Instructions for use Efstat film-coated tablets 80 mg blister No. 28
Composition
active ingredient: febuxostat;
1 film-coated tablet contains 80 mg or 120 mg of febuxostat;
excipients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, sodium lauryl sulfate, anhydrous lactose, colloidal anhydrous silicon dioxide, magnesium stearate, purified water;
film coating: polyvinyl alcohol (E 1203), titanium dioxide (E 171), macrogol 3350 (E 1521), talc (E 553b), iron oxide yellow (E 172), purified water.
Dosage form
Film-coated tablets.
Main physicochemical properties: film-coated tablets, oblong, biconvex, pale yellow to yellow in color, engraved with "80" or "120" on one side and with a smooth surface on the other side.
Pharmacotherapeutic group
Medicines for the treatment of gout. Medicines that inhibit the formation of uric acid. Febuxostat. ATC code M04A A03.
Pharmacological properties
Pharmacodynamics.
Uric acid is the end product of purine metabolism in humans and is formed during the following reaction: hypoxanthine → xanthine → uric acid. Xanthine oxidase catalyzes both steps of this reaction. Febuxostat is a 2-arylthiazole derivative, the therapeutic effect of which is associated with a decrease in serum uric acid concentration by selective inhibition of xanthine oxidase. Febuxostat is a potent and selective non-purine inhibitor of xanthine oxidase, with an in vitro Ki (inhibition constant) of less than 1 nM. Febuxostat has been shown to significantly inhibit the activity of both the oxidized and reduced forms of xanthine oxidase. At therapeutic concentrations, febuxostat does not affect other enzymes involved in purine or pyrimidine metabolism, such as guanine deaminase, hypoxanthine-guanine phosphoribosyltransferase, orotidine monophosphate decarboxylase, or purine nucleoside phosphorylase.
Pharmacokinetics.
In healthy volunteers, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) increased in a dose-proportional manner after single and multiple doses of febuxostat in doses ranging from 10 to 120 mg. At doses ranging from 120 to 300 mg, the increase in AUC was greater than dose-proportional. There was no accumulation of febuxostat after doses of 10 to 240 mg administered every 24 hours. The estimated mean terminal elimination half-life (t1/2) of febuxostat was approximately 5 to 8 hours.
Absorption. Febuxostat is rapidly (tmax (time to maximum concentration) – 1.0–1.5 hours) and well (84%) absorbed. After single and multiple oral administration of febuxostat at doses of 80 mg or 120 mg once daily, Cmax is 2.8–3.2 μg/ml and 5.0–5.3 μg/ml, respectively. The absolute bioavailability of febuxostat tablets has not been studied. After multiple administration of 80 mg once daily or a single administration of 120 mg in combination with a fatty meal, Cmax decreased by 49% and 38%, and AUC decreased by 18% and 16%, respectively. However, this was not accompanied by clinically significant changes in the degree of reduction in plasma uric acid levels (with multiple administration at a dose of 80 mg). Therefore, the drug can be used regardless of food intake.
Distribution: The estimated steady-state volume of distribution (Vss/F) for febuxostat ranges from 29 to 75 L after oral administration of 10 to 300 mg. The extent of plasma protein binding (primarily albumin) is 99.2% and does not change with increasing doses from 80 to 120 mg. For the active metabolites of febuxostat, the extent of plasma protein binding ranges from 82 to 91%.
Metabolism: Febuxostat is extensively metabolized by conjugation via uridine phosphate gluconyltransferase (UDP-gluconyltransferase) and oxidation via cytochrome P450 (CYP) enzymes. A total of 4 pharmacologically active hydroxyl metabolites of febuxostat have been described, 3 of which have been identified in plasma. In vitro studies with human liver microsomes have shown that these oxidized metabolites are formed primarily by CYPA1, CYPA2, CYP2C8 and CYP2C9, while febuxostat glucuronide is formed primarily by UDP-gluconyltransferase 1A1, 1A8, 1A9.
Elimination: Febuxostat is eliminated from the body via the liver and kidneys. Following oral administration of 80 mg 14C-febuxostat, approximately 49% was excreted in the urine as unchanged febuxostat (3%), acylglucuronide of the active substance (30%), known oxidized metabolites and their conjugates (13%), and other unknown metabolites (3%). In addition to renal excretion, approximately 45% was excreted in the feces as unchanged febuxostat (12%), acylglucuronide of the active substance (1%), known oxidized metabolites and their conjugates (25%), and other unknown metabolites (7%).
Special patient groups
During multiple dosing of febuxostat at a dose of 80 mg, no changes in febuxostat Cmax were observed in patients with mild, moderate, or severe renal impairment compared to patients with normal renal function. The mean total AUC of febuxostat increased approximately 1.8-fold from 7.5 μg/h/mL in patients with normal renal function to 13.2 μg/h/mL in patients with severe renal impairment. The Cmax and AUC of the active metabolites increased 2- and 4-fold, respectively. However, no dose adjustment is required in patients with mild, moderate, or severe renal impairment.
Liver failure.
Multiple dosing of febuxostat at a dose of 80 mg did not reveal any significant changes in Cmax and AUC of febuxostat and its metabolites in patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment compared to patients with normal hepatic function. The drug has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Age: After multiple oral doses of febuxostat, no significant changes in AUC of febuxostat and its metabolites were observed in elderly patients compared to young healthy volunteers.
Gender: During multiple oral administration of febuxostat, febuxostat Cmax and AUC were 24% and 12% higher in females than in males, respectively. However, weight-adjusted Cmax and AUC were similar in both groups, and no dose adjustment of febuxostat is necessary based on gender.
Indication
For 80 mg and 120 mg dosages
Treatment of chronic hyperuricemia in diseases accompanied by the deposition of urate crystals, including the presence of tophi and/or gouty arthritis at present or in history.
For 120 mg dosage
Treatment and prevention of hyperuricemia in adult patients undergoing chemotherapy for hematological malignancies at moderate or high risk of tumor lysis syndrome (TLS).
The medicine is indicated for adult patients.
Contraindication
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Interaction with other medicinal products and other types of interactions
Mercaptopurine/azathioprine.
Due to its mechanism of action, febuxostat inhibits xanthine oxidase, and its concomitant use with mercaptopurine and azathioprine is not recommended. Inhibition of xanthine oxidase may lead to increased plasma concentrations of both drugs, which may cause toxic reactions. Interaction studies of febuxostat with drugs metabolized by xanthine oxidase have not been conducted.
Interaction studies of febuxostat during cytotoxic chemotherapy have not been conducted.
In a study, patients with tumor lysis syndrome (TLS) were treated with febuxostat 120 mg on multiple chemotherapy regimens, including monoclonal antibodies. However, drug-drug and drug-disease interactions were not investigated in this study. Therefore, potential interactions with any concomitantly administered cytotoxic drugs cannot be excluded.
Rosiglitazone/CYP2C8 substrates.
Febuxostat is a weak inhibitor of CYP2C8 in vitro. In a study in healthy volunteers, co-administration of 120 mg of febuxostat once daily with a single dose of 4 mg of rosiglitazone had no effect on the pharmacokinetics of rosiglitazone and its metabolite N-desmethyl rosiglitazone, indicating that febuxostat does not inhibit the CYP2C8 enzyme in vivo. Therefore, no dose adjustment of these medicinal products is required when febuxostat is co-administered with rosiglitazone or other CYP2C8 substrates.
Theophylline.
An interaction study of febuxostat was conducted in healthy volunteers to assess the effect of xanthine oxidase inhibition on the increase in circulating theophylline levels observed with other xanthine oxidase inhibitors. The results showed that concomitant administration of febuxostat 80 mg and theophylline 400 mg did not result in any pharmacokinetic interactions or effects on the safety of theophylline. Therefore, febuxostat 80 mg can be co-administered with theophylline without any special precautions. There are no data available for the 120 mg dose of febuxostat.
Naproxen and other glucuronidation inhibitors.
Febuxostat metabolism is dependent on the activity of the enzyme UDP-glucuronyltransferase. Drugs that inhibit glucuronidation, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and probenecid, could theoretically alter the elimination of febuxostat. In healthy volunteers, coadministration of febuxostat with naproxen 250 mg twice daily resulted in an increase in febuxostat exposure (Cmax 28%, AUC 41%, t1/2 26%). In clinical studies, the use of naproxen and other NSAIDs/COX-2 inhibitors was not associated with a clinically significant increase in adverse reactions.
Febuxostat can be used concomitantly with naproxen without changing the dose of these drugs.
Strong inducers of UDP-glucuronyltransferase may increase the metabolism and reduce the efficacy of febuxostat. In patients receiving strong inducers of glucuronidation, it is recommended to monitor plasma uric acid levels after 1–2 weeks of concomitant therapy. When the inducer of glucuronidation is discontinued, febuxostat plasma levels may increase.
Colchicine/indomethacin/hydrochlorothiazide/warfarin.
Febuxostat can be used concomitantly with colchicine or indomethacin without changing the dose of the drugs.
There is also no need to change the dose of febuxostat when used simultaneously with hydrochlorothiazide.
Concomitant use of febuxostat with warfarin does not require a change in the dose of warfarin. Co-administration of febuxostat (80 mg or 120 mg once daily) with warfarin does not affect the pharmacokinetics of warfarin. Co-administration with febuxostat also does not affect the international normalized ratio (INR) and factor VII activity.
Desipramine/CYP2D6 substrates.
In vitro data indicate that febuxostat is a weak inhibitor of CYP2D6. In a study in healthy volunteers receiving 120 mg of febuxostat once daily, a 22% increase in the AUC of desipramine (a CYP2D6 substrate) was observed, indicating that febuxostat is a weak inhibitor of the CYP2D6 enzyme in vivo.
Therefore, there is no need to adjust the doses of febuxostat and CYP2D6 substrates when used concomitantly.
Antacids.
When used simultaneously with antacids containing magnesium hydroxide and aluminum hydroxide, a delay in the absorption of febuxostat (approximately 1 hour) and a decrease in Cmax by 32% are noted, however, the AUC of febuxostat does not change significantly, therefore febuxostat can be combined with the use of antacids.
Application features
Cardiovascular diseases.
Treatment of chronic hyperuricemia
Febuxostat is not recommended for use in patients with ischemic heart disease or congestive heart failure.
In the APEX and FACT studies, an increased number of cardiovascular events (Anti-Platelet Trialists' Collaboration (APTC)) (endpoints defined in the APTC joint analysis of antiplatelet therapy, including fatal cardiovascular disease, non-fatal myocardial infarction, non-fatal stroke) were reported in the overall febuxostat group compared to the allopurinol group (1.3 versus 0.3 events per 100 patient-years), in contrast to the CONFIRMS study. The incidence of cardiovascular events reported in the APTC studies in the combined phase III studies (APEX, FACT, and CONFIRMS studies) was 0.7 versus 0.6 events per 100 patient-years for febuxostat and allopurinol, respectively. In long-term large-scale studies, the incidence of these cardiovascular disorders was 1.2 and 0.6 cases per 100 patient-years for febuxostat and allopurinol, respectively. The differences were not statistically significant, and a causal relationship between these disorders and the use of febuxostat was absent. Identified risk factors in these patients were diseases resulting from atherosclerosis and/or myocardial infarction or congestive heart failure in history.
Prevention and treatment of hyperuricemia in patients at risk of developing (SLP)
Patients undergoing chemotherapy for hematological malignancies with moderate or high risk of SLE and using febuxostat should be monitored by a cardiologist if clinically indicated.
Drug allergy/hypersensitivity.
There have been rare reports of serious allergic/hypersensitivity reactions, including life-threatening Stevens-Johnson syndrome, toxic epidermal necrolysis and acute anaphylactic reactions/shock, during post-marketing surveillance. Most of these reactions occurred within the first month of febuxostat use. Several patients had a history of renal impairment and/or hypersensitivity to allopurinol. Severe hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), have been associated with fever, haematological, renal or hepatic failure in some cases.
Patients should be informed of the signs and symptoms of hypersensitivity/allergy and monitored for the development of such reactions. In the event of serious allergic/hypersensitivity reactions, including Stevens-Johnson syndrome, febuxostat should be discontinued immediately, as early discontinuation improves the prognosis. If a patient has experienced an allergic/hypersensitivity reaction, including Stevens-Johnson syndrome, and acute anaphylactic reactions/shock, then re-administration of febuxostat is contraindicated.
Exacerbation (attack) of gout.
In case of an attack while taking febuxostat, treatment is continued. At the same time, appropriate individual therapy for gout exacerbation is carried out. With prolonged use of febuxostat, the frequency and severity of gout attacks are reduced.
Xanthine deposition.
In patients with accelerated urate formation (e.g., against the background of malignant neoplasms and their treatment or in Lesch-Nyhan syndrome), a significant increase in the absolute concentration of xanthines in the urine, accompanied by their deposition in the urinary tract, is possible. This was not observed in the pivotal clinical study of febuxostat in SLP. Due to limited experience with the use of febuxostat in this condition, the drug is not indicated in such patients.
Mercaptopurine/azathioprine.
Febuxostat is not recommended for use in patients receiving concomitant mercaptopurine/azathioprine.
If the combination cannot be avoided, patients should be closely monitored. It is recommended to reduce the dose of mercaptopurine or azathioprine to avoid possible hematological effects.
Patients who have undergone organ transplantation.
There is no experience with the use of febuxostat in this category of patients, therefore the use of the drug is not indicated for them.
Theophylline.
A single concomitant administration of febuxostat 80 mg and theophylline 400 mg did not reveal any pharmacokinetic interactions. Febuxostat 80 mg can be administered concomitantly with theophylline without the risk of increased plasma theophylline concentrations. There are no data available for febuxostat 120 mg.
Liver disease.
In the combined phase III clinical trials, 5.0% of patients treated with febuxostat experienced minor changes in liver function tests, therefore it is recommended to check liver function tests before prescribing febuxostat and during treatment if indicated.
Thyroid disease.
Elevated TSH (> 5.5 μIU/mL) was observed in 5.5% of patients receiving febuxostat for a long time in long-term open-label extension studies. Therefore, the drug should be prescribed with caution in patients with thyroid dysfunction.
Important information about excipients.
The medicine contains lactose, therefore it is not indicated for patients with rare hereditary diseases associated with galactose intolerance, Lapp lactase deficiency or glucose/galactose malabsorption.
The medicine contains sodium, therefore patients on a controlled sodium diet should be careful when using it.
Use during pregnancy or breastfeeding
Pregnancy.
Limited experience with the use of febuxostat during pregnancy indicates no adverse effects on the course of pregnancy and the health of the fetus/newborn. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development or parturition. The potential risk to humans is unknown. Therefore, febuxostat is contraindicated during pregnancy.
Breastfeeding period.
It is not known whether febuxostat is excreted in human milk. Animal studies have shown that febuxostat is excreted in breast milk and has adverse effects on the development of breastfed infants. The risk of the drug passing into breast milk cannot be excluded. Therefore, the use of febuxostat during breastfeeding is contraindicated.
Fertility.
Animal fertility studies at a dose of 48 mg/kg/day did not reveal any dose-related adverse reactions. The effect of febuxostat on human reproductive function is unknown.
Ability to influence reaction speed when driving vehicles or other mechanisms
There have been reports of drowsiness, dizziness, paresthesia, and blurred vision with the use of febuxostat, therefore patients using febuxostat are advised to be cautious when driving or operating machinery until they are certain that the above-mentioned adverse reactions have not occurred.
Method of administration and doses
Dosage
Gout.
The recommended dose is 80 mg once daily orally, without regard to food intake. If serum uric acid levels exceed 6 mg/dL (357 μmol/L) after 2–4 weeks of treatment, an increase in the dose of febuxostat to 120 mg once daily should be considered. The onset of action of the drug is rapid, allowing for repeat uric acid levels to be measured after 2 weeks. The goal of treatment is to reduce uric acid levels and maintain them below 6 mg/dL (357 μmol/L).
The duration of prevention of gout attacks is at least 6 months.
Tumor lysis syndrome (TLS).
The recommended dose is 120 mg once daily. Administer orally, with or without food. Efstat should be initiated two days prior to the start of cytotoxic therapy and continued for at least 7 days, but may be extended to 9 days depending on the duration of chemotherapy and clinical assessment.
No dose adjustment is required in patients with mild or moderate renal impairment. The efficacy and safety of the drug have not been adequately studied in patients with severe renal impairment (creatinine clearance < 30 ml/min).
Liver failure.
The efficacy and safety of febuxostat in patients with severe hepatic impairment (Child-Pugh Class C) have not been studied.
– Gout. For mild hepatic impairment, the recommended dose is 80 mg. Experience with the drug in moderate hepatic impairment is limited.
– Tumor lysis syndrome (TLS). No dose adjustment is required for patients with mild or moderate hepatic impairment based on liver function.
Elderly patients.
No dose adjustment is required for this category of patients.
Patients who have undergone organ transplantation.
There is no experience with the use of febuxostat in this category of patients, therefore the use of the drug is not indicated.
Method of application.
It is administered orally, regardless of meals.
Children
The use of febuxostat in patients under 18 years of age is not indicated due to the lack of experience with its use in pediatrics.
Overdose
In case of overdose, symptomatic and supportive therapy is indicated.
Adverse reactions
The most common adverse reactions in clinical trials (4072 patients receiving doses of 10 to 300 mg) and post-marketing surveillance in patients with gout were gout flares, liver dysfunction, diarrhea, nausea, headache, rash, and edema. These reactions were mostly mild to moderate in severity. Rare cases of serious hypersensitivity reactions to febuxostat, some with systemic reactions, have been reported during post-marketing surveillance.
The following table lists the adverse reactions that have occurred in patients receiving febuxostat and are classified as: common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000). The frequencies are based on studies and post-marketing experience in patients with gout. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Adverse reactions observed in phase 3 combined randomized long-term extension studies and post-marketing surveillance in patients with gout
Organ system classes
Adverse reactions by frequency
Blood and lymphatic system disorders
Rare: pancytopenia, thrombocytopenia, agranulocytosis*.
On the part of the immune system
Rare: hypersensitivity reactions, including anaphylactic reactions*.
From the endocrine system
Uncommon: increased blood levels of thyroid-stimulating hormone.
From the organs of vision
Rare: blurred vision.
From the side of metabolism, metabolism
Common***: exacerbations (attacks) of gout.
Uncommon: diabetes mellitus, hyperlipidemia, decreased appetite, weight gain.
Rare: weight loss, increased appetite, anorexia.
From the psyche
Uncommon: decreased libido, insomnia.
Rare: nervousness.
From the nervous system and sensory organs
Common: headache.
Uncommon: dizziness, paresthesia, hemiparesis, drowsiness, altered taste perception, decreased sense of smell, hypoesthesia.
From the side of the organs of hearing and vestibular apparatus
Rare: tinnitus.
From the heart
Uncommon: atrial fibrillation, palpitations, ECG abnormalities, left bundle branch block (see section "Tumor lysis syndrome"), sinus tachycardia (see section "Tumor lysis syndrome").
From the vascular side
Uncommon: hypertension, hot flushes, hot flushes, bleeding (see section "Tumor lysis syndrome").
Respiratory, thoracic and mediastinal disorders
Uncommon: dyspnoea, bronchitis, upper respiratory tract infections, cough.
Gastrointestinal tract
Common: diarrhea**, nausea.
Uncommon: abdominal pain, bloating, gastroesophageal reflux disease, vomiting, dry mouth, dyspepsia, constipation, frequent bowel movements, flatulence, stomach or intestinal discomfort.
Rare: pancreatitis, mouth ulcers.
Liver and biliary tract
Common: liver dysfunction**.
Uncommon: gallstone disease.
Rare: hepatitis, jaundice*, hepatic failure*.
Skin and subcutaneous tissue disorders
Common: rash (including rash with a lower frequency of occurrence).
Uncommon: dermatitis, urticaria, pruritus, skin discolouration, skin lesion, petechiae, macular rash, maculopapular rash, papular rash.
Rare: toxic epidermal necrolysis*, Stevens-Johnson syndrome*, angioedema*, drug reactions with eosinophilia and systemic symptoms*, generalised rash (serious)*, erythema, exfoliative, follicular, vesicular, pustular, pruritic*, erythematous, choroid-like rash, alopecia, increased sweating.
Musculoskeletal and connective tissue disorders
Uncommon: joint pain, arthritis, muscle pain, musculoskeletal pain, muscle weakness, muscle cramps, muscle stiffness, bursitis.
Renal and urinary disorders
Uncommon: renal failure, urolithiasis, hematuria, pollakiuria, proteinuria.
Rare: tubulointerstitial nephritis*, urinary urgency.
Reproductive system and mammary gland function
Rare: erectile dysfunction.
General disorders
Common: edema.
Uncommon: fatigue, chest pain, chest discomfort.
Rare: thirst.
Laboratory indicators
Uncommon: increased blood amylase, decreased platelet count, decreased white blood cell count, decreased lymphocyte count, increased blood creatinine, decreased blood haemoglobin, increased blood urea, increased blood triglycerides, increased blood cholesterol, decreased haematocrit, increased blood lactate dehydrogenase (LDH), increased blood potassium.
Rare: increased blood glucose, prolonged activated partial thromboplastin time, decreased red blood cell count, increased blood alkaline phosphatase, increased blood creatine phosphokinase*.
* Adverse reactions observed within the framework of post-marketing analysis.
** Diarrhea and liver function test abnormalities requiring therapy observed during clinical trials occurred more frequently in patients receiving concomitant colchicine therapy.
*** Gout flares (attacks) were usually observed shortly after initiation of treatment and during the first months of treatment. The frequency of gout attacks decreased over time.
Description of selected adverse reactions.
During post-marketing surveillance, rare cases of serious hypersensitivity reactions to febuxostat have been reported, including Stevens-Johnson syndrome, toxic epidermal necrolysis and anaphylactic reactions/shock. Stevens-Johnson syndrome and toxic epidermal necrolysis are characterised by a progressive skin rash with bullous lesions of the skin or mucous membranes and irritation of the mucous membranes of the eyes. Hypersensitivity reactions to febuxostat may present with the following symptoms: skin reactions in the form of an infiltrated maculopapular rash, generalised or exfoliative rash, as well as skin lesions, facial oedema, fever, haematological abnormalities such as thrombocytopenia and eosinophilia, and single or multiple organ involvement (liver and kidney including tubulointerstitial nephritis).
Gout flares (attacks) were usually observed shortly after initiation of treatment and during the first months of treatment. The frequency of gout attacks decreased over time. Prevention of acute gout attacks is recommended after the use of febuxostat.
Tumor lysis syndrome (TLS)
Summary of safety profile.
In the randomized, double-blind, pivotal phase 3 FLORENCE study (FLO-01) comparing febuxostat and allopurinol (346 patients undergoing chemotherapy for hematological malignancies with moderate or high risk of SLE), only 22 (6.4%) patients experienced adverse reactions (11 (6.4%) patients in each treatment group). Most adverse reactions were mild or moderate in severity.
Overall, the FLORENCE study did not raise any additional concerns regarding the safety of febuxostat in patients with gout, with the exception of the following three adverse reactions (see table).
From the side of the cardiac system:
Uncommon: left bundle branch block, ventricular tachycardia.
From the vascular system:
Uncommon: bleeding.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after the marketing authorisation of a medicinal product is an important procedure. It allows for continued monitoring of the benefit-risk balance of the medicinal product in question. Healthcare professionals should report any suspected adverse reactions via the national reporting system.
Expiration date
3 years.
Storage conditions
Store in original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Packaging
14 tablets in a blister; 2 blisters in a pack.
Vacation category
According to the recipe.
Producer
Genepharm SA.
Location of the manufacturer and address of its place of business
18 km Merezonoc Ave, Pallini Attica, 15351, Greece.
Applicant
PrJSC "Pharmaceutical Company "Darnitsa".
Location of the applicant and its business address
Ukraine, 02093, Kyiv, Boryspilska St., 13.
