Uloric

ULORIC (febuxostat) is a xanthine oxidase inhibitor. The active ingredient in ULORIC is 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid, with a molecular weight of 316.38. The empirical formula is C16H16N2O3S.

The chemical structure is:

Febuxostat is a non-hygroscopic, white crystalline powder that is freely soluble in dimethylformamide; soluble in dimethylsulfoxide; sparingly soluble in ethanol; slightly soluble in methanol and acetonitrile; and practically insoluble in water. The melting range is 205°C to 208°C.

ULORIC tablets for oral use contain the active ingredient, febuxostat, and are available in two dosage strengths, 40 mg and 80 mg. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, silicon dioxide and magnesium stearate. ULORIC tablets are coated with Opadry II, green.

Included as part of the PRECAUTIONS section.

Uloric is a prescription medication used to prevent gout attacks. Gout is a type of arthritis in which uric acid builds up in the joints and causes sudden attacks of redness, swelling, pain, and heat in one or more joints. Uloric belongs to a group of drugs called xanthine oxidase inhibitors. It works by decreasing the amount of uric acid that is made in the body. 

Uloric comes in tablet form. It is taken once daily, with or without food.

Common side effects include nausea and joint pain.

Uloric can cause dizziness and blurred vision. Do not drive or operate heavy machinery until you know how Uloric affects you.

Serious side effects have been reported with Uloric. See the "Uloric Precautions" section.

Common side effects of Uloric include:

• nausea
• joint pain

This is not a complete list of Uloric side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X - are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Uloric falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Uloric crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweight the risk of using Uloric.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• how you respond to this medication

The recommended dose of Uloric is 40 or 80 mg once daily.

General

• Acute gout attacks (gout flare) may occur after initiation of febuxostat.1 Consider gout flare prophylaxis with an NSAIA or colchicine; start these agents when febuxostat therapy is initiated.1 Gout flare prophylaxis may be beneficial for up to 6 months.1 During these acute attacks, continue febuxostat and manage the gout flare as appropriate.1

• Testing for target serum urate concentrations can be performed after 2 weeks of febuxostat therapy.1

Administration

Oral Administration

Administered orally without regard to meals or antacids.1 10

Dosage

Adults

Initial dosage is 40 mg once daily.1 Increase dosage to 80 mg once daily in patients who do not achieve serum urate concentrations of <6 mg/dL after 2 weeks of therapy with febuxostat 40 mg once daily.1

Special Populations

Dosage adjustment is not needed in patients with mild to moderate renal or hepatic impairment.1 8

In the U.S.

• Uloric

Available Dosage Forms:

• Tablet

Therapeutic Class: Antigout

Pharmacologic Class: Xanthine Oxidase Inhibitor

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Abdominal or stomach fullness or pain
• arm, back, or jaw pain
• black, tarry stools
• bloody nose
• blurred vision
• chest pain or discomfort
• chills
• cloudy urine
• confusion
• cough
• dark urine
• decreased frequency or amount of urine
• diarrhea
• difficult or labored breathing
• difficulty with moving
• dizziness
• dry mouth
• fainting
• fast, irregular, pounding, or racing heartbeat or pulse
• feeling of fullness
• fever
• gaseous abdominal or stomach pain
• general tiredness and weakness
• headache
• heavier menstrual periods
• inability to speak
• increase in heart rate
• increased thirst
• itching
• joint pain, stiffness, or swelling
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• lightheadedness
• loss of appetite
• loss of bladder control
• muscle aching or cramping
• nausea and vomiting
• nervousness
• pain, swelling, or redness in the joints
• painful or difficult urination
• pale skin
• pinpoint red spots on the skin
• pounding in the ears
• rapid breathing
• rash
• redness of the skin
• right upper abdominal or stomach pain and fullness
• runny nose
• seizures
• severe or sudden headache
• shivering
• shortness of breath
• slow or fast heartbeat
• slurred speech
• sore throat
• sores, ulcers, or white spots on the lips or in the mouth
• sunken eyes
• sweating
• swelling
• temporary blindness
• thirst
• tightness in the chest
• trouble sleeping
• troubled breathing or swallowing
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of blood or material that looks like coffee grounds
• weakness in the arm or leg on one side of the body, sudden and severe
• weight gain
• wheezing
• wrinkled skin
• yellow eyes and skin

• Blistering, peeling, or loosening of the skin
• diarrhea
• difficulty with swallowing
• hives
• muscle cramps or spasms
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• red skin lesions, often with a purple center
• red, irritated eyes

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• anxiety
• bad, unusual, or unpleasant (after) taste
• blistering, crusting, irritation, itching, or reddening of the skin
• body aches or pain
• breast pain
• bruising
• burning feeling in the chest or stomach
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• change in taste
• changes in hair color
• constipation
• continuing ringing or buzzing or other unexplained noise in the ears
• cough producing mucus
• cracked, dry, or scaly skin
• decrease in smell
• decreased interest in sexual intercourse
• depression
• ear congestion
• excess air or gas in the stomach or intestines
• feeling of constant movement of self or surroundings
• fruit-like breath odor
• gum pain
• hair loss or thinning of the hair
• hearing loss
• heartburn
• hyperventilation
• inability to have or keep an erection
• inability to move the arms and legs
• increased or decreased appetite
• increased sensitivity of the skin to sunlight
• increased sweating
• increased urination
• irritability
• large, flat, blue, or purplish patches in the skin
• loss in sexual ability, desire, drive, or performance
• loss of appetite
• loss of consciousness
• loss of voice
• muscle or bone pain or stiffness
• muscle spasm, tightness, or weakness
• muscle twitching
• nasal congestion
• painful blisters on the trunk of the body
• pains in the stomach, side, or abdomen, possibly radiating to the back
• sensation of spinning
• severe or continuing stomach pain
• severe sunburn
• shakiness in the legs, arms, hands, or feet
• skin rash, encrusted, scaly, and oozing
• sleepiness or unusual drowsiness
• small red or purple spots on the skin
• sneezing
• stomach discomfort, upset, or pain
• sudden numbness and weakness in the arms and legs
• sweating
• swelling of the breasts or breast soreness in both females and males
• throat irritation
• trembling or shaking of the hands or feet
• trouble sleeping
• unexplained weight loss
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• weight loss

• Aggressive thoughts
• delusions
• hallucinations

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

Uloric is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout.

Uloric is not recommended for the treatment of asymptomatic hyperuricemia.

• 40 mg tablets, light green to green, round, debossed with "TAP" and "40"
• 80 mg tablets, light green to green, teardrop shaped, debossed with "TAP" and "80"

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 patients with hyperuricemia and gout were treated with Uloric 40 mg or 80 mg daily in clinical studies. For Uloric 40 mg, 559 patients were treated for ≥6 months. For Uloric 80 mg, 1377 patients 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 six 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 treatment groups and at least 0.5% greater than placebo.

The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of Uloric 40 mg, 1.2% of Uloric 80 mg, and in 0.9% of patients treated with allopurinol.

In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of patients treated with Uloric 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 patients and in more than one subject treated with doses ranging from 40 mg to 240 mg of Uloric. This list also includes adverse reactions (less than 1% of patients) 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-Barré 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, EEG 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 Safety

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% CI 0.00-6.16), Uloric 40 mg 0 (95% CI 0.00-1.08), Uloric 80 mg 1.09 (95% CI 0.44-2.24), and allopurinol 0.60 (95% CI 0.16-1.53).

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

Overall, a higher rate of APTC events was observed in Uloric than in patients treated with allopurinol. A causal relationship with Uloric has not been established. Monitor for signs and symptoms of MI and stroke.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Uloric. 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 to drug exposure.

Blood and Lymphatic System Disorders: agranulocytosis, eosinophilia.

Hepatobiliary Disorders: hepatic failure (some fatal), jaundice, serious cases of abnormal liver function test results, liver disorder.

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, erythema multiforme, drug reaction with eosinophilia and systemic symptoms, toxic epidermal necrolysis.

Uloric was studied in healthy patients in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities. No overdose of Uloric was reported in clinical studies. Patients should be managed by symptomatic and supportive care should there be an overdose.

Advise the patient to read the FDA-approved patient labeling (Patient Information)

Patients should be advised of the potential benefits and risks of Uloric. Patients should be informed about the potential for gout flares, elevated liver enzymes and adverse cardiovascular events after initiation of Uloric therapy.

Concomitant prophylaxis with an NSAID or colchicine for gout flares should be considered.

Patients should be instructed to inform their healthcare professional if they develop a rash, chest pain, shortness of breath or neurologic symptoms suggesting a stroke. Some serious skin and allergic reactions such as rash, skin reddening, pain, swelling or blistering of lips, eyes or mouth, skin peeling and flu-like symptoms have been reported in patients taking Uloric. Patients who had previous reactions to allopurinol may be at greater risk for these skin conditions [see Warnings and Precautions (5.4)].

Patients should be instructed to inform their healthcare professional of any other medications they are currently taking with Uloric, including over-the-counter medications.