Febuxostat is a combination of Uloric, Adenuric,and Feburic. It is a drug that inhibits the activity of enzyme xanthine oxidase and decreases serum uric acid levels. 

Febuxostat tablet uses:

It is used to treat chronic hyperuricemia in gout patients, particularly in those who are intolerant to allopurinol (Zyloric) or who don't respond well to treatment with the maximum allopurinol dose. Treatment of asymptomatic hyperuricemia is not recommended. The following brandnew medications are being researched for the treatment of hyperuricemia:

• Pegloticase (Polyethylenglicol-uricase)
• Rasburicase
• Y-700 (xanthine oxidoreductase inhibitor)
• RDEA-806

One Phase III research showed that febuxostat was superior to allopurinol in this situation. After three months, 62, 53, and 21% of patients receiving febuxostat 120 mg, 80 mg, and 300 mg daily, respectively, saw a decrease in blood uric acid levels to less than 6 mg/dl  [Ref]. In patients with baseline uric acid levels greater than 8 mg/dl, febuxostat in doses of 40 mg and 80 mg was combined with lesinurad (inhibits uric acid reabsorption) in doses of 400 mg and 600 mg to achieve the target serum uric acid levels of less than 6 mg/dl (or less than 5 mg/dl in some patients). Nearly all of the patients reached the desired serum uric acid levels. [Ref].

Cardiovascular Safety of Febuxostat vs allopurinol:

In the CARES trial, febuxostat was found non-inferior in terms of:

• Non-fatal stroke
• Composite of cardiovascular deaths
• Urgent revascularization due to unstable angina
• Non-fatal myocardial infarction

However, it was found inferior in terms of cardiovascular death and death from any cause [Ref].

Uloric BLACK BOX Warning

FDA issues a BLACK BOXED WARNING regarding the use of Febuxostat by patients with heart disease. If any of these symptoms occur while taking febuxostat, the FDA recommends medical examination.

• • Breathing difficulties
  • Palpitations and sinking in the heart
  • Apprehension
  • Either a rapid heartbeat or an irregular one
  • Dizziness
  • Chest pain
  • Trouble talking
  • Any weakness in any part of the body
  • facial deviation

However, the FDA recommends to seek medical attention rather than stopping the medicine as it may flare up a gouty attack [Ref].

Allopurinol vs febuxostat for CKD

In the Nu-Flash Trial, patients undergoing heart surgery who had chronic renal disease were treated for hyperuricemia with allopurinol versus febuxostat [Ref]. The authors concluded:

• • • The uric acid decrease was earlier 
    • Febuxostat showed greater renoprotective effect 
    • Febuxostat has greater antioxidant and anti-inflammatory effects

Likewise, febuxostat 80 mg was superior to febuxostat 40 mg and allopurinol in lowering serum uric acid levels in diabetic patients with hyperuricemia [Ref]. Febuxostat 40mg was less effective for patients with moderate renal dysfunction than it was for non-diabetic subjects.

When should you stop Febuxostat

Patients with recurrent attacks or chronic tophaceous arthritis, or persistent risk factors such as kidney disease, deficiency of enzyme, and/or persistent risk factors for hyperuricemia (Lesh Nyhan Syndrome) should continue the use of febuxostat indefinitely. Intermittent therapy may be necessary for some patients. Patients with mild hyperuricemia or gouty arthritis may find intermittent therapy cost-effective. There have been many different types of intermittent therapy. Patients with mild to moderate hyperuricemia have had their treatment for two months, six months, and a year.

Febuxostat vs Allopurinol

Febuxostat Dose in Adults

Febuxostat dosage for adults in Hyperuricemia:

• Note:
  • To prevent gout flare patients should continue it for up to six months
  • For flare, NSAIDs should be given and febuxostat should be continued.

Dose in Hyperuricemia:

• Orally take 40mg one time a day
• If after two weeks the serum uric acid does not decrease to less than 6 mg/dl, the dose may be increased to 80 mg once daily.
• Patients who don't respond well enough may receive a dose as high as 120 mg.

Febuxostat (Uloric) dose in children:

• Efficacy and safety in children has not been established.
• One retrospective study evaluated the role of febuxostat in the prevention of tumor lysis syndrome in children and used a fixed dose of 10 mg daily [Ref].

Febuxostat (Uloric) pregnancy Risk Category: C

• Adverse effects on fetus have been reported in animal studies.

Use of ulroic during breastfeeding.

• The drug's potential for excretion into breastmilk is unknown.
• Manufacturers claim benefits for the mother and the infant.

Febuxostat (Uloric) dosage in kidney disease:

• Renal impairment that is mild to moderate (CrCl 30 to 89 mL/min):

  • There is no need to change the dosage.

• Use with caution if you have severe renal impairment (CrCl 30 mL/min):

  • The daily intake shouldn't be more than 40 mg at the most.

• Dialysis:

  • It has not been studied in patients with renal impairment, however, small scale studies have not found any alteration in the pharmacokinetics of the drug in hemodialysis patients.

Dose of Febuxostat (Uloric) in liver disease:

• Hepatic impairment of mild to moderate severity (Child-Pugh class A or B):

  • There is no need to change the dosage.

• Kidney dysfunction that is severe (Child-Pugh class C):

  • It should be used with caution, however, the manufacturer has not recommended any adjustment in the dose.

Febuxostat side effects (40 mg and 80 mg):

• Skin rash
• Nausea
• Increased serum aspartate aminotransferase
• Hepatic insufficiency
• Arthralgia

Rare side effects:

• Endocrine & metabolic:

  • Acute gout attack

 Febuxostat Contraindications:

• • •  

      • • • Concurrent use with azathioprine or mercaptopurine should be avoided.
          • Appearance of allergy symptoms to febuxostat  and any formulation ingredients

Precautions and Warnings for Febuxostat

• US Boxed Warning; Cardiovascular death:

  • Compared to allopurinol, cardiovascular disease patients who are being treated for gout, the rates of deaths due to cardiovascular diseases are high.
  • Febuxostat should only be given to these patients if the patients are intolerant of allopurinol, show no proper response to the  allopurinol, or when allopurinol can not be advised.
  • Patients should be closely monitored for any new-onset aggravation of their cardiac symptoms.
  • Prophylactic aspirin should be advised to patients with a history of cardiovascular disease.

• Hepatic failure

  • Clinical trials have shown liver toxicity and postmarketing reports have also documented it.
  • During treatment, it is important to monitor the liver functions.
  • Patients with liver toxicities such as jaundice, nausea, right hypochondrial pain, or jaundice should be investigated immediately.
  • Treatment should be stopped if ALT is above the normal upper limit.
  • Patients who have hepatic impairment and raised ALT 

• Hypersensitivity

  • Extreme allergy and cutaneous reactions such Stevens Johnson syndrome, toxic epidermal necrolysis, and DRESS have all been connected to it.
  • Patients who have had previous skin reactions to allopurinol are more likely to experience allergic reactions.
  • Patients who are allergic should not use it.

• Hepatic impairment

  • This drug has not been tested for severe liver disease patients therefore should be avoided.

• Secondary hyperuricemia

  • Secondary hyperuricemia has not been studied therefore should not be recomended to patients at increased risk of urate formation such as those with cancers, patients receiving chemotherapy, and Lesch-Nyhan syndrome).

Febuxostat: Drug Interaction

Categories of drug interaction:

• Monitor When Using Combination for Risk Factor C
• Consider Treatment Modification for Risk Factor D
• Avoid Concomitant Use for Risk Factor X

Monitor:

• Prior to beginning medication, and then frequently, liver function tests must be monitored
• Serum uric acid concentrations before and after the first two weeks of treatment.
• Cardiovascular events symptoms
• Severe allergic reactions and symptoms.

How to administer Febuxostat?

It may be taken with or without meals or antacids.

Febuxostat Mechanism of Action:

It functions as a selective nonpurine inhibitor of the xanthine oxidease enzyme. Xanthine oxide is responsible for converting hypoxanthine into xanthine and uric acid. It blocks both the reduced as well as oxidized forms xanthine oxide oxidase. The inhibition of xanthineoxidase results in a reduction in uric acids. It is very selective and does not  block any other enzymes involved in pyrimidine or purine production. AbsorptionThe drug has a 49% success rate 99 percent of the drug isProtein-boundMostly to albumin. It is Metabolized via conjugation and oxidation by uridine diphosphate glucuronosyltransferases and cytochrome P450 (CYP) 1A2, 2C8, and 2C9. It has been ahalf-life eliminationIt takes between 5 and 8 hours. It takes approximately 1 to 1.5 hours for plasma concentration to peak. After MetabolicIt is converted into inactive metabolitesexcretedVia urine and feces  

Febuxostat brand names (International):

• Uloric
• Adenuric
• Agout
• Atenurix
• Fabuzest
• Febsan
• Febuday
• Feburic
• Febus
• Febux
• Febuxtat
• Fexorin
• Fexurix
• Furic
• Goustat
• Goutex
• Goutil
• Goutseal-40
• Goutseal-80
• Rui Yang
• Turazive
• Urica
• Urinorm
• Urostat
• Zurig

Febuxostat price in the US:

• 40 mg tablet retails for $10.07 - $12.38

• 80 mg tablet retails for $10.07 - $12.38

Febuxostat in Pakistan: