Zentogout-40 Davipharm treatment (2 blisters x 10 tablets)

Pharmacological group: Gout treatment, synthetic inhibition of uric acid.

Mechanism of impact

Uric acid is the final product of the human metabolism and is created in hypoxanthin → xanthin → uric acid. Both enter these changes catalyzed by xanthin oxidase (XO). Febuxostat is a 2-anlthiazol derivative whose treatment effect reduces serum uric acid by selecting septic inhibitors. Febuxostat is a strong, selective purin inhibitor (NP-Sixo). Febuxostat has been shown to inhibit both oxidative and non -oxidant forms of the XO. At the concentration of Febuxostat treatment does not inhibit other enzymes involved in the metabolism of purin or pyrimidin, specifically, guanin deaminase, hypoxanthin guanin phosphoribosyltransferase, phosphoribosyltransferon orotate, OROTIDIN decarboxylase monophosphate phosphorylase.

pharmacokinetics

in healthy people, maximum concentrations in plasma (cmax) and the area under the curve (AUC) of Febuxostat increases proportionally with the dose after the only dose and multiple of 10 mg to 120 mg. For dose from 120 mg and 300 mg, increasing the rate larger than the AUC dose observed for Febuxostat. There is no significant accumulation when using 10 mg to 240 mg every 24 hours. The average half-life of Febuxostat (T1/2) is about 5-8 hours.

absorption

Febuxostat is quickly absorbed (TMAX of 1.0-1.5 hours) effectively (at least 84%). After taking single-dose or multiple doses of 80 and 120 mg once a day, cmax is about 2.8-3.2 mg/ml, and 5.0-5.3 mg/ml, respectively. The absolute bioavailability of the form of Febuxostat has not been studied.

After taking the repeated dose of 80 mg/ day or single -dose 120 mg, along with a high -fat meal, CMAX decreased 49% and 38%; AUC decreased by 18% and 16%, respectively. However, the degree of decrease in uric acid concentration in serum does not change significantly in the test (80 mg multi -dose). Febuxostat can be used with food or not.

Distribution

The distribution volume in stable state (VSS/ F) of Febuxostat is 29 - 75 l in the dose of 10 - 300 mg. Attached with plasma protein is about 99.2%, (mainly with albumin), and unchanged at a dose of 80 and 120 mg. The metabolites have a plasma protein activity about 82 - 91%.

Metabolism

Febuxostat is strongly metabolized by the conjugate process by uridin diphosphate glucuronosyltransferase (UDPGT) and oxidation through the Cytochrom P450 (CYP) system. The four pharmacological hydroxyl metabolites have been determined, including three substances present in human plasma. In research with liver liver microsome shows that oxidative metabolites are formed mainly by CYP1A1, CYP1A2, CYP2C8 or CYP2C9 and Glucuronid Febuxostat formed mainly by UGT 1A1, 1A8 and 1A9.

Elimination

Febuxostat is removed by both liver and kidney lines. After taking Febuxostat 80 mg, about 49%of the dose is released in urine in the form of febuxostat unchanged (3%), glucuronide acyl active ingredient (30%), oxidative metabolites and their compounds (13%), and other unknown metabolites (3%). In addition to appearing in urine, about 45%of the dose found in feces such as febuxostat does not change (12%), glucuronid acyl active ingredient (1%), oxidative metabolites and their compounds (25%), and other unknown metabolites (7%).

Special subjects

Patients with renal failure

After taking multiple doses of 80 mg Febuxostat in patients with mild, medium or severe renal failure, Febuxostat's CMAX does not change, compared to those with normal kidney function. The average AUC total of Febuxostat increases about 1.8 times compared to 7.5 μg · hours/ml in the normal kidney function group up to 13.2 μg · hours/ml in the severe kidney dysfunction group. CMAX and AUCs of metabolites operate to 2 and 4 times, respectively. However, do not need to adjust the dose in patients with mild or moderate renal failure.

Patients with liver failure

After taking multiple doses of 80 mg of Febuxostat in patients with mild hepatic impairment (Child-Pugh Class A) or medium (Child-Pugh Class B), the cmax and AUC of Febuxostat and its metabolites do not change significantly compared to those with normal liver function. No research has been conducted in patients with severe liver failure (group C).

Age

AUC of Febuxostat or its metabolites has not changed significantly after using Febuxostat to dose the oral repetition in the elderly than younger people.

Gender

After many doses of Febuxostat, CMAX and AUC are 24% and 12% higher than men, respectively. However, the weight of CMAX and AUC correction is similar between gender. No need to adjust the dose is necessary based on gender.

Uncommon, 1/1,000

Precautions when using

cardiovascular disease

Do not use Febuxostat in people with ischemic heart disease or congestive heart failure.

There has been a report on the incidence of unwanted effects on the heart (including cardiovascular death, non -fatal myocardial infarction), stroke on Febuxostat larger than on allopurinol. However, causal relationship has not been established. Recommended monitoring signs of myocardial infarction and stroke.

Hypersensitivity/allergies to drugs

rarely occur allergic/hypersensitivity reactions, including Stevens - Johnson syndrome (life -threatening). Poisoned epidermis and anaphylactic/acute shock reaction have been reported. Most occur in the first month using Febuxostat. Serious hypersensitivity reactions, including drugs with eosinophilia and systemic symptoms (Drug reaction with Eosinophilia and Systemic Symptoms (Dress) accompanied by symptoms of fever, hematology, kidney or liver occur in some cases.

Patients need advice on signs, symptoms and closely monitor the symptoms of allergic/hypersensitivity reactions. Stop the drug if there is a serious hypersensitivity/hypersensitivity, including Stevens-Johnson syndrome, and does not use Febuxostat in this patient.

Grade gout

Do not start treatment with Febuxostat until the gout attack completely recovers. Acute gout may occur at the beginning of treatment due to changes in serum uric acid levels, resulting in tissue accumulated urate transport. When starting with Febuxostat treatment, it is recommended to use NSAID or Colchichin to prevent acute attack for at least 6 months.

If the acute gout attack occurs, the drug should not be stopped. Acute gout can be treated simultaneously with each patient. Continuous treatment with Febuxostat reduces the frequency and intensity of the acute gout.

deposited xanthin

In patients with high risk of urate formation (such as malignant tumors and them, lesch-nylos syndrome) The absolute concentration of xanthin in the urine can increase enough to cause deposition in the urinary tract (rarely occur). Because there is no adequate information, Febuxostat should not be used in these patients.

Organs

There is no adequate information, do not recommend drugs for these patients.

Theophyllin

Simultaneous use of Febuxostat 80 mg and theophylllin single dose of 400 mg in healthy people do not see any drug interactions. Febuxostat 80 mg can be used with theophyllin, there is no risk of increasing theophyllin concentration in plasma. No information for febuxostat dose 120 mg.

liver disease

In phase 3 clinical research, abnormalities of mild liver function tests have been observed in patients treated with Febuxostat (5.0%). Recommended liver function test before starting treatment with Febuxostat and periodically later based on clinical evaluation.

Timely testing for liver tests in patients with symptoms shows liver damage, including fatigue, anorexia, abnormal abnormalities, dark urine or jaundice. If the patient has an abnormal liver test (ALT is 3 times higher than the upper limit of normal interval), Febuxostat should be stopped and tested to find the cause. Febuxostat should not be reused in these patients before finding another cause for liver testing abnormalities.

Patients with serum alt 3 times higher than the upper limit of normal interval with whole bilirubin with serum 2 times higher than normal without other causes of liver damage due to severe drugs and should not reuse Febuxostat. Patients with alt or serum bilirubin increases lower or other specific causes, can use Febuxostat but need to be cautious.

thyroid disorders

Increase TSH 5.5 UIU/ml) is observed in long -term treatment patients with Febuxostat (5.5%). Be careful when using Febuxostat in patients with thyroid dysfunction.

The drug contains lactose, patients with rare genetic diseases galactose, Lapp Lactase deficiency or glucose - galactose absorption disorders should not use this drug.

Using drugs for women during pregnancy and lactation

Pregnant women

Data on pregnant women is limited, not seeing any disadvantage of Febuxostat on pregnant women, fetus/ infant. Animal research does not show direct or indirect harm to pregnancy, embryo/ fetal development or birth. Because the risk is still unknown, Febuxostat should not be used during pregnancy.

breastfeeding women

It is not known whether Febuxostat is distributed in breast milk or not. Animal research has shown the distribution of the drug in milk and reduces the growth of milk animals. Due to the risk in newborns, Febuxostat should not be used in nursing women.

fertility

In animals, the dose of up to 48 mg/kg/day on animals does not see unwanted effect depending on the dose on fertility. It is unclear the effect of febuxostat on human fertility.

The effect of the drug on the ability to drive and operate machinery

The drug can cause drowsiness, dizziness, paresthesia and blurred vision. Be cautious before driving, use machinery or participate in dangerous activities until sure Febuxostat does not adversely affect the ability to exercise.

Drug interaction

mercaptopurin azathioprin

Do not recommend shared, because Febuxostat inhibits xanthin oxidase, it can increase the plasma concentration of Mercaptopurin/ Azathioprin increases toxicity. Febuxostat drug interaction research with drugs metabolized by xanthin oxidase has not been done.

Researching interactions between Febuxostat and cytotoxic drugs of chemotherapy is not conducted. There is no data related to the safety of Febuxostat in cytotoxic treatment.

rosiglitazon/substrate of CYP2C8

Febuxostat shows a weak inhibitor CYP2C8 in vitro. However, a study showed that Febuxostat was not a CYP2C8 In Vivo enzyme inhibitor. Therefore, the prediction does not need to adjust the dose when sharing Febuxostat with Rosiglitazon or the substrate of CYP2C8.

Theophyllin

Simultaneous use of Febuxostat 80 mg and theophylllin single dose of 400 mg in healthy people do not see any drug interactions. Febuxostat 80 mg can be used with theophyllin, there is no risk of increasing theophyllin concentration in plasma. No information for febuxostat dose 120 mg.

naproxen and other glucuronid inhibitors

Metabolism of Febuxostat depends on the uridin glucuronosyl transferase enzyme (UGT). Glucuronid inhibitors, such as NSAIDs and Probenecid, can affect Febuxostat elimination. In healthy people using Naproxen 250 mg twice a day, increasing CMAX (28%), AUC (41%), and Tiz (26%) of Febuxostat. In clinical studies using Naproxen or other NSAIDs/COX-2 inhibitors, there is no increase in unwanted effects.

No need to adjust the dose of Naproxen or Febuxostat when shared.

Glucuronid -causing drugs

Powerful induction drugs can increase metabolism and reduce the effectiveness of Febuxostat. Recommended monitoring of serum uric acid levels from 1-2 weeks after being used with strong induction substances Glucuronid. On the contrary, stop using the glucuronid -sensitive substance that can lead to increased febuxostat levels in plasma.

colchicin/indometacin/hydrochlorothiazide/warfarin

Can be used simultaneously Febuxostat with Colchicin or Indomethacin without the dose.

No need to adjust the dose of febuxostat when used with hydrochlorothiazid.

No need to adjust the Warfarin dose when used with Febuxostat.

Desipramin/substrate of CYP2D6

Febuxostat is a weak inhibitor CYP2D6 in vitro. In research in healthy people, using Febuxostat 120 mg/day increases 22% AUC of Desipramin, a substrate of CYP2D6, showing that Febuxostat inhibits weak enzyme CYP2D6 in Vivo. Therefore, the prediction is not adjusted when using Febuxostat with other substrates of CYP2D6.

antacid

Antacids contain magnesium hydroxyd and aluminum hydroxyd slow down the absorption of Febuxostat (about 1 hour) and reduce CMAX, there is no significant change of AUC. Therefore, Febuxostat can be used with Antacid without adjusting the dose.