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Febrista

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The main component of febusistat is febusistat, whose chemical name is 2 - [(3-cyano-4-isobutyloxy) phenyl ]-4-Methyl-5- Thiazole carboxylic acid 。 by xanthine oxidase （XO） inhibitor , for with gout Symptomatic hyperuricemia Long-term treatment.

The latest entry into China Febristat Tablets (Fibuli) was approved by the State Drug Administration to be listed on the Chinese market on September 4, 2018.^[1]

Drug name: Febrista
Foreign name: Febuxostat Tablets
Alias: Febuzosta 、 Feibusotan (generic name)

Dosage form: Regular oral dosage form^[2]
Whether included in medical insurance: yes
Drug type: Anti gout drug^[2]
Chinese Pinyin: fēi bù sī tā

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Composition

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The main ingredient of this product is non Buzostat, and its chemical name is 2 - [(3-cyano-4-isobutyloxy) phenyl] - 4-methyl-5-thiazole carboxylic acid.

Structural type:

Molecular Structure Diagram

Molecular formula: C16H16N2O3S

Molecular weight: 316.37

character

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This product is white powder

indication

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This product is xanthine oxidase （XO） inhibitor , for those with gout symptoms hyperuricemia Long-term treatment.

This product is not recommended for the treatment of asymptomatic Hyperuricemia (Symptoms).

Dosage form

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tablet

Specifications

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20mg/tablet; 40mg/tablet; 80mg/tablet

Usage and dosage

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Recommended dose

The initial dose is 20mg, once a day, and large doses may cause Blood uric acid The rapid decrease of value will induce Gouty arthritis （ gout Seizure). The patient can take 20mg of fepristat for 4 weeks and gradually increase it by 20mg each time according to the blood uric acid value under the guidance of the doctor.

The maximum daily dose is 80mg. Blood uric acid level reaches target value (less than 6mg/dL or 360 μ m mol/L ）After, maintain Minimum effective dose 。 Administration Without considering food and Antacid For details, please refer to Doctor's order 。

Special population

Elderly patients : No dose adjustment is required.

Light, medium Hepatic insufficiency Patient: There is no need to adjust the dose.

Light, medium Renal insufficiency Patient: There is no need to adjust the dose.

chronic kidney disease （ CKD ）Stage 4-5 patients: the recommended starting dose is 20mg/day, and the maximum dose is 40mg/day.

Children: At present, it is uncertain whether the safety and Effectiveness 。 If medication is needed, please use it under the guidance of doctors and adult supervision.

It can be carried out after 2 weeks of treatment with this product Serum uric acid Re inspection of. Treatment objectives It is to reduce and maintain the serum uric acid level below 6mg/dL.

It is recommended to use drugs for at least 6 months to prevent acute gout attack (see [Precautions]).

Gout attack

Altered serum uric acid The level will lead to the activity of the deposited urate, so the beginning of administration of this product will lead to gout attack.

It is recommended to use this product at the same time NSAIDs (NSAID) or Colchicine To prevent gout attack. It is recommended to use drugs for at least 6 months to prevent acute gout attack.

If gout occurs during the administration treatment, drug withdrawal is not necessary. The gout of individual patients should be treated accordingly.

Secondary hyperuricemia

yes secondary Patients with hyperuricemia (including organ transplant Patient) No research has been conducted on the drug administration; This product is not recommended for patients with increased urate production rate (such as malignant disease and its treatment, Lehmann Naphthalene syndrome). Urine in rare cases xanthine The concentration of will increase significantly and deposit in the urinary tract.

Adverse reactions

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In the clinical trial, 2757 patients with hyperuricemia and gout were given 40 mg or 80 mg of this product every day. 559 patients were given 40mg of this product for ≥ 6 months. Among the patients who received 80mg of this product, 1377 patients continued for ≥ 6 months, 674 patients were treated for ≥ 1 year, and 515 patients were treated for ≥ 2 years.

common Adverse reactions

Three items are randomized and controlled clinical research (Study 1, 2, 3), lasting for 6-12 months, reported adverse reactions caused by drugs.

Table 1 summarizes at least 1% of the drug administration group incidence rate Adverse reactions and ratio of Blank control group Adverse reactions with an incidence of at least 0.5% higher

The incidence of adverse reactions in the drug administration group is ≥ 1% and at least 0.5% higher than that in the blank control group
Adverse reactions	Blank control group	Non Buzostat Group		Allopurinol group*
Adverse reactions	（N=134）	40mg per day （N=757）	80mg per day （N=1279）	（N=1277）
Abnormal liver function nausea Arthralgia Rash	0.7% 0.7% 0% 0.7%	6.6% 1.1% 1.1% 0.5%	4.6% 1.3% 0.7% 1.6%	4.2% 0.8% 0.7% 1.6%

*According to renal function Injury, Administration Allopurinol In the patient group, 10 cases were given 100mg, 145 cases were given 200mg, and 1122 cases were given 300mg.

The most common adverse reactions leading to drug withdrawal during treatment are Abnormal liver function , the 40mg group was 1.8%, the 80mg group was 1.2%, and the allopurinol group was 0.9%. In addition to the adverse reactions listed in Table 1 dizzy The adverse reactions were also more than 1%, but less than 0.5% compared with the blank control group.

Less adverse reactions

In the Phase II and Phase III clinical studies, the incidence of the following adverse reactions was lower than 1%, and it was higher when the dosage range of this product was 40mg~240mg. The following includes the adverse reactions (less than 1%) of organ system in the precautions.

Blood and lymphatic system ： anemia 、 Idiopathic thrombocytopenic purpura 、 Leukocytosis /Reduce addiction Neutrophil granulocyte Reduction of symptoms Pancytopenia 、 Splenomegaly 、 Thrombocytopenia 。

Heart disease: angina pectoris , Atrium Fibrous fibrillation 、 Cardiac murmur ECG abnormality palpitation 、 Sinus bradycardia 、 Tachycardia 。

Abnormalities in ear and inner ear: deaf 、 tinnitus 、 vertigo 。

Eye disease: blurred vision.

Gastrointestinal disorders: abdominal distention 、 abdominal pain , constipation, dry mouth indigestion , Intestine Gastric distention , frequent defecation gastritis , Gastroesophagus Reflow Disease, gastrointestinal discomfort, gingival pain haematemesis 、 Hyperacidity of stomach , blood in stool mouth ulcer Formation pancreatitis 、 Peptic ulcer , vomiting.

General symptoms and administration: weakness Chest pain /Discomfort, edema, fatigue Emotional abnormality , gait obstacle Influenza Symptoms, ruffian qi, pain, thirst.

liver bile duct Symptoms: cholelithiasis / cholecystitis 、 Hepatic steatosis 、 hepatitis 、 Hepatomegaly 。

Immune system diseases: hypersensitivity 。

Infections and infections: zoster 。

complication ： contusion 。

Metabolic disorders: apositia 、 Anorexia /Reinforcement, dehydration diabetes 、 Hypercholesterolemia 、 hyperglycemia High fat Hematemia , High triglyceride Blood sickness Hypokalemia Weight loss/increase.

Musculoskeletal and connective tissue Symptoms: arthritis 、 Ankylosis of joint , joint swelling Muscle spasm /Muscle twitching/contraction/weakness, musculoskeletal pain/ Ankylosis of limbs 、 Myalgia 。

nervous system Symptoms: taste change, imbalance apoplexy Syndrome, Guillain Barr é syndrome headache 、 Hemiparesis 、 Insensitivity 、 Anosmia , lacunar infarction, drowsiness, mental damage migraine 、 Paresthesia , drowsiness, transience ischemia Seizure, tremor.

Psychosis : excitement, anxiety, depression, insomnia, irritability, decreased libido, nervousness Panic attack , personality changes.

Kidney urinary system Symptoms: hematuria 、 Nephrolithiasis , frequency of urination proteinuria 、 renal failure , renal insufficiency Urgency of urination , Incontinence.

reproductive system and breast Changes: breast pain Erectile dysfunction Men's and women's breasts.

Breathing, chest and Mediastinum Symptoms: bronchitis 、 cough 、 dyspnea 、 Epistaxis , dry nasal hair, excessive nasal sinus secretion, pharyngeal edema respiratory tract Hyperemia, sneezing, throat irritation upper respiratory tract infection 。

Skin and Subcutaneous tissue Symptom: hair loss Angioedema 、 dermatitis , skin scratch Ecchymosis 、 eczema Hair discoloration, abnormal hair growth hyperhidrosis , skin peeling petechiae , photosensitivity itch 、 Purpura , skin discoloration skin disease Damage, abnormal smell of skin Urticaria 。

Vascular disease: blushing, hot flashes hypertension 、 hypotension 。

Laboratory parameters: prolongation of activated partial thrombokinase time creatine Add Bicarbonate Decrease, sodium increase, EEG abnormality glucose Add cholesterol Add triglyceride Add amylase Increase, potassium increase TSH Add platelet count Count decrease Hematocrit Reduce hemoglobin Reduce MCV Add RBC Reduce Creatinine Add Blood urea Add BUN /Increased creatinine ratio Creatine phosphokinase （ CPK ）Add Alkaline phosphoric acid (ester) enzyme increase LDH Add PSA Increase, urine Discharge Increase/decrease Lymphocyte count Reduced, neutral white blood cell Count decrease, WBC increase/decrease, urine test protein Exceptions Low density lipoprotein (LDL) increase prothrombin time Extension Catheter type Urine leucocyte and protein are positive.

Cardiovascular safety

In a randomized controlled long-term extended study, cardiovascular The event and death are APTC events (cardiovascular death, non fatal myocardial infarction Non fatal stroke) is a predefined endpoint indicator. In the phase III randomized controlled study, the reported incidence of APTC events in 100 patients: blank control group 0 (95% CI 0.00-6.16), 40mg group 0 (95% CI 0.00-1.08), 80mg group 1.09 (95% CI 0.44-2.24), allopurinol 0.60 (95% CI 0.16-1.53).

In a long-term extended study, the reported incidence of APTC events was 0.97 (95% CI 0.57-1.56) in the 80mg group and 0.58 (95% CI 0.02-3.24) in the allopurinol group.

The study found that the incidence of APTC events of this product was higher than that of patients in the allopurinol group. The relevant mechanism is still uncertain. Should be monitored MI And signs and symptoms of stroke.

matters needing attention

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Gout attack

After starting the treatment with this product, an increase in gout attack can be observed. This is caused by the activity of deposited urate due to the decrease of the changing serum uric acid level.

To prevent gout attack during administration of this product, simultaneous administration is recommended NSAIDs Or colchicine (see【 Usage and dosage 】）。

Cardiovascular disease

In the randomized controlled study, the patients who used this product [0.74 per 100 P-Y (95% CI 0.36-1.37)] were compared with those who received the drug Allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)] patients are more prone to cardiovascular thrombotic events (cardiovascular death, non fatal myocardial infarction, non fatal stroke) (see [adverse reactions]). The relevant reasons have not been clarified. The signs and symptoms of myocardial infarction (MI) and stroke should be monitored.

Increased liver enzymes

In a randomized controlled study, it was observed that transaminase The level is 3 times higher than the normal upper limit (the AST of patients treated with this product and allopurinol is 2%, 2% ALT ：3%，2%）。

Not found The improvement of transaminase has Dose effect relationship 。 liver function Laboratory analysis It is recommended to use this product for 2 and 4 months, and then periodically.

taboo

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Taking Azathioprine 、 Mercaptopurine or Cholaphylline % of the patients are forbidden to use this product.

Special drugs

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Pregnant women and Lactating women Medication

1. Pregnant women

Class C drugs: there is no sufficient control study for pregnant women. Pregnant women can only take this product if the potential benefits and risks to infants are equal.

During the organogenesis period, rats and rabbits were orally administered with febuzostat at a dose of 48 mg/kg (according to Body surface area When calculated as 40 and 50 times of 80mg/day for human administration, none Teratogenicity 。 During organogenesis and Lactation period For pregnant rats, the dosage of this product reached 48mg/kg (40 times of 80mg/day for human) Neonatal mortality Increase, Newborn weight Increase and decrease.

2. Breastfeeding women

Febuzostat is secreted by rat milk. It is unknown whether febuzostat is secreted by human milk. Because many drugs pass Human milk Secretion, so be careful when administering this product to lactating women.

Children's medication

The safety and effectiveness of this product for children below 18 have not been determined.

Medication for the elderly

Elderly patients do not need to use this product Dose adjustment 。 And others age group In comparison, there is no clinical evidence in terms of safety and effectiveness significant difference However, it is not excluded that some elderly patients are sensitive to this product. The Cmax and AUC24 of elderly patients (≥ 65 years old) after multi dose oral administration of febuzostat were similar to those of young patients (18-40 years old).

Drug interaction

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Mercaptopurine/ Azathioprine etc.

Feebzos He is xanthine oxidase (XO) inhibitor. Although this product is associated with the metabolism of drugs through XO (such as cholangine, mercaptopurine Azathioprine ）No research has been conducted on the interaction of XO, but the effect of this product on XO inhibition It will increase the concentration of these drugs in the plasma and cause toxicity. This product is prohibited for patients who are taking azathioprine, mercaptopurine or cholaphylline.

Cytotoxin Chemotherapy drugs

This product and cytotoxin chemotherapy Pharmaceutical Interaction No research has been conducted. There is no reliable data on the safety of this product during cytotoxic chemotherapy.

in vivo Drug interaction Research

According to the drug interaction study of healthy subjects, this product, together with colchicine naproxen 、 indometacin 、 Hydrochlorothiazide 、 warfarin 、 Desipamine No clinically significant interaction. Therefore, this product can be combined with these drugs.

Overdose

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For healthy subjects, the dosage of this product reaches 300mg per day for 7 days, without Dose limiting toxicity 。 No cases of drug overdose were reported.

Patients with overdose should receive symptomatic and supportive treatment.

Pharmacology and toxicology

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Action mechanism

Feebzos He is Xanthine oxidase inhibitor The curative effect is achieved by reducing serum uric acid.

This product will not inhibit at the therapeutic concentration purine and pyrimidine Other enzymes in the process of synthesis and metabolism.

Toxicological study

with Beagle dogs The toxicity study conducted for 12 months found that xanthine sediment crystals and stone 。 yes Rat After administration of 48mg/kg (about 35 times of human administration of 80mg/day), similar stone formation was also found due to xanthine crystal deposition in the 6-month study.

carcinogenicity : F344 rats and B6C3F1 mice A two-year carcinogenicity study was conducted. For male rats and female mice, 24 mg/kg (25 times of the recommended maximum dose of 80mg/day) and 18.75 mg/kg (12.5 times of the recommended maximum dose of 80mg/day) were administered, respectively Transitional cell Papilloma and Bladder cancer Increase. Bladder tumor It's the kidney and bladder stone Formed.

Mutagenicity : With or without metabolism Activator When, Chinese hamster lung Fibroblast in vitro chromosome aberration The test result is positive. Carry out with this product Ames test And people Peripheral blood lymphocytes And L5178Y mice lymphoma Cell chromosome aberration test and other in vitro studies, mice micronucleus test , Rats Unprogrammed DNA synthesis , Rats marrow cells In vivo studies, the results were negative.

Reproductive toxicity : Oral administration of this product to male and female rats at a dose of 48mg/kg/day (about 35 times of 80mg/day for humans) has no effect on fertility and reproduction.

Pharmacokinetics

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In health Subjects Medium, febuzostat 10mg~120mg Single dose Or multiple doses, Cmax and AUC showed Dose dependence To increase. each 24 hours The therapeutic dose was not observed Accumulation 。 Non Buzos His Apparent Average End Elimination half-life (t1/2) is about 5-8 hours.

Population Pharmacokinetics Analytical hyperuricemia And gout patients Pharmacokinetics The parameters were similar to those of healthy subjects.

absorb

Oral administration After radiolabeled non buzostatin, at least 49% was absorbed (according to radioactivity rate of recovery ）。 The maximum plasma concentration of febuzostat can be reached after administration for 1-1.5 hours. After repeated oral administration of 40 and 80 mg daily doses, Cmax was about 1.6 ± 0.6 μ g/ml (N=30) and 2.6 ± 1.7 μ g/ml (N=227), respectively. Non Buzostat Tablets Absolute bioavailability Not yet studied.

Cmax and AUC decreased by 49% and 18% respectively after the daily dose of 80mg was repeatedly taken orally with a high-fat diet. However, no clinical serum uric acid concentration was detected percentage Significant changes (diet 85%, Fasting 51%）。 Therefore, food effects may not be considered when taking this product.

80mg single dose of febuzostat and antacid include magnesium hydroxide and Aluminium hydroxide In combination, the results show that the absorption of non-Buzostatin is delayed (about 1 hour), leading to a 31% reduction in Cmax and a 15% reduction in AUC ∞. Because AUC is related to drug effect, the change of AUC is considered as no clinical Significance 。 Therefore, the effect of antacids may not be considered when taking this product.

distribution

Non Buzos His Average Apparent Steady State Distribution volume (Vss/F) is about 50L.

Non Buzosta Plasma protein binding rate About 99.2% (mainly related to albumin ）And remained unchanged within the concentration range reached by 40 and 80 mg doses.

metabolize

Non Buzos can pass the second phosphoric acid Uridine Glucoside Acid transfer enzyme (UDPGT) system (including UGT1A1, UGT1A3, UGT1A9 and UGT2B7) binding and Cytochrome P450 (CYP) systems (including CYP1A2, 2C8, 2C9 and non P450 enzymes) are extensively metabolized by oxidation. The interaction of various enzymes in the metabolic process of febuzostat is still unclear. Isobutyl Side chain Oxidation to form four pharmacologically active hydroxyl groups Metabolites , but the concentration range is far lower than that of non buzostatin.

Metabolites of this product in urine and feces acyl Glucoside Acid (35% of the dose), oxidation metabolite 67M-1 (10% of the dose), 67M-2 (11% of the dose) Secondary metabolites 67M-4 (14% of the dose) is the main metabolite of febuzostat in vivo.

eliminate

Febuzostat is cleared by the liver and kidney. After oral administration of 80mgC labeled febuzostat, 49% of the dose appeared in the urine, of which the original form of febuzostat was 3%, Active ingredient 30% acyl glucosidic acid, 13% known oxidative metabolites and their conjugates, and 3% other unknown metabolites. In addition to excretion through urine, about 45% of the dose appears in the feces, including 12% of the original form of non Buzostat, 1% of the effective ingredient acylglucoside, 25% of the known oxidation metabolites and their conjugates, and 7% of other unknown metabolites.

The apparent average terminal elimination half-life (t1/2) of febuzostat is about 5-8 hours.

special matter

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1. Children's medication

No patient under 18 years old has used this product Pharmacokinetics Research.

2. Medication for elderly patients

After multi dose oral administration of this product to elderly patients (≥ 65 years old), the Cmax and AUC of febuzostat and its metabolites are similar to those of young patients (18-40 years old). In addition, the serum uric acid concentration of the elderly and young subjects decreased percentage Similar. No dose adjustment is required for elderly patients to use this product.

three Renal insufficiency

After taking 80mg orally for patients with mild (Clcr 50-80 mL/min), moderate (Clcr 30-49 mL/min) or severe (Clcr 10-29 mL/min) renal insufficiency at multiple doses, the Cmax of non Buzostat remained unchanged, which was equivalent to that of normal (Clcr higher than 80 mL/min) renal function subjects. Compared with patients with normal renal function, AUC and half life Increased, renal dysfunction was similar in the three groups. The average AUC value of this product in patients with renal insufficiency is more than 1.8 times higher than that in subjects with normal renal function. The Cmax and AUC of active metabolites increased to 2 and 4 times respectively. However, the percentage of decrease in serum uric acid concentration in patients with renal insufficiency was comparable to that in patients with normal renal function (58% in patients with normal renal function, 55% in patients with severe renal insufficiency).

Patients with mild to moderate renal insufficiency do not need dose adjustment. The recommended starting dose of this product is 40mg, once a day. For patients whose sUA value is still higher than 6mg/dLd after two weeks of administration of 40mg, the recommended dosage is 80mg. There is no sufficient research data for the use of this product in patients with severe renal insufficiency, so such patients should be cautious when taking this product.

This product has not yet been used for patients with severe renal function damage in the late stage undergoing dialysis Related research 。

four Liver injury

Light（ cirrhosis Grade A), moderate (liver cirrhosis grade B) patients with liver injury after oral administration of 80mg of multiple doses, and normal liver function Compared with subjects, Cmax and AUC24 (total and unconjugated) increased by 20-30%. The percentage of decrease in serum uric acid concentration among different groups was similar (62% of healthy subjects, 49% of mild liver function injury group, and 48% of moderate liver function injury group).

No research has been carried out in patients with severe (cirrhosis grade C) liver injury, so the application of this product in such patients should be cautious.

5. Gender

After taking multiple doses of this product orally, the Cmax and AUC24 of women are about 30% and 14% higher than those of men respectively. However, weight adjusted Cmax and AUC were similar in both sexes. In addition, the percentage of decrease in serum uric acid concentration was similar between the sexes. There is no need to adjust the dose according to gender.

6. Race

This product is suitable for different races Pharmacokinetics No research has been done.

Storage

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Light proof and sealed, stored at room temperature of 15-30 ℃.

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