the simultaneous use of febuxostat with strong inducers of glucuronidation, it is possible to increase its metabolism and decrease its effectiveness. With simultaneous use, it is necessary to control the concentration of uric acid in the blood serum 1-2 weeks after the start of therapy. With the abolition of the glucuronidation inducer, an increase in Cmax of febuxostat is possible. Colchicine / indomethacin / hydrochlorothiazide / warfarin

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

Also, dose adjustment of febuxostat is not required with simultaneous use with hydrochlorothiazide.

The simultaneous use of febuxostat (80 mg or 120 mg once a day) with warfarin does not affect the pharmacokinetics of warfarin, INR (international normalized ratio) and factor VII activity in healthy volunteers. With the simultaneous use of febuxostat with warfarin, dose adjustment of warfarin is not required.

Desipramine / CYP2D6 isoenzyme substrates

According to in vitro data,  febuxostat  is a weak inhibitor of the CYP2D6 isoenzyme. In a study in healthy volunteers with the use of febuxostat at a dose of 120 mg once a day, an increase in AUC of desipramine (substrate of the CYP2D6 isoenzyme) was noted by 22%, which indicates a weak inhibitory effect of febuxostat on the CYP2D6 isoenzyme in vivo. Thus, with the simultaneous use of febuxostat and substrates of the CYP2D6 isoenzyme, dose adjustment is not required.

Antacids

With simultaneous use with antacids containing magnesium hydroxide or aluminum hydroxide, there is a decrease in the absorption of febuxostat (by about 1 hour) and a decrease in Cmax by 32%, however, the AUC of febuxostat did not change significantly. Thus,  febuxostat  can be taken simultaneously with antacids.

Inside . The drug Adenurik® is taken once a day, regardless of food intake.

Gout

The recommended starting dose is 80 mg of febuxostat once a day.

After 2-4 weeks, it is recommended to control the concentration of uric acid in the blood serum; if the indicator exceeds 6 mg / dl (357 μmol / l), the dose of the drug can be increased to 120 mg once a day.

The decrease in the concentration of uric acid in the blood serum during the use of the drug Adenurik® occurs rather quickly, and therefore the control of the concentration of uric acid can be carried out two weeks after the start of the drug. The goal of the treatment is to reduce and maintain a serum uric acid concentration of 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 a day, regardless of food intake. The drug Adenurik® should be taken two days before the start of cytostatic therapy. The duration of use of the drug Adenuric® should be at least 7 days. Depending on the duration of the chemotherapy course, the duration of the use of Adenuric® can be increased to 9 days.

Elderly patients

No dose adjustment is required.

Patients with liver failure

Gout

In patients with mild hepatic insufficiency (class A on the Child-Pugh scale: 5-6 points), the recommended dose of the drug is 80 mg 1 time per day. The experience of using the drug with moderate liver failure is limited.

Tumor Decay Syndrome

In the FLORENCE study, dose adjustment of febuxostat depending on liver function was not required (patients with severe liver failure were not included in the study).

Studies on the efficacy and safety of using febuxostat in patients with severe liver failure (grade C on the Child-Pugh scale: 10-15 points) have not been conducted.

Patients with kidney failure

In patients with mild to moderate renal failure, dose adjustment is not required.

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

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

Symptoms:  increased side effects.