Dagrablock^® (Tablets) Instructions for Use

Marketing Authorization Holder

Belupo, Pharmaceuticals & Cosmetics d.d. (Croatia)

ATC Code

M04AA03 (Febuxostat)

Active Substance

Febuxostat (Rec.INN registered by WHO)

Dosage Forms

	Dagrablock®	Film-coated tablets 80 mg: 28 or 56 pcs.
		Film-coated tablets 120 mg: 28 or 56 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from light yellow to yellow in color, with an imprint “80” on one side, oblong, biconvex.

Excipients: microcrystalline cellulose PH101, microcrystalline cellulose PH102, lactose monohydrate, anhydrous lactose, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, sodium lauryl sulfate, colloidal anhydrous silicon dioxide; film coating Opadry II yellow 85F42129: polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol 3350 (E1521), talc (E533b), iron oxide yellow dye (E172).

14 pcs. – blister (2) – cardboard packs.
14 pcs. – blister (4) – cardboard packs.

Film-coated tablets from light yellow to yellow in color, with an imprint “120” on one side, oblong, biconvex.

Excipients: microcrystalline cellulose PH101, microcrystalline cellulose PH102, lactose monohydrate, anhydrous lactose, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, sodium lauryl sulfate, colloidal anhydrous silicon dioxide; film coating Opadry II yellow 85F42129: polyvinyl alcohol (E1203), titanium dioxide (E171), macrogol 3350 (E1521), talc (E533b), iron oxide yellow dye (E172).

14 pcs. – blister (2) – cardboard packs.
14 pcs. – blister (4) – cardboard packs.

Clinical-Pharmacological Group

Drug affecting uric acid metabolism. Antigout drug

Pharmacotherapeutic Group

Antigout agent – xanthine oxidase inhibitor

Pharmacological Action

Selective non-purine xanthine oxidase inhibitor, a derivative of 2-arylthiazole.

The enzyme xanthine oxidase catalyzes two stages of purine metabolism: the oxidation of hypoxanthine to xanthine, and then the oxidation of xanthine to uric acid.

As a result of selective inhibition of xanthine oxidase (oxidized and reduced forms) by febuxostat, the concentration of uric acid in the blood serum decreases. The inhibition constant in vitro is less than 1 nM.

At therapeutic concentrations, Febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism, such as guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase, or purine nucleoside phosphorylase.

The use of febuxostat leads to a more effective reduction in uric acid concentration and maintenance of its level in the blood serum compared to allopurinol.

No clinically significant differences in the degree of reduction of uric acid concentration in the blood serum compared to healthy volunteers were noted (the reduction in uric acid concentration in the group of patients with normal renal function is 58%, in the group with severe renal failure – 55%).

When using febuxostat for the prevention and treatment of tumor lysis syndrome, a more intensive and rapid decrease in uric acid concentration in the blood serum was observed compared to allopurinol.

Pharmacokinetics

After oral administration, Febuxostat is rapidly and almost completely (at least 84% of the administered dose) absorbed from the gastrointestinal tract. With multiple administration of febuxostat at a dose of 80 mg or a single dose of 120 mg simultaneously with a fatty meal, the C_max of febuxostat in blood plasma decreased by 49% and 38%, respectively, and AUC by 18% and 16%. However, this did not affect the clinical efficacy of reducing uric acid concentration in the blood serum (with multiple administration of febuxostat at a dose of 80 mg), therefore Febuxostat can be taken regardless of food intake.

C_max is reached 1.0-1.5 hours after a single or multiple oral administration and is 2.8-3.2 µg/ml when taken at a dose of 80 mg and 5-5.3 µg/ml when taken at a dose of 120 mg. No accumulation was observed with multiple oral administration of febuxostat at doses of 10-240 mg once a day.

In healthy volunteers, with single or multiple oral administration of febuxostat, C_max and AUC increase linearly with increasing dose in the range from 10 mg to 120 mg, and in the dose range from 120 mg to 300 mg, an increase in AUC is noted to a greater extent than proportional to the dose.

The apparent V_d at steady state varies from 29 L to 75 L after oral administration of 10-300 mg of febuxostat. The degree of binding to plasma proteins (mainly albumin) reaches 99.2% and does not change when the dose is increased from 80 mg to 120 mg. For active metabolites, the degree of binding to plasma proteins varies from 82% to 91%.

Febuxostat is metabolized by conjugation involving UGT and oxidation involving cytochrome P450 enzymes. Four pharmacologically active hydroxyl metabolites were isolated, three of which are found in human plasma. In vitro studies on human liver microsomes have shown that oxidized metabolites are formed mainly under the influence of isoenzymes CYP1A1, CYP1A2, CYP2C8 or CYP2C9, while febuxostat glucuronide is formed mainly under the influence of isoenzymes UGT 1A1, UGT 1A8 and UGT 1A9.

Febuxostat and its metabolites are excreted from the body through the intestines and kidneys. After oral administration of radioisotope-labeled ¹⁴C febuxostat at a dose of 80 mg, approximately 49% is excreted by the kidneys: unchanged – about 3%, in the form of acylglucuronide – 30%, in the form of oxidized metabolites and their conjugates – 13%, in the form of other metabolites – 3%. Approximately 45% of febuxostat is excreted through the intestines: in the form of unchanged substance – 12%, acylglucuronide – 1%, oxidized metabolites and their conjugates – 25%, other metabolites – 7%.

The apparent T_1/2 is 5-8 hours.

Indications

Treatment of chronic hyperuricemia in conditions accompanied by the deposition of urate crystals (in the presence of tophi and/or gouty arthritis, including in the anamnesis).

Treatment and prevention of hyperuricemia in adult patients during cytostatic therapy for hemoblastosis with a moderate to high risk of tumor lysis syndrome (only for the 120 mg dose).

ICD codes

Dosage Regimen

Take orally once daily.

Initiate treatment at a dose of 80 mg.

If the serum uric acid level remains above 6 mg/dL (357 µmol/L) after 2-4 weeks, increase the dose to 120 mg.

For chronic hyperuricemia with gout, the recommended starting dose is 80 mg.

For the treatment and prevention of hyperuricemia in adult patients during cytostatic therapy for hemoblastosis with a moderate to high risk of tumor lysis syndrome, use only the 120 mg dose.

The treatment goal is to achieve and maintain a serum uric acid concentration below 6 mg/dL (357 µmol/L).

Begin therapy only after an acute gout attack has fully resolved.

Concomitant administration of an NSAID or colchicine for at least the first 6 months is recommended to prevent acute gout flares.

Dose adjustment is not required for patients with mild or moderate renal impairment.

Use with caution in patients with severe renal impairment (CrCl less than 30 mL/min).

No dose adjustment is necessary for patients with mild or moderate hepatic impairment.

Use with caution in patients with severe hepatic impairment.

The drug can be taken with or without food.

Administration with a high-fat meal may decrease the maximum concentration but does not affect the overall reduction in serum uric acid.

Do not co-administer with azathioprine or mercaptopurine.

Regular monitoring of serum uric acid levels is advised to assess therapeutic response.

Periodically monitor liver function tests during treatment.

Adverse Reactions

From the hematopoietic system infrequently – decrease in platelet count, leukocyte count, lymphocyte count, decrease in hemoglobin concentration, decrease in hematocrit; rarely – pancytopenia, thrombocytopenia, decrease in red blood cell count.

From the immune system hypersensitivity reactions.

From the nervous system often – headache; infrequently – dizziness, paresthesia, hemiparesis, drowsiness, taste perversion, hypoesthesia, hyposmia (weakening of the sense of smell).

From the endocrine system infrequently – increase in TSH concentration in blood plasma.

From metabolism often – gout attacks; infrequently – diabetes mellitus, hyperlipidemia, decreased appetite, increased body weight, increased urea concentration in blood plasma, increased triglycerides concentration in blood plasma, increased cholesterol concentration in blood plasma, increased potassium content in blood plasma; rarely – increased glucose concentration in blood plasma, decreased body weight, increased appetite, anorexia.

From the psyche infrequently – decreased libido, insomnia; rarely – nervousness.

From the organ of vision rarely – blurred vision.

From the organ of hearing and labyrinthine disorders rarely – tinnitus.

From the cardiovascular system infrequently – atrial fibrillation, palpitations, ECG changes, left bundle branch block, sinus tachycardia, increased blood pressure, facial flushing, feeling of heat, hemorrhages.

From the respiratory system infrequently – dyspnea, bronchitis, upper respiratory tract infections, cough.

From the digestive system often – diarrhea (more often with simultaneous use of colchicine), nausea; infrequently – abdominal pain, abdominal distension, gastroesophageal reflux disease, vomiting, dry oral mucosa, dyspeptic symptoms, constipation, frequent stools, flatulence, abdominal discomfort, increased amylase activity in blood plasma; rarely – pancreatitis, ulcerative stomatitis.

From the liver and biliary tract often – impaired liver function (more often with simultaneous use of colchicine); infrequently – cholelithiasis, increased ALP, LDH activity in blood plasma; rarely – hepatitis, jaundice, liver damage.

From the skin and subcutaneous tissues often – rash (including various types of rash mentioned below with lower frequency); infrequently – dermatitis, urticaria, skin itching, skin discoloration, skin lesions, petechiae, macular rash, maculopapular rash, papular rash; rarely – severe forms of generalized rash, erythema, exfoliative rash, follicular rash, vesicular rash, pustular rash, pruritic rash, erythematous rash, measles-like rash, alopecia, hyperhidrosis.

Allergic reactions rarely – angioedema, severe allergic reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylactic reactions and shock, drug reaction with eosinophilia and systemic symptoms.

From the musculoskeletal system infrequently – arthralgia, arthritis, myalgia, musculoskeletal pain, muscle weakness, muscle spasm, muscle tension, bursitis; rarely – rhabdomyolysis, increased CPK concentration in blood plasma, joint stiffness, muscle stiffness.

From the urinary system infrequently – renal failure, nephrolithiasis, hematuria, pollakiuria, proteinuria, increased creatinine and creatine content in blood plasma; rarely – tubulointerstitial nephritis, imperative urination urges.

From the reproductive system infrequently – erectile dysfunction.

General reactions often – edema; infrequently – increased fatigue, chest pain, feeling of discomfort in the chest area; rarely – thirst. In clinical studies in patients receiving Febuxostat for hemoblastosis, tumor lysis syndrome with the development of adverse events of mild or moderate severity was observed in 6.4% of cases.

Contraindications

Pregnancy, breastfeeding period; children under 18 years of age; hypersensitivity to febuxostat.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Use with caution in the following diseases and conditions: severe renal failure (CrCl<30 ml/min) (efficacy and safety have not been sufficiently studied); hepatic failure; history of serious allergic reactions (hypersensitivity reactions); coronary artery disease; congestive heart failure; thyroid diseases; simultaneous use with mercaptopurine/azathioprine (possible increase in the concentration of these substances in the blood plasma and enhancement of their toxicity); conditions after organ transplantation (experience with the use of febuxostat is limited); Lesch-Nyhan syndrome (experience with the use of febuxostat is limited).

The use of febuxostat should be started only after the acute attack of gout has been relieved. The use of febuxostat can provoke the development of an acute attack of gout due to the release of urates from tissue depots and a subsequent increase in the concentration of uric acid in the blood serum. For the prevention of gout attacks, simultaneous use of NSAIDs or colchicine for at least 6 months is recommended.

Simultaneous use with mercaptopurine, azathioprine is not recommended. If simultaneous use is necessary, to reduce the toxic effect on the hematopoietic system, a reduction in the dose of mercaptopurine/azathioprine and careful medical supervision are recommended.

Patients should be informed about possible signs and symptoms of allergic reactions (hypersensitivity reactions), and should be carefully monitored for the development of symptoms of allergic reactions/hypersensitivity reactions.

In case of severe allergic reactions/hypersensitivity reactions, including Stevens-Johnson syndrome, it is necessary to immediately stop the use of febuxostat (earlier withdrawal is associated with a better prognosis). If the patient has previously experienced severe allergic reactions or hypersensitivity reactions, including Stevens-Johnson syndrome, acute anaphylactic reactions/shock, repeated use of the drug is not recommended.

In patients undergoing cytostatic therapy for hemoblastosis with a moderate to severe risk of tumor lysis syndrome (with clinical manifestations from the heart), Febuxostat should be used under appropriate supervision.

At the beginning of the use of febuxostat and periodically in the presence of clinical manifestations, it is recommended to monitor liver function.

Effect on ability to drive vehicles and mechanisms

When using febuxostat, drowsiness, dizziness, paresthesia and blurred vision may occur, and, as a result, a decrease in reaction and ability to concentrate, therefore, during the treatment period, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require concentration and speed of psychomotor reactions.

Drug Interactions

Considering the mechanism of action of febuxostat, based on the inhibition of xanthine oxidase, simultaneous use with mercaptopurine, azathioprine is not recommended. Inhibition of xanthine oxidase by febuxostat can lead to an increase in the concentration of mercaptopurine, azathioprine in the blood plasma and an enhancement of their toxic effect.

A potential interaction of febuxostat with simultaneously used cytotoxic chemotherapeutic agents cannot be excluded.

According to in vitro data, Febuxostat is a weak inhibitor of the CYP2C8 isoenzyme. With simultaneous use of febuxostat and rosiglitazone (or other substrates of the CYP2C8 isoenzyme), dose adjustment is not required.

Simultaneous use of febuxostat and naproxen or other NSAIDs/COX-2 inhibitors was not accompanied by a clinically significant increase in the incidence of adverse events. Dose adjustment with simultaneous use of febuxostat and naproxen is not required.

With simultaneous use of febuxostat with strong inducers of glucuronidation, an increase in its metabolism and a decrease in effectiveness are possible. Upon withdrawal of the glucuronidation inducer, an increase in C_max of febuxostat is possible.

Desipramine/substrates of the CYP2D6 isoenzyme

According to data obtained in vitro, Febuxostat is a weak inhibitor of the CYP2D6 isoenzyme. With simultaneous use of febuxostat and substrates of the CYP2D6 isoenzyme, dose adjustment is not required.

With simultaneous use with antacids containing magnesium hydroxide or aluminum hydroxide, a decrease in the absorption of febuxostat (by approximately 1 hour) and a decrease in C_max by 32% were noted, but the AUC of febuxostat does not change significantly. Thus, Febuxostat can be taken simultaneously with antacids.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.