Febuxostat (Page 6 of 7)

14.2 Cardiovascular Safety Study

A randomized, double-blind, allopurinol-controlled CV outcomes study (CARES) was conducted to evaluate the CV risk of febuxostat tablets. The study compared the risk of MACE between patients treated with febuxostat tablets (N=3098) and allopurinol-treated patients (N=3092). The primary endpoint was the time to first occurrence of a MACE defined as the composite of CV death, nonfatal MI, nonfatal stroke, or unstable angina with urgent coronary revascularization. The study was designed to exclude a prespecified risk margin of 1.3 for the hazard ratio of MACE. An independent committee conducted a blinded evaluation of serious CV adverse events according to predefined criteria (adjudication) for determination of MACE. The study was event driven and patients were followed until a sufficient number of primary outcome events accrued. The median on-study follow-up time was 2.6 years.

Patients randomized to febuxostat tablets initially received 40 mg once daily which was increased to 80 mg once daily, if their sUA was ≥6mg/dL at Week 2. For patients randomized to allopurinol, those who had normal renal function or mild renal impairment (estimated creatinine clearance (eClcr ) ≥60 to ˂90 mL/minute) initially received 300 mg once daily with 100 mg/day dose increments monthly until either sUA ˂6mg/dL or an allopurinol dosage of 600 mg once daily was achieved; those who had moderate renal impairment (eClcr ≥30 to ˂60 mL/minute) initially received 200 mg once daily with 100 mg/day dose increments monthly until either a sUA ˂6 mg/dL or an allopurinol dosage of 400 mg once daily was achieved.

The mean age of the population was 65 years (range: 44 to 93 years). Most patients were male (84%) and Caucasian (69%). Patients had a diagnosis of gout for approximately 12 years, a mean baseline sUA of 8.7 mg/dL, and 90% had experienced at least one gout flare in the past year. CV history included MI (39%), hospitalization for unstable angina (28%), cardiac revascularization (37%), and stroke (14%). The most prevalent comorbid conditions were hypertension (92%), hyperlipidemia (87%), diabetes mellitus (55%), diabetes mellitus with micro- or macrovascular disease (39%), and renal impairment [92% with an eClcr 30 to 89 mL/minute]. The use of CV disease medication was balanced across treatment groups. Baseline CV disease medications included: ACE inhibitors or ARBs (70%), lipid modifying agents (74%), aspirin (62%), beta-blockers (59%), calcium channel blockers (26%), and nonaspirin antiplatelet medications (31%).

Table 5 shows the study results for the primary MACE composite endpoint and its individual components. For the composite primary endpoint, the febuxostat tablets group was non-inferior compared with the allopurinol group. The rates of nonfatal MI, stroke, and unstable angina with urgent coronary revascularization were similar. There was a higher rate of CV deaths in patients treated with febuxostat tablets (134 CV deaths; 1.5 per 100 PY) than in allopurinol-treated patients (100 CV deaths; 1.1 per 100 PY). Sudden cardiac death was the most common cause of adjudicated CV deaths in the febuxostat tablets group (83 of 3,098; 2.7%) as compared to the allopurinol group (56 of 3,092; 1.8%). The biological plausibility of CV death associated with febuxostat tablets is unclear.

All-cause mortality was higher in the febuxostat tablets group (243 deaths [7.8%]; 2.6 per 100 PY) than the allopurinol group (199 deaths [6.4%]; 2.2 per 100 PY) [Hazard Ratio: 1.22, 95% CI: 1.01, 1.47], due to a higher rate of CV deaths.

Table 5: Patients with MACE in CARES (Cardiovascular Outcomes Study in Patients with Gout)
Febuxostat tablets N=3098 Allopurinol N=3092 Hazard Ratio
Number of Patients with Event (%) Rate per 100 PY* Number of Patients with Event (%) Rate per 100 PY* 95% CI
Composite of primary endpoint MACE 335 (10.8) 3.8 321 (10.4) 3.7 1.03 (0.89, 1.21)
Cardiovascular Death 134 (4.3) 1.5 100 (3.2) 1.1 1.34 (1.03, 1.73)
Nonfatal MI 111 (3.6) 1.2 118 (3.8) 1.3 0.93 (0.72, 1.21)
Nonfatal stroke 71 (2.3) 0.8 70 (2.3) 0.8 1.01 (0.73, 1.41)
Unstable angina with urgent coronary revascularization 49 (1.6) 0.5 56 (1.8) 0.6 0.86 (0.59, 1.26)

* Patient Years (PY)

16 HOW SUPPLIED/STORAGE AND HANDLING


Febuxostat tablets 40 mg tablets are light green to green coloured, round, biconvex, film coated tablet debossed with “18” on one side and “I” on the other side and supplied as:
NDC NumberSize
14445-156-30 Bottle of 30 Tablets
14445-156-90 Bottle of 90 Tablets
14445-156-05 Bottle of 500 Tablets
Febuxostat tablets 80 mg tablets are light green to green coloured, tear drop shaped, biconvex, film coated tablet debossed with “19” on one side and “I” on the other side and supplied as:
NDC NumberSize
14445-157-30 Bottle of 30 Tablets
14445-157-01 Bottle of 100 Tablets
14445-157-00 Bottle of 1000 Tablets
Protect from light. Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

CV Death

Inform patients that gout patients with established CV disease treated with febuxostat tablets had a higher rate of CV death compared to those treated with allopurinol in a CV outcomes study. Inform all patients of the higher rate of CV death with febuxostat tablets compared to allopurinol. Instruct all patients (those with and without CV disease) to be alert for the development of signs and symptoms of CV events [see Warnings and Precautions (5.1)].

Gout Flares

Inform patients that after initiation of febuxostat tablets there was an increased frequency of gout flares. Instruct patients that it is recommended to initiate and continue gout prophylaxis therapy for six months while taking febuxostat tablets [see Warnings and Precautions (5.2)].

Hepatic Effects

Inform patients that hepatic effects have occurred in patients treated with febuxostat tablets and instruct them to inform their healthcare provider if they experience liver injury symptoms [see Warnings and Precautions (5.3)].

Serious Skin Reactions

Inform patients that serious skin and hypersensitivity reactions have occurred in patients treated with febuxostat tablets. Instruct patients to discontinue febuxostat tablets if they develop symptoms of these reactions [see Warnings and Precautions (5.4)].

MEDICATION GUIDE

Febuxostat tablets
(fe bux’ oh stat)

tablets, for oral use
Read the Medication Guide that comes with febuxostat tablets before you start taking it and each time you get a refill. There may be new information. The Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information that I should know about febuxostat tablets?

Febuxostat tablets may cause serious side effects, including:

Heart -related deaths.

Call your doctor or get emergency medical help right away if you have any of the following symptoms, especially if they are new, worse, or worry you:

  • chest pain
  • shortness or breath or trouble breathing
  • dizziness, fainting or feeling lightheaded
  • rapid or irregular heartbeat
  • numbness or weakness in one side of your body
  • slurring of speech
  • sudden blurry vision or sudden severe headache

What are febuxostat tablets?

Febuxostat tablet are prescription medicine called a xanthine oxidase (XO) inhibitor used to lower blood uric acid levels in adults patients with gout when allopurinol has not worked well enough or when allopurinol is not right for you. Febuxostat tablet is not for use in people who do not have symptoms of high blood uric acid levels.

It is not known if febuxostat tablets are safe and effective in children.

Who should not take febuxostat tablets?

Do not take febuxostat tablets if you:

  • take azathioprine (Azasan, Imuran)
  • take mercaptopurine (Purinethol, Purixan)

What should I tell my doctor before taking febuxostat tablets?

Before taking febuxostat tablets tell your doctor about all of your medical conditions, including if you:

  • have taken allopurinol and what happened to you while you were taking it.
  • have a history of heart disease or stroke
  • have liver or kidney problems
  • are pregnant or plan to become pregnant. It is not known if febuxostat tablets will harm your unborn baby. Talk with your doctor if you are pregnant or plan to become pregnant.
  • are breastfeeding or plan to breastfeed. It is not known if febuxostat tablets passes into your breast milk. You and your doctor should decide if you should take febuxostat tablet while breastfeeding.

Tell your doctor about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Febuxostat tablets may affect the way other medicines work, and other medicines may affect how febuxostat tablets works.


Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take f ebuxostat tablets?

  • Take febuxostat tablets exactly as your doctor tells you to take it.
  • Febuxostat tablets can be taken with or without food.
  • Febuxostat tablets can be taken with antacids.
  • Your gout may get worse (flare) when you start taking febuxostat tablets. Do not stop taking febuxostat tablets because you have a flare.

Your doctor may do certain tests while you take febuxostat tablets.

What are the possible side effects of febuxostat tablets?

Febuxostat tablets may cause serious side effects, including:

  • Heart problems. See “What is the most important information I should know about febuxostat tablets?”.
  • Gout Flares. Gout flares can happen when you first start taking Febuxostat tablets. Your doctor may give you other medicines to help prevent your gout flares.
  • Liver problems. Liver problems can happen in people who take febuxostat tablets. Your doctor may do blood tests to check how well your liver is working before and during your treatment with febuxostat tablets. Tell your doctor if you get any of the following signs or symptoms of liver problems:
    • fatigue
    • loss of appetite for several days or longer
    • pain, aching, or tenderness on the right side of your stomach-area
    • dark or “tea-colored” urine
    • your skin or the white part of your eyes turns yellow (jaundice)
  • Severe skin and allergic reactions. Serious skin and allergic reactions that may affect different parts of the body such as your liver, kidneys, heart or lungs, can happen in people who take febuxostat tablets. Call your doctor right away or get emergency medical help if you have any of the following symptoms:
    • rash
    • red and painful skin
    • severe skin blisters
    • peeling skin
    • sores around the lips, eyes or mouth
    • swollen face, lips, mouth, tongue or throat
    • flu-like symptoms

The most common side effects of febuxostat tablets include:

  • abnormal liver function tests
  • nausea
  • joint pain
  • rash

These are not all of the possible side effects of febuxostat tablets.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store febuxostat tablets?

  • Store febuxostat tablets between 59 ºF to 86ºF (15ºC to 30ºC).
  • Keep febuxostat tablets out of the light.

Keep febuxostat tablets and all medicines out of the reach of children.

General information about the safe and effective use of febuxostat tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use febuxostat tablets for a condition for which it was not prescribed. Do not give febuxostat tablets to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your doctor or pharmacist for information about febuxostat tablets that is written for health professionals.

What are the ingredients in febuxostat tablets?

Active ingredient: febuxostat hemihydrate

Inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, colloidal silicon dioxide magnesium stearate and Opadry II, green. The components of Opadry II, green are D&C yellow #10 aluminium lake, FD&C blue #1/ Brilliant blue FCF aluminum lake, FD&C blue #2/ Indigo Carmine AL, Macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, titanium dioxide

Manufactured by:

Indoco Remedies Limited

L- 32, 33 & 34,

Verna Industrial Estate,

Verna, Goa — 403722, India.

All other trademarks are the property of their respective owners.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: January 2020

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