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Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 2757 subjects with hyperuricemia and gout were treated with ULORIC (febuxostat) 40 mg or 80 mg daily in clinical studies. For ULORIC (febuxostat) 40 mg, 559 patients were treated for ≥ 6 months. For ULORIC (febuxostat) 80 mg, 1377 subjects were treated for ≥ 6 months, 674 patients were treated for ≥ 1 year and 515 patients were treated for ≥ 2 years.

Most Common Adverse Reactions

In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were 6 to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug. Table 1 summarizes adverse reactions reported at a rate of at least 1% in ULORIC (febuxostat) treatment groups and at least 0.5% greater than placebo.

Table 1: Adverse Reactions Occurring in ≥ 1% of ULORIC (febuxostat) -Treated Patients and at Least 0.5% Greater than Seen in Patients Receiving Placebo in Controlled Studies

The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of ULORIC (febuxostat) 40 mg, 1.2% of ULORIC (febuxostat) 80 mg, and in 0.9% of allopurinol-treated subjects.

In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of ULORIC (febuxostat) -treated subjects although not at a rate more than 0.5% greater than placebo.

Less Common Adverse Reactions

In Phase 2 and 3 clinical studies the following adverse reactions occurred in less than 1% of subjects and in more than one subject treated with doses ranging from 40 mg to 240 mg of ULORIC (febuxostat) . This list also includes adverse reactions (less than 1% of subjects) associated with organ systems from WARNINGS AND PRECAUTIONS.

Blood and Lymphatic System Disorders: anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia.

Cardiac Disorders: angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia.

Ear and Labyrinth Disorders: deafness, tinnitus, vertigo.

Eye Disorders: vision blurred.

Gastrointestinal Disorders: abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting.

General Disorders and Administration Site Conditions: asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst.

Hepatobiliary Disorders: cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly.

Immune System Disorder: hypersensitivity.

Infections and Infestations: herpes zoster.

Procedural Complications: contusion.

Metabolism and Nutrition Disorders: anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased.

Musculoskeletal and Connective Tissue Disorders: arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia.

Nervous System Disorders: altered taste, balance disorder, cerebrovascular accident, Guillain-Barre syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor.

Psychiatric Disorders: agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change.

Renal and Urinary Disorders: hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence.

Reproductive System and Breast Changes: breast pain, erectile dysfunction, gynecomastia.

Respiratory, Thoracic and Mediastinal Disorders: bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection.

Skin and Subcutaneous Tissue Disorders: alopecia, angio-edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria.

Vascular Disorders: flushing, hot flush, hypertension, hypotension.

Laboratory Parameters: activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEC abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein.

Cardiovascular Safely

Cardiovascular events and deaths were adjudicated to one of the pre-defined endpoints from the Anti-Platelet Trialists' Collaborations (APTC) (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the randomized controlled and long-term extension studies. In the Phase 3 randomized controlled studies, the incidences of adjudicated APTC events per 100 patient-years of exposure were: Placebo 0 (95% Cl 0.00-6.16), ULORIC (febuxostat) 40 mg 0 (95% Cl 0.00-1.08), ULORIC (febuxostat) 80 mg 1.09 (95% Cl 0.44-2.24), and allopurinol 0.60 (95% Cl 0.16-1.53).

In the long-term extension studies, the incidences of adjudicated APTC events were: ULORIC (febuxostat) 80 mg 0.97 (95% Cl 0.57-1.56), and allopurinol 0.58 (95% Cl 0.02-3.24).

Overall, a higher rate of APTC events was observed in ULORIC (febuxostat) than in allopurinol-treated patients. A causal relationship with ULORIC (febuxostat) has not been established. Monitor for signs and symptoms of Ml and stroke.

Postmarketing Experience

Adverse reactions have been identified during post approval use of ULORIC (febuxostat) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship.

Immune System Disorders: anaphylaxis, anaphylactic reaction.

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis.

Psychiatric Disorders: psychotic behavior including aggressive thoughts.

Renal and Urinary Disorders: tubulointerstitial nephritis.

Skin and Subcutaneous Tissue Disorders: generalized rash, Stevens Johnson Syndrome, hypersensitivity skin reactions.

Xanthine Oxidase Substrate Drugs

ULORIC (febuxostat) is an XO inhibitor. Based on a drug interaction study in healthy subjects, febuxostat altered the metabolism of theophylline (a substrate of XO) in humans [see CLINICAL PHARMACOLOGY]. Therefore, use with caution when co-administering ULORIC (febuxostat) with theophylline.

Drug interaction studies of ULORIC (febuxostat) with other drugs that are metabolized by XO (e.g., mercaptopurine and azathioprine) have not been conducted. Inhibition of XO by ULORIC (febuxostat) may cause increased plasma concentrations of these drugs leading to toxicity [see CLINICAL PHARMACOLOGY]. ULORIC (febuxostat) is contraindicated in patients being treated with azathioprine or mercaptopurine [see CONTRAINDICATIONS].

Cytotoxic Chemotherapy Drugs

Drug interaction studies of ULORIC (febuxostat) with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC (febuxostat) during cytotoxic chemotherapy.

In Vivo Drug Interaction Studies

Based on drug interaction studies in healthy subjects, ULORIC (febuxostat) does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine [see CLINICAL PHARMACOLOGY]. Therefore, ULORIC (febuxostat) may be used concomitantly with these medications.

Last reviewed on RxList: 3/21/2011
This monograph has been modified to include the generic and brand name in many instances.