Treatment Options for Gout by Jon Brady, Pharmd; Sarah Pupo, Pharmd; Eric Sidman, Pharmd; and Jennifer Malinowski Pharmd

continuing education

Treatment Options for Gout by Jon Brady, PharmD; Sarah Pupo, PharmD; Eric Sidman, PharmD; and Jennifer Malinowski PharmD

pon successful completion of this the body and dietary protein break down. Patients with activity, the pharmacist should be gout may produce more uric acid than can be solubi- able to: lized (overproduction) or they may not be able to excrete 1. Describe the pathophysiology enough uric acid (underexcretion). of gout. gout was first characterized thousands of years U2. Recognize the clinical characteristics and ago. It was incorrectly thought to be a “disease of kings” various manifestations of gout. because of its predilection towards wealthier individuals 3. Explain symptom management strategies for who consume food and drink in excess. Interestingly, the acute gout attacks. treatment of gout preceded the actual understanding 4. Identify patients who are candidates for pro- of the pathophysiologic mechanisms. Herbal therapies phylactic therapy and select an appropriate such as active colchicum are still a part of therapeu- agent and dose based on patient and drug tic plans today. Standard treatment of gout has not characteristics. changed much in the past 50 years. However, recent 5. Establish monitoring plans for gout treat- drug approvals offer new approaches to therapy. The ments. purpose of this article is to highlight the pathophysiolo- 6. Provide appropriate patient education on gy, risk factors, non-pharmacologic, and pharmacologic non-pharmacologic strategies for gout, phar- treatments for gout, and to summarize the pros and macologic agents for acute gout and gout cons of each treatment. prophylaxis. Pathophysiology Upon successful completion of this activity, the Gout is a type of arthritis associated with a disorder of pharmacy technician should be able to: purine metabolism characterized by the deposition of 1. Describe the pathophysiology of gout. monosodium urate (MSU) crystals in joints, bones, and 2. List the clinical characteristics and various soft tissues. These crystals result in a local immune manifestations of gout. response leading to pain, erythema, and inflammation 3. Recognize patients who may be experienc- at the affected site. Prolonged presence of crystals can ing an acute gout attack and recommend cause a sustained inflammatory response, often resulting pharmacist intervention. in tissue damage. 4. Explain non-pharmacologic symptom man- MSU crystals are derived from uric acid, a water-sol- agement strategies for acute gout attacks uble substance which has no physiological function and and prophylaxis. is an end product of purine metabolism. Purines ingested as dietary protein, as well as purines released from the More than six million adults in the United States DNA of degraded cells throughout the human body, are suffer from gout. Gout is an inflammatory joint metabolized in a stepwise process. The final steps in disease associated with abnormal uric acid the metabolic pathway involve the conversion of purine metabolism. Uric acid is formed when cells in nucleotides to hypoxanthine, which is then converted

www.americaspharmacist.net March 2013 | america’s Pharmacist 37 to xanthine via the enzyme xanthine oxidase. Xanthine follows the activation of these mediators and oxidase is also responsible for the conversion of xanthine neutrophils invade the affected area, removing to the uric acid end product. The majority of uric acid MSU crystals through the process of phagocy- excretion occurs renally and a small amount of uric acid tosis. The neutrophils are then lysed, releasing is broken down by bacteria in the colon and excreted via proteolytic enzymes into the joint or soft tissues the gastrointestinal tract. that further increase inflammation and contrib- Elevated serum concentration of uric acid and de- ute to the manifestation of gout symptoms. creased temperature of the local environment promote the precipitation of MSU crystals responsible for a gouty Patient Case attack. Increased uric acid concentrations are caused JG is a 45-year-old, obese, white male who by an imbalance between the metabolism and excretion comes to the pharmacy to purchase a bottle of of purines. aspirin for a swollen, painful toe. He appears the vast majority of gout patients (85–90 percent) to be very uncomfortable and is limping. He are underexcretors and do not eliminate uric acid effi- denies recent trauma to his foot and states he ciently. Primary causes of uric acid underexcretion include “never had pain this bad before and it’s been inherited disorders such as polycystic kidney disease, getting worse over the past hour.” His past familial juvenile hyperuricemic nephropathy, and medul- medical history is significant for hypertension, lary kidney disease. Secondary causes of decreased which is treated with losartan 50 mg daily, and renal excretion of uric acid include hypertension, chronic high cholesterol, which he manages with diet kidney disease, medications, and several metabolic and over-the-counter niacin. He quit smoking disorders. The resultant buildup of uric acid leads to the a couple years ago but does drink “a couple precipitation of MSU crystals in tissues, consequently 6-packs” on weekends. causing a gouty attack. overproducers, the minority of patients, synthesize Clinical Presentation of Gout excessive amounts of uric acid. Primary causes include The clinical presentation of gout is character- inherited enzymatic defects such as glucose-6-phos- ized by two clinical phases. The first phase phate dehydrogenase deficiency (G6PD), hypoxanthine- is associated with acute intermittent arthritis guanine phosphoribosyl transferase deficiency, and attacks that resolve on their own after seven to phosphoribosyl pyrophosphate synthetase deficiency. ten days. If high uric acid levels (defined as uric Secondary causes of uric acid overproduction include acid 6.8 mg/dL or more) are allowed to persist, excessive dietary purine intake, ethanol consumption, a second phase of chronic arthritis may occur. medications (such as chemotherapy agents), and Tophi, or crystal deposition, may be observed proliferative cancers. Increased uric acid production at this stage. Presence of tophi is considered may be compensated via increased renal elimination. a pathognomonic feature of gout. Chronic However, if renal elimination is not adequate to overcome tophaceous gout is seen more commonly in overproduction, serum uric acid levels rise. As with patients with gout for more than 20 years and is underexcretors, hyperuricemia from overproduction associated with multiple joint involvement and results in MSU crystal precipitation and gout symptoms. symptoms in between attacks. Deposition of MSU crystals results in the activation An acute gout attack is rapid, painful and of the innate immune system. MSU crystals are believed severely worsens within the first 24 hours. to interact with receptors of local dendritic cells and Table 1 summarizes the typical subjective and macrophages, which activate the immune response. The objective findings associated with an acute resultant production of interleukin 1 (IL-1) initiates a cas- gout attack. The most common site is the cade of pro-inflammatory mediators such as neutrophil metatarsophalangeal joint of the big toe and chemotactic factors, tumor necrosis factor  (TNF ), knee joints. Gouty joint involvement is typically interleukin 6 (IL-6), and interleukin 8 (IL-8). Inflammation monoarticular (involves a single joint). Patients

38 america’s Pharmacist | March 2013 www.americaspharmacist.net Table 1. Clinical Features of Gout Subjective Objective • Joint pain resulting in acute distress • Joint swelling • Unable to sleep due to pain • Erythematous joint • Severe pain on urination (gout kidney stones) • Joint is warm to touch • Elevated uric acid (can be normal) • Elevated erythrocyte sedimentation rate (ESR) • Mild fever • Uric acid calculi (kidney stones) • Joint damage and tophi of common sites such as the hand, wrist, elbow, and/or knee

65 years and older may present atypically with estrogen may increase uric acid secretion. There also ap- an insidious onset and involvement of multiple pears to be a link between family history of gout and risk joints and/or the hand or wrist. of developing symptoms. Drug-induced gout is an important therapeutic prob- Risk Factors lem for pharmacists to recognize. Thiazide diuretics and Table 2 summarizes common risk factors as- low-dose aspirin are two common medications associ- sociated with gout. Gout is strongly associated ated with hyperuricemia. Other medications associated with hyperuricemia, variably defined as serum with hyperuricemia are listed in Table 2. The majority of uric acid levels greater than 6.8–7mg/dL. One medications reduce renal elimination of uric acid, with study suggests levels of uric acid greater than the exception of chemotherapy which is associated with 10 mg/dL are associated with a 30 percent risk increased uric acid production due to cellular death. of developing gout over a five-year span. Men Substitution of therapeutic alternatives for these agents, are more likely to develop gout than women ini- when possible, may help to diminish attacks. Most clini- tially, although once women reach menopause cians opt to continue cardioprotective doses of aspirin as the difference is minimal. Declining amounts of the benefits outweigh the risks. Initiation of urate-lowering

Table 2. Causes of Hyperuricemia Under-excretion Overproduction • Chronic kidney disease • Dyslipidemia • Renal failure/insufficiency • Myeloproliferative disorders • Menopause, estrogen deficiency • lymphoproliferative disorders • Hypertension • Exercise • Dehydration • Obesity • Increased lactic acid levels • High purine diet • Sarcoidosis • Alcohol consumption • Hypothyroidism • Chemotherapy/cytotoxic agents • Hyperparathyroidism • Obesity • Alcohol consumption • Low dose aspirin • Thiazide and loop diuretics • Cyclosporine • Levodopa • Pyrazinamide • Ethambutol • Niacin

www.americaspharmacist.net March 2013 | america’s Pharmacist 39 therapy is also associated with triggering acute attacks, is a reliable method for diagnosis. Patients pre- possibly from increased mobilization of urate stores out senting with joint pain, swelling, and redness of the joints and into the bloodstream. that develop within 24 hours (particularly in the metatarsophalangeal joint of the great toe) are Patient Case Continued extremely likely to have gout. When accompa- JG’s presentation is indicative of a gout attack. The nied by hyperuricemia, 82 percent of patients attack appeared to be acute in onset, associated with presenting with these symptoms are likely to severe pain, and it is located in his big toe. He presents have gout. Differential diagnoses that should with several risk factors including: obesity, hypertension, be ruled out include septic arthritis, lupus, and and alcohol use. It is important to take note of the OTC rheumatoid arthritis. vitamin product he is using for cholesterol. Niacin should be discontinued if possible because it can precipitate a Goals of Therapy gout attack. Fenofibrate is a reasonable substitute that Treatment goals for gout include pain relief; iden- is also associated with reduced uric acid. Small studies tifying and remove exacerbating factors; prevent- suggest that fenofibrate counteracts the increased urate ing complications; and reducing recurrence. levels seen in patients on hydrochlorothiazide. Losartan is a logical substitute for hydrochlorothiazide based on its Non-Pharmacologic Management uricosuric properties. Other angiotensin receptor block- Affected joints should be immobilized for ers and angiotensin converting enzyme inhibitors such as several days following an acute attack to avoid lisinopril do not appear to possess a urate lowering effect. mechanical stimulation and further inflamma- the patient should be warned that aspirin could tion. Immobilization may decrease the need for potentially worsen his pain if he is experiencing an acute acute pharmacological therapy. The use of ice gout attack. The effect of aspirin on uric acid is dose-de- packs should also be encouraged, but heating pendent. For example, doses greater than 3 grams daily pads should be avoided. enhance the renal excretion of uric acid, while aspirin Lifestyle modifications may help reduce dosed between 1–2 grams daily reduce uric acid excre- the number of gout attacks. Overall, lifestyle tion. Cardioprotective aspirin doses around 75 mg daily modifications have been found to decrease uric are associated with a 15 percent reduction in uric acid acid levels and monthly attacks by 18 percent elimination. Low dose aspirin for myocardial infarction and 67 percent respectively, after four months. and stroke prevention may be considered if cardiopro- The 2012 American College of Rheumatology tective benefit outweighs the risk of gouty attacks. It is (ACR) Gout guidelines provide guidance on best to refer the patient to his primary care provider and diet. Quantity limits for “limit” and “encourage” discourage the aspirin purchase at this time. dietary are consciously not defined due to lack of consistent data on serving sizes and risk/ Clinical Diagnosis benefit for gout. A general guideline for phar- Although microscopic evaluation of MSU crystals in sy- macists is to recognize that patients with gout novial fluid (or tophi) is the gold standard, crystal inspec- should avoid high-purine foods such as liver, tion is not common in routine diagnostic practice due to sweetbreads and kidney. Newer findings sug- invasiveness. Hyperuricemia is considered a risk factor gest a correlation between high fructose corn for the development of gout. However, high uric acid syrup sweetened sodas and products; the ACR levels are not always present during an acute attack. recommends patients with gout avoid these Therefore, uric acid level measurement is not the most beverages and foods. useful tool for diagnosis. Radiographic changes may be Patients should maintain an overall present but are not specific to gout. healthy diet and exercise regimen. Smoking Another reason why aspiration is not always needed cessation and weight loss for obese patients is because the clinical presentation associated with gout should be emphasized. Complete elimination

40 america’s Pharmacist | March 2013 www.americaspharmacist.net of dietary purine is not necessary, although Patient Case Continued Atkins type diets should be discouraged. Red JG agrees to see his doctor but will not be seen for two meats such as beef, lamb, pork and shell- more hours. He is wondering if he should purchase a fish may be consumed in moderation. Strict heating pad for relief. The pharmacist advises JG not to purine restriction typically results in a maxi- purchase a heating pad, explaining that it could exacer- mum of 1 mg/dL reduction in uric acid levels. bate his pain. The pharmacist encourages him to apply Adherence concerns may arise when dietary ice to the area around his painful toe and to rest the joint modifications are too strict and patients feel if possible until he is seen by his physician. deprived. Patients may benefit from consulta- tion with a nutritionist. Pharmacologic Management of Gout— Advise patients to maintain hydration by Acute attack Management drinking at least eight glasses of water daily to The 2012 ACR Gout guidelines outline the following treat- prevent dehydration and promote renal excre- ment principles for acute gout attacks: first, pharmaco- tion of uric acid. logic therapy should be started within the first 24 hours; Alcohol use should be limited in patients urate lowering treatment such as allopurinol should be suffering from gout. Short-term alcohol use continued during acute gout attacks; and first line options can decrease uric acid excretion, while long- include non-steroidal anti-inflammatory drugs (NSAIDs), term use increases purine levels. Patients corticosteroids and oral colchicine. should not consume any alcohol during an Patient-specific characteristics such as allergies, acute gout attack. Increased intake of coffee intolerances, and hepatic or renal impairment should be and vitamin C may reduce attack frequency, used to decide which treatment option is most appropri- but more data is needed to recommend this ate for each patient. Severity of pain and number of joints universally. Increased consumption of low fat involved also influence selection. Corticosteroids may dairy products may reduce the frequency of be administered intramuscularly or intra-articularly, which attacks and is recommended by the ACR. may be helpful in patients with adherence barriers or Therapeutic lifestyle changes that benefit who have only one joint affected. Polyarticular gout may other comorbidities linked with gout such as benefit from combination therapy. hypertension and dyslipidemia should be en- Various head to head clinical trials do not show an couraged and include low salt and high fiber advantage of colchicine over NSAIDs for efficacy. In either food plans. case, the medication should be started in the first 12–24

Table 3. Sample Oral Dosage Regimens For Acute Gout Treatment Drug Dose/Route/Frequency Notes Indomethacin 50 mg PO TID Decrease to 50 mg BID beginning on day 4

Ibuprofen 600–800 mg PO TID or QID Naproxen 500–1,000 mg PO in divided doses Decrease to 500 mg or 750 mg daily in divided doses beginning on day 4 Colchicine 1.2 mg PO at symptom onset then 0.6 mg 1 hour later May administer 0.6 mg PO once or twice daily during prophylactic administration. Dose adjustments warranted for concomitant CYP 3A4 inhibitors, P-glycoprotein inhibitors and renal dysfunction. Prednisone 0.5 mg/kg/day x 5–10 days Some experts suggest tapering over 7–10 days. May give triamcinolone 60 mg IM x 1 followed by oral Methylprednisolone dose pack may be an option. prednisone

# ACR guidelines recommend full dose treatment until gout attack resolves. Dose reduction can be considered in patients with multiple comorbidities. TID: three times a day, QID: four times a day, BID: twice a day, PO: by mouth;

www.americaspharmacist.net March 2013 | america’s Pharmacist 41 Table 4. Examples of CYP3A4 Inhibitors Table 5. Examples of PGP Inhibitors Moderate Strong Grapefruit juice Grapefruit juice Protease inhibitors Protease inhibitors Cimetidine Isoniazid Clarithromycin, Erythromycin Erythromycin Clarithromycin Itraconazole, Ketoconazole Tetracyclines Telithromycin Reserpine Fluconazole Itraconazole Atorvastatin Metronidazole Ketoconazole Propranolol, Carvedilol Sertraline Nefazodone Nicardipine Diltiazem, Verapamil Nicardipine Verapamil Amiodarone Quinidine Amiodarone, Dronedarone Cyclosporine Imatinib Cyclosporine, Tacrolimus Tyrosine kinase inhibitors Epidermal growth factor inhibitors Tamoxifen hours after onset of symptoms for maximal benefits. Dosing for acute regimens is summarized in Table 3.

NSAIDs Colchicine NSAIDs are a logical choice for the treatment of acute Colchicine is a narrow therapeutic index drug gout, given the inflammatory nature of an attack. FDA- used for the treatment of gout attacks for de- approved NSAIDs include naproxen, indomethacin, and cades. Historically, colchicine has been used sulindac. Other NSAIDs may be equally effective. Indo- at high doses such as 0.6 mg orally every one methacin is not recommended in the elderly because of to two hours until the patient obtained suffi- increased central nervous system adverse events. cient pain relief or experienced severe diar- nSAIDs are usually dosed higher for the first few rhea. The maximum dose was typically 5–7 days, then rapidly tapered and continued for at least one mg. In 2010, a study was published compar- to two days after the patient is symptom-free. Complete ing high-dose and low-dose colchicine vs. relief is usually achieved within two weeks. placebo in the treatment of acute gout. While nSAIDs should be avoided in patients who suffer both dosage regimens produced similar effi- from peptic ulcer disease, congestive heart failure, he- cacy at 24 hours, the low dose colchicine regi- patic or renal impairment (creatinine clearance <50ml/ men (defined as 1.8mg of colchicine admin- min), and those patients taking anticoagulants. NSAIDs istered within one hour of onset of symptoms) should also be avoided in patients with hypersensitivity had a lower incidence of adverse effects. to aspirin or NSAIDs. Potential side effects of NSAIDs Adverse effects seen in low-dose colchicine include but are not limited to: nausea, vomiting, peptic were comparable to the placebo regimen. The ulcers, increased bleeding risk (including GI bleeds), FDA-approved dosage regimen of colchicine nephrotoxicity, and increased blood pressure. The use for the treatment of acute gout is 1.2 mg at the of proton pump inhibitors in patients taking NSAIDs time of symptom onset, followed by 0.6 mg has been shown to decrease the risk of peptic ulcers. one hour later, limiting patients to 1.8 mg in Suggest taking the medication with food to reduce dys- one hour. Higher doses have not been ap- pepsia. Blood pressure may be monitored and a basic proved by the FDA. metabolic chemistry should be drawn to monitor for colchicine dose should be adjusted in the nephrotoxicity and/or electrolyte imbalances. Patients elderly, in patients with hepatic or renal disease, with elevated blood pressure at baseline may benefit and in patients taking interacting medications from intra-articular administration of corticosteroids to within the last two weeks (Tables 4 and 5). limit systemic exposure and prevent further increases in Cytochrome P450 (CYP) 3A4 inhibitors and blood pressure. p-glycoprotein (PGP) inhibitors are associated

42 america’s Pharmacist | March 2013 www.americaspharmacist.net with increased toxicity and should be avoided term use include fluid retention, increased blood glucose, if possible. Avoid use of colchicine in patients poor wound healing, GI bleeding, increased blood pres- with arrhythmias and patients on dialysis. sure, insomnia and mood disturbances. Patients taking the most common side effects of colchi- steroids for longer periods of time should be monitored cine are nausea, vomiting, and diarrhea. In for symptoms of Cushing’s syndrome, osteoporosis, the study comparing high-dose colchicine to glaucoma, and liver dysfunction. low-dose colchicine, 80 percent of patients on the higher dosage regimen complained of GI Patient Case Continued effects. Rare but serious side effects include JG calls the pharmacy to thank the pharmacist for en- myopathy, bone marrow suppression, alope- couraging a doctor visit. He was told his uric acid level cia, and neuropathy. Monitoring parameters for was over 10 mg/dL and, although they did not aspirate patients on long-term treatment include a CBC, the joint, he was diagnosed presumptively with gout CrCl, and liver function tests (LFTs). Patients and prescribed prednisone. He verbalized understand- should be educated to discontinue colchicine if ing that he should not use niacin anymore. What ad- severe side effects occur. ditional advice should the pharmacist offer the patient colchicine was previously available intrave- at this time? nously; this formulation was removed from the First, the pharmacist should encourage the patient market over concerns of toxicity. to take prednisone with food to counteract adverse GI events. All acute oral regimens used for gout may pre- Corticosteroids dispose the patient to stomach upset. JG should avoid Corticosteroids play an important role in the alcohol and to reduce his weight through diet and exer- treatment of acute gout for patients who have cise. Weight loss, in addition to lowering his risk for gout, contraindications to or are intolerant of NSAIDs will also help his blood pressure and cholesterol. The or colchicine. Some clinicians consider corti- pharmacist should emphasize that if the patient cannot costeroids first line because they are useful in avoid alcohol altogether, beer intake should be limited to patients with renal disease and are available in no more than two alcoholic servings per day (one serv- numerous product formulations. ing for women). Beer is more likely than other alcoholic oral steroids often produce relief in five beverages to cause symptoms of gout. Other alcoholic to seven days, but they can be used up to 14 beverages less likely to increase uric acid should still days. It was previously thought that five day, be consumed in moderation. If JG cannot refrain from short course therapy would result in rebound at- drinking alcohol, a referral to his primary care provider or tacks, but recent studies did not show a differ- Alcoholics Anonymous should be considered. ence between short and long course strategies. JG should inform his physician that he was previ- Steroids can be injected into the affected ously taking niacin to account for future changes to lipid joint if the patient cannot be treated with sys- panel results and initiate an alternative treatment. The temic medications and only suffers from gout pharmacist may wish to refer to reliable health information in one joint. Intra-articular administration ap- websites to download education handouts for JG which pears to produce similar results to oral steroid may encourage discussion (Table 6). regimens and oral NSAIDs indomethacin and naproxen. There is limited outcome data avail- Pharmacologic Management of Gout— able comparing intra-articular and intramuscular Prophylactic Treatment routes. Corticosteroids should be avoided in The focus of preventative treatment is to lower the risk of patients with active peptic ulcer disease. recurrence by reducing the uric acid level below 6 mg/ corticosteroid use is associated with many dL. Some patients may require levels as low as 5mg/ side effects, though gout regimens are tempo- dL to reduce attacks. Most patients will require pharma- rary. Potential side effects associated with short- cologic treatment to sufficiently reduce uric acid levels.

www.americaspharmacist.net March 2013 | america’s Pharmacist 43 Table 6. Gout Websites for Patients and Providers Website Description http://www.rheumatology.org Provides fact sheets primarily directed at patients related to gout in both English and Spanish. Also has links to help locate rheumatologists. Free to public. http://www.nlm.nih.gov/medlineplus/gout.html Provides definitions and an introduction to gout. Links to diagnostics, treatment, clinical trials, directories, organizations, and patient handouts. Appropriate for patients and professionals depending on types of information sought. http://www.arthritis.org/ Provides overview of gout and treatment at the patient level. Many links to arthritistoday.org included for further information. Also contains much information about other arthritic conditions and includes links for advocacy and research. http://www.cdc.gov/arthritis/basics/gout.htm Provides an excellent overview for professionals on gout. Includes prevalence and incidence data. Links to resources are included. Review of citied sources leads to further analysis. http://www.niams.nih.gov/Health_Info/Gout/default.asp Provides definitions of gout, as well as management and treatment options. Links to research and outside resources also available.

Because prophylaxis is usually continued indefinitely, tive if there is a contraindication or adverse cost-effectiveness of therapy must be considered for event associated with XOI therapy. It should each patient before prophylactic treatment is initiated. not be used if creatinine clearance is less Patient indicators for chronic therapy include two or than 50 ml/minute. Quantified, 24-hour urine more gouty attacks per year or patients with gouty collection to differentiate between overpro- complications (tophi, joint damage, kidney stones). ducers and underexcretors is used rarely and Severity of flares and patient preference should also be restricted for patients with urate kidney stones considered when initiating lifelong treatment. Recurrent or early gout onset. flares should be treated without interruption of chronic the use of uricosuric agents such as pro- suppressive therapy. benecid is limited. Uricosurics are ineffective in the main classes of chronic gout therapy are the patients with renal impairment and should be uricostatics, uricosurics, and recombinant uricase. avoided in overproducers and patients with a Uricostatic agents decrease the formation of uric acid, history of, or who are at risk for, nephrolithia- specifically by inhibiting the enzyme xanthine oxidase. sis. Patients should be counseled to expect a Allopurinol (Zyloprim®) and febuxostat (Uloric®) are potential flare during initiation of urate-lowering the two xanthine oxidase inhibitors used for the chronic treatment. They should be advised to continue management of gout. Uricosuric agents, namely proben- the urate-lowering therapy. Patients should ecid, decrease serum uric acid levels by increasing the receive anti-inflammatory prophylaxis if it is not renal elimination of uric acid. The PEGylated recombinant contraindicated. Agents such as colchicine or uricase enzyme, pegloticase (Krystexxa®), decreases NSAIDs may be used concomitantly in order to uric acid levels by facilitating the transformation of uric reduce the risk of precipitation or exacerbation acid to allantoin. Dose recommendations for prophylactic of an acute gouty attack. Concurrent colchi- regimens are listed in Table 7. cine or NSAID therapy should be continued the 2012 ACR guidelines recommend xanthine oxi- until goal serum uric acid levels are achieved dase inhibitors (XOI) as first line therapy. The guidelines or up to six months. A significant change in do not prefer allopurinol over febuxostat. Febuxostat the 2012 ACR guidelines includes the recom- has less long-term safety data and significantly higher mendation that urate-lowering therapy should cost implications. Probenecid is considered an alterna- be initiated during an acute attack. Previously,

44 america’s Pharmacist | March 2013 www.americaspharmacist.net Table 7. Prophylactic Gout Regimens Medication Initial Dose and Titration Renal Impairment Dose Adjustment Allopurinol 50–100 mg/day (up to 800 mg/ day with normal CrCl 10–20 ml/min 200 mg/day renal function) • 100 mg daily typical initial dose CrCl less than 10 ml/min 100 mg/day or less • 50 mg daily for CrCL <30ml/min • Titrate gradually every 2–5 weeks based on uric acid level CrCl less than 3 ml/min Increase dosage interval • Doses > 300 mg daily should be divided • Maximum dose may exceed 300 mg daily with CrCl < 20 ml/min if needed. Monitor for rash. (Package insert states max dose is 200 mg daily) Probenecid 250 mg twice daily (up to 500–2,000 mg/day in CrCl less than 50 ml/min Avoid Use divided doses)

Febuxostat Start with 40 mg po once a day; increase to 80 mg once Minimal data available if CrCl is less than 30 ml/min a day if uric acid is greater than 6 mg/dL after 2 weeks

Pegloticase 8 mg intravenous infusion (over 2 hours) every N/A 2 weeks

CrCl-creatinine clearance urate-lowering therapy was avoided from one or urate nephropathy. Patients with renal insufficiency to four weeks after resolution of an attack. require dose reductions. Regardless of the chronic anti-hyperurice- Allopurinol is effective at lowering serum urate levels mia therapy chosen, goal serum uric acid levels in both underexcretors and overproducers. Allopurinol should be set at less than, or equal to 6 mg/dL is well-absorbed orally and has a relatively short half- (357 μmol/L) . Reduction of urate levels below life, ranging from two to three hours. Despite a short 6 mg/dL results in significantly fewer acute gout drug half-life, once-daily dosing of allopurinol is possible flares, reduction in tophi size, and fewer MSU because the half-life of the active metabolite oxypurinol crystals in joints. Medication regimens should is approximately 24 hours. The elimination of oxypurinol be adjusted every two to five weeks to achieve is primarily renal excretion. Therefore, renal function has goal serum urate levels. During an acute attack, significant implications for patient-specific therapy. urate-lowering therapy should be continued and Allopurinol initiation disrupts the balance between se- acute treatment initiated. rum, tissue, and synovial fluid concentrations of uric acid. Efficacy of urate-lowering therapy can be These rapid concentration changes may cause additional objectively monitored by evaluating serum MSU crystals to precipitate, worsening gouty arthritic uric acid levels at baseline and with allopuri- symptoms. Concurrent prophylactic colchicine or NSAID nol adjustment. Once stabilized, repeat uric therapy during the initiation of allopurinol is beneficial. acid levels should be rechecked every six to initiation of allopurinol at a low dose, such as 100 12 months. Subjective monitoring of efficacy mg/day, followed by slow titration every two to five includes patient reported frequency of acute weeks to a dose sufficient to achieve goal serum urate attacks, as well as development of tophi. levels may reduce the risk of symptom exacerbation and hypersensitivity reactions. Goal serum urate levels Xanthine Oxidase Inhibitors are achieved in 47–85 percent of patients treated at a Allopurinol (Zyloprim®) dose of 300 mg/day. To reach therapeutic goals, the Allopurinol is first line therapy for a vast dose of allopurinol can be increased to a maximum spectrum of patients, including overproduc- of 800 mg/day. However, before increasing the dose, ers, patients experiencing tophaceous gout, clinicians should determine patient adherence with and patients with a history of nephrolithiasis the current dose. Pharmacists should talk to patients

www.americaspharmacist.net March 2013 | america’s Pharmacist 45 taking allopurinol about frequency of flares, and if the Patients taking allopurinol should be coun- patient takes the prescribed dose every day. According seled to drink plenty of water to avoid kidney to a 2004 retrospective study of allopurinol adherence, stones, and should report painful urination or nearly half of patients undergoing treatment were not hematuria immediately. Allopurinol may be taking the prescribed daily dosage. Renal function taken after meals to reduce stomach upset and should also be considered when titrating doses. There remind patients that they may be more prone is limited long-term experience with doses beyond 300 to gouty attacks for the first two to six weeks of mg daily. allopurinol therapy. Skin rash and fever should Allopurinol is well-tolerated. The most commonly be reported to the prescriber. experienced adverse reactions related to allopurinol use include nausea, diarrhea, maculopapular rash, Patient Case Continued elevated LFTs, alkaline phosphatase elevations, and JG accompanies his father to the pharmacy acute attacks of gout. The maculopapular rash, which where his father is picking up a refill for 100 mg occurs in approximately 2 percent of patients, is fairly of allopurinol. They are both a bit anxious about mild. Concurrent treatment with ampicillin increases the their gout diagnoses and hope that the pharma- maculopapular rash incidence to up to 20 percent of cist can help. patients. Progression of the generalized rash to severe His father is complaining because he skin reactions, such as Stevens-Johnson syndrome, doesn’t think the allopurinol is helping and can occur. wonders if he should stop it since he had two the most significant adverse reaction of allopurinol attacks in the past couple months. JG also therapy, known as allopurinol hypersensitivity syndrome questions why his father is taking allopurinol for (AHS), is a life-threatening condition with a 20 percent his gout and he is not. Should his twin brother mortality rate. The syndrome is characterized by des- have his uric acid checked just in case he is at quamating skin lesions, high fever (>102.2°F), leukocy- risk too? What should the pharmacist advise? tosis, hepatic dysfunction, and renal failure. Clinicians usually, more than one gout attack is war- should monitor patients carefully to quickly identify ranted before prophylactic treatment should be possible hypersensitivity reactions. Patients should be considered. Recall that JG was taking niacin instructed to report skin rashes. Patients with a history that could have triggered the event, it was of AHS should never be re-challenged with the medica- discontinued when he presented with acute tion. The ACR guidelines suggest that HLA-B*5801 gene gout. The pharmacist should encourage non- testing be considered in patients at high risk for severe pharmacological strategies to reduce risk. No allopurinol hypersensitivity reactions. These include prophylactic therapy is warranted at this time. Koreans with stage 3 or higher kidney disease, and the pharmacist should recognize that patients of Han Chinese or Thai heritage. Universal phar- adherence rates with allopurinol are usually low. macogenomics testing is not warranted for all patients JG’s father’s adherence to allopurinol should be started on allopurinol. assessed using objective refill history data and Several significant drug interactions are associated patient interview to address barriers (adverse with allopurinol use. The effects of both theophylline and events, knowledge, etc). If he is adherent to warfarin can be increased by allopurinol, although data therapy, and because he is on the lowest dose, regarding warfarin is conflicting. Allopurinol can signifi- a uric acid level should be checked to deter- cantly increase levels of purine analogues azathioprine mine if it is below 6 mg/dL for best outcomes. and 6-mercaptopurine. Purine analogue dose reductions Before suggesting any dose modification, of 25–33 percent are necessary to avoid toxicity. Clini- the pharmacist should refer JG’s father to his cians must be aware of such drug interactions for pa- primary care provider; preexisting renal impair- tients receiving allopurinol therapy, and monitor or modify ment may have played a role in setting the therapy appropriately. dose. The patient interview should also include

46 america’s Pharmacist | March 2013 www.americaspharmacist.net an evaluation of gout history that includes the also be limited during concomitant treatment with simv- number of past attacks, severity of attacks, and astatin. Fenofibrate may be an alternative in the future for presence of risk factors that can be modified to triglyceride reduction if goals are not met; it also benefits improve patient understanding of the medica- in lowering uric acid levels. tion purpose. JG’s brother does not need to have a uric acid level JG’s father admits his “diet is not the best” checked just because his brother and father have a and upon observation appears obese. He has history of gout attacks. Isolated high uric acid levels in been cutting back on his daily bottle of beer the absence of symptoms are not typically treated. His intake to two drinks per day. His blood pres- brother may wish to be proactive by adopting non-phar- sure is 160/90 mmHg and heart rate is 72 beats macologic strategies to prevent gout, such as alcohol in per minute. He states he rarely takes the HCTZ moderation, weight loss if he is overweight, and avoid- because it makes him run to the bathroom; ance of high-protein fad diets. he only takes it on weekends when he is not at work. He also takes fish oil 1,000 mg twice Febuxostat (Uloric)® a day and was prescribed pravastatin 10 mg Febuxostat, a non-purine-selective xanthine oxidase daily last month but did not start it because inhibitor, was approved by the FDA in 2009 for the he was already on the fish oil for cholesterol. treatment of chronic hyperuricemia associated with He only takes the allopurinol a couple times a gout. Structurally, febuxostat and allopurinol differ week since it doesn’t seem to work. He was not significantly. Febuxostat may be significantly more aware he was to take it continuously. potent with respect to decreasing serum urate levels, the pharmacist should target some of as well as decreasing acute attack frequency and tophi the adherence barriers noted with allopurinol, formation. However, fixed dose allopurinol was used in HCTZ and pravastatin. He should be educated clinical trials instead of patient-specific dose titration to that acute attacks may occur during allopuri- achieve goal serum urate levels. Therefore, the clinical nol initiation; colchicine and NSAIDs are often superiority of febuxostat over allopurinol remains to be used concomitantly for six months. Because of sufficiently demonstrated. his blood pressure, colchicine is preferred. He the starting dose of febuxostat is 40 mg orally, once should report attacks to his provider. daily. After two weeks, if serum uric acid levels have not interestingly, his poor adherence to HCTZ decreased to goal, the dose can be increased to 80 mg might have reduced gout attacks as it is a once daily. In contrast to allopurinol, dose adjustments of known risk for hyperuricemia. The provider febuxostat are not necessary for mild to moderate renal should be contacted for an alternative an- impairment since it is metabolized in the liver. tihypertensive, once other co-morbidities Febuxostat is relatively well-tolerated by patients. are addressed; losartan may be considered Common adverse reactions include rash, LFT abnor- for its beneficial effects in lowering uric acid malities, and non-gouty arthralgias. As with allopurinol, levels. The patient should be educated that febuxostat decreases the metabolism of azathioprine simvastatin targets the low density lipoprotein and 6-mercaptopurine. Febuxostat is contraindicated in concentration, unlike fish oil which benefits combination with these agents. triglycerides. He should be encouraged to currently, the exact role of febuxostat in the anti- start simvastatin. Simple diet tips can be ac- hyperuricemic treatment of gout is not well established. cessed online (Table 6) and written material While structural differences between allopurinol and may be used to supplement recommendations febuxostat seem to offer an alternative for patients intol- reviewed earlier. The patient should be ap- erant to allopurinol, more data is needed. The possible plauded for his attempt to reduce beer intake. superiority of febuxostat may make it an option for pa- He should be advised that no beer should be tients who do not experience adequate serum uric acid consumed during an attack. Alcohol should lowering on allopurinol.

www.americaspharmacist.net March 2013 | america’s Pharmacist 47 Patient Case Continued ness, nausea, vomiting, sore gums, and flush- JG asks about a medication he read about in a maga- ing. Blood dyscrasias may occur in patients zine, febuxostat. Should he or his father be on it also? with G6PD deficiency. Febuxostat is usually used if allopurinol does not Probenecid drug interactions that alter achieve uric acid goals or if the patient has adverse the metabolism and elimination of several effects from allopurinol. It is a more expensive agent frequently used medications limit its use. The with less long term experience. JG has not had enough plasma concentration of various penicillins can attacks to justify prophylactic therapy, though he should increase by approximately 200–400 percent be referred to his provider if he has additional ques- as a result of decreased elimination. Patients tions. Since his father was nonadherent, the allopurinol undergoing methotrexate therapy should not is worth a try first. Allopurinol and febuxostat are not receive probenecid, as plasma concentration of used together. methotrexate may become toxic. Higher aspirin doses (600–1,200 mg daily) may blunt the Uricosurics uricosuric response to probenecid and should Probenecid be avoided in combination. Clinicians should Probenecid is a member of the urate-lowering medica- exercise caution when prescribing probenecid tions known as the uricosurics. Uricosuric medications to patients with type II diabetes as sulfonylurea reduce hyperuricemia by correcting the most common concentrations may rise to levels sufficient to physiologic abnormality associated with gout, the un- develop hypoglycemia. The serum levels of derexcretion of uric acid. Probenecid increases the renal non-steroidal anti-inflammatory drugs (NSAIDs) elimination of uric acid by inhibiting the organic URAT1 may be elevated by probenecid, increasing the transporter. Inhibition of URAT1, which is located on the risk of toxicity. apical membrane of the proximal convoluted tubule, initiation of probenecid at a low dose, such results in decreased reabsorption of uric acid. as 250 mg twice daily, is recommended to the use of probenecid should be limited to patients reduce the risk of precipitating an acute gouty with demonstrated underexcretion of uric acid. It is inef- flare, exacerbating existing symptoms, or devel- fective in overproducers. It is also ineffective in patients oping renal uric acid crystals. Specific recom- with impaired renal function (CrCl<50ml/min). Occasion- mendations vary with respect to dose titration. ally, it may be used in combination with allopurinol in patients not achieving uric acid goals. Recombinant Uricase Patients should be advised to maintain adequate Pegloticase (Krystexxa®) hydration during therapy to minimize the risk of nephro- Pegloticase is an intravenously administered, lithiasis. It is recommended they consume 1.5–2 liters pegylated, recombinant form of the enzyme (six to eight, 8-ounce glasses) of fluid per day. This is uricase. It is FDA-approved for the treatment because upon initiation of probenecid therapy, as the of gout. The enzyme uricase is responsible concentration of uric acid in the urine will increase tempo- for the oxidation of uric acid to allantoin. Al- rarily as a result of increased renal elimination. Elevated lantoin is a water soluble substance readily concentrations of uric acid in the lumen of the kidney eliminated by the kidneys. Uricase is not found increase the risk for deposition of uric acid crystals there, in humans, thus the need for a recombinant and subsequent nephrolithiasis. Consideration may be product. The addition of polyethylene glycol to given to the use of potassium citrate or sodium bicarbon- the recombinant uricase increases the half-life ate to alkalinize the urine, providing additional protection and decreases immunogenicity of the protein. against nephrolithiasis. Patients with a history of nephroli- Upon administration, pegloticase catalyzes thiasis should not receive probenecid. the oxidation reaction of uric acid to allantoin, the most common side effects experienced during subsequently reducing the levels of uric acid in probenecid therapy include gastrointestinal upset, dizzi- the body.

48 america’s Pharmacist | March 2013 www.americaspharmacist.net Pegloticase should be reserved for patients Conclusion with refractory gout due to the inconvenience Gout is a common but straightforward disease to treat. of intravenous administration, expense, and Pharmacists can assist patients with gout by providing the risk of anaphylaxis and other immunogenic education on non-pharmacologic treatments, identify- reactions. It is contraindicated in patients with ing drug interactions, and preventing adverse events. G6PD deficiency. Clinicians should perform Pharmacists can help physicians navigate gout treat- screening in patients at higher risk for G6PD de- ment options by discussing the pros and cons of each ficiency (such as patients of African or Mediter- treatment and recognizing and promoting management ranean descent). of risk factors. A black box warning is established regarding the elevated risk of anaphylaxis and infusion-related reactions. Pretreatment with Jon Brady, PharmD, is ambulatory care pharmacist at Geisinger Health an antihistamine and intravenous corticoste- System. roid is recommended prior to each infusion. Patients with elevated serum uric acid levels Sarah Pupo, PharmD, PGY1, is a resident in pharmacy practice at (greater than or equal to 6 mg/dL) appear to Geisinger Medical Center, Danville Pa. be at greater risk of anaphylaxis. Serum uric Eric Sidman, PharmD, PGY1, is a resident in pharmacy practice at acid concentrations should be monitored Upstate Medical Center, Syracuse N.Y. prior to infusions; clinicians should consider discontinuing therapy in patients with persis- Jennifer Malinowski, PharmD, is associate professor of pharmacy tently elevated uric acid levels (such as two practice at Wilkes University School of Pharmacy, Wilkes-Barre Pa. consecutive labs show uric acid greater than 6 mg/dL). the most common serious adverse Editor’s Note: For the list of references used in this article, events associated with pegloticase include please contact America’s Pharmacist Managing Editor Chris anaphylaxis, infusion-reactions, and gout Linville at 703-838-2680, or at [email protected]. flares. Other side effects commonly experienced include nausea and nasopharyngitis. As with other urate-lowering therapies, the risk of gout flares is increased during treatment initiation. Therefore, prophylaxis with colchicine or NSAIDs should begin one week prior to pegloticase treatment. the usual dose of pegloticase is 8 mg via intravenous infusion (over two hours) every two weeks. Renally impaired patients do not require a dose adjustment. Long-term treatment dura- tions have not yet been clearly established. Pegloticase administration is typically reserved to specialty care. Pharmacists can advise patients to expect gout flares during the initial months of treatment and report attack frequency to the provider. NSAIDs or colchicine should be started a week before therapy begins. Patients should be advised on the expense associated with pegloticase.

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Treatment Options for Gout March 1, 2013 (expires March 1, 2016) • Activity Type: Knowledge-based

To earn continuing education credit: ACPE Program Answer sheet for your use below 207-000-13-003-H04-P; 207-000-13-003-H04-T a b c d e a b c d e 1. q q q q q 11. q q q q q A score of 70 percent is required to successfully complete q q q q q q q q q q the C.E. quiz. If a passing score is not achieved, one free 2. 12. 3. q q q q q 13. q q q q q reexamination is permitted. 4. q q q q q 14. q q q q q 5. q q q q q 15. q q q q q 6. q q q q q 16. q q q q q FREE ONLINE C.E. To take advantage of free C.E for this 7. q q q q q 17. q q q q q program, pharmacists and pharmacy technicians must 8. q q q q q 18. q q q q q achieve a passing score of 70% on the on-line continuing 9. q q q q q 19. q q q q q education quiz online for this program. To take this test— 10. q q q q q 20. q q q q q go to the Continuing Education section of the NCPA Web site (www.ncpanet.org) by clicking on “Professional To enter your answers, go online to www.pharmacistelink.com Development” under the Education heading. You will receive NCPA® is accredited by the Accreditation Council for Pharmacy immediate online test results and submission of your CEUs Education as a provider of continuing pharmacy education. NCPA to the CPE Monitor system. To obtain your CPE Monitor has assigned 1.5 contact hours (0.15 CEU) of continuing education e-Profile ID, please go to www.cpemonitor.com to register. credit to this article. Eligibility to receive continuing education credit for this article expires three years from the month published.

CONTINUING EDUCATION QUIZ 3. JM is a 49-year-old male who states he re- Select the correct answer. cently recovered from his first acute gout attack a little over a week ago. He heard that patients 1. The pathophysiology of gout is characterized by el- who suffer from gout may experience joint dam- evated concentrations of which substance? age. He asks if he should be afraid of this since a. Sodium chloride he just experienced an attack. What is the best b. Ammonium response for JM? c. Uric acid a. JM should be concerned because joint d. Sodium bicarbonate destruction generally follows the first acute attack. 2. The inflammation associated with gout symptoms is b. JM should be reassured joint damage and caused by the lysis of which of the following components chronic symptoms are normally only present of the immune system? in individuals who have lived with gout for a. Helper T-cells many years. b. Neutrophils c. JM should schedule an appointment with an c. Cytotoxic T-cells orthopedic surgeon for evaluation. d. B-cells d. JM should be reassured his gout most likely will never return so he should not worry.

4. Common features that best describe an acute gout attack include: a. Intense pain that progresses quickly, usually in the toe joint b. Bilateral joint involvement, intense pain that progresses over a few weeks c. Blurry vision, stomach upset, shoulder pain d. Sore lower back, elevated red blood cells, renal failure

50 america’s Pharmacist | March 2013 www.americaspharmacist.net

5. NH is a 62-year-old female questioning 7. BG is diagnosed with gout. Appropriate non-pharmaco- whether her dietary habits or medications could logic approaches to treatment include: be causing her increased gout attacks over the a. Immobilize the affected joint and apply ice. past couple months. She has been treated for b. Massage the affected joint and use a heating pad. hypertension and high triglycerides with amlo- c. Normal use of affected joint and use of an ice pack dipine, lisinopril, and fenofibrate for years and d. Elevate affected joint and use of a heating pad started taking hydrochlorothiazide a couple months ago. She consumes red meat, yogurt 8. Which of the following choices would be most appro- and potatoes daily, and consumes 1–2 beers priate to treat BG’s acute gout? a day, “sometimes more.” The best strategy to a. Ibuprofen prevent future gout attacks in NH is: b. Colchicine a. Increase yogurt intake, consult her doctor to c. Indomethacin switch from lisinopril to losartan d. Sulindac b. Consult her doctor to stop amlodipine and fenofibrate immediately 9. A patient fills a new prescription for clarithromycin for a c. Limit beer and moderate intake of red meat; chest infection. He is taking colchicine once a day for a few consult her doctor to evaluate hydrochloro- months while he is started on allopurinol. He is not taking thiazide use any other medications at this time. He would like to know if d. None of the above are appropriate strategies. he can take all the meds at once. What do you advise? a. Colchicine has very few interactions with other drugs 6. BG is a 65-year-old male presenting with and can be taken along with his other meds. severe joint pain in his left big toe beginning b. Allopurinol decreases absorption of clarithromycin; suddenly the night before. The joint appears separate administration by two hours. swollen and is red. He has a history of osteo- c. Clarithromycin inhibits metabolism of colchicine arthritis in his right shoulder, hypertension, and increasing side effect risk; contact his doctor for a dyslipidemia. The only medications he takes substitute antibiotic. are acetaminophen and simvastatin. He has a d. Colchicine should be taken twice a day while on clar- history of a gastric ulcer from ibuprofen. He is ithromycin due to metabolism induction. overweight but tries to exercise regularly and watch his diet. He was told at a routine physical 10. Colchicine should not be used in a patient with which a month ago that his uric acid level was high of the following scenarios? and wonders why they didn’t do anything about a. Hypertension it then. He has no history of gout. The best ad- b. Type 2 diabetes mellitus vice regarding uric acid levels for BG is: c. Dermatitis a. Uric acid levels have nothing to do with gout d. Cardiac arrhythmias and should never be measured. b. Uric acid levels over 10 mg/dL should be treat- 11. You are working in an ambulatory care clinic when ed even if the patient has no history of gout. a nurse practitioner asks for a recommendation for the c. Uric acid levels over 6 mg/dL should be treat- treatment of acute gout in a 65-year-old with a history of ed even if the patient has no history of gout. chronic kidney disease and depression which is being d. High uric acid levels are a risk factor for de- treated with nefazodone. His most recent creatinine clear- veloping gout but the risk of drug side effects ance was 25ml/min. Which of the following would you outweighs the benefit of treatment before recommend? symptoms start. a. Prednisone b. Naproxen c. Colchicine d. Indomethacin

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12. A patient calls your pharmacy complaining of another 16. As you are filling the allopurinol prescrip- gout attack. He was recently hospitalized with a gastric tion at the pharmacy, you notice several other bleed caused by a peptic ulcer and was just discharged medications in the patient’s profile. The dose last week. He previously took naproxen to treat his gout of which of the patient’s current medications and wants to know if he can still use naproxen. What is must be adjusted to avoid significant drug- your best reply? drug interactions? a. “Naproxen is not a good choice because it is known to a. Theophylline potentially cause ulcers and bleeding. I’ll ask your doc- b. Pravastatin tor about starting you on prednisone.” c. Losartan b. “Naproxen is not a good choice because it is known to d. Clonazepam potentially cause ulcers and bleeding. I’ll ask your doctor about starting you on colchicine.” 17. Which of the following medications used for c. “Naproxen is not a good choice because it is known to the prophylactic treatment of gout is associated potentially cause ulcers and bleeding. I’ll ask your doc- with a hypersensitivity syndrome character- tor about starting you on ibuprofen.” ized by desquamating skin lesions, high fever d. “Naproxen is safe to take as long as you eat some- (>102.2°F), leukocytosis, hepatic dysfunction, thing when you take it.” and renal failure? a. Allopurinol 13. A physician asks for your recommendation for the b. Febuxostat treatment of acute gout in a 62-year-old male who is c. Probenecid HIV-positive. He takes lopinavir/ritonavir and reports d. Recombinant Uricase trouble breathing with ibuprofen. Which of the following do you recommend? 18. A physician is developing a prophylactic a. Indomethacin treatment regimen for a patient with mild renal b. Prednisone impairment. Which of the following medication c. Colchicine options would not require a dose adjustment in d. Naproxen such a patient? a. Probenecid 14. What scenario would justify prophylactic treatment? b. Febuxostat a. Two or more gout attacks per year c. Allopurinol b. Tophaceous gout d. Colchicine c. Uric acid kidney stones d. All of the above 19. The prophylactic therapy best reserved for patients with refractory, tophaceous gout is: 15. The physician decides to initiate prophylactic therapy a. Probenecid for a patient with normal renal function. He prescribes b. Febuxostat allopurinol, but is unsure of the appropriate starting dose. c. Allopurinol Which of the following starting doses should be recom- d. Pegloticase mended for the patient? a. 40–80 mg orally once a day 20. Prophylactic gout therapy should be titrated b. 8 mg IV every two weeks to a uric acid level less than: c. 100 mg orally once a day a. 10 mg/dL d. 250 mg orally twice daily b. 5 mg/dL c. 6 mg/dL d. 1 mg/dL

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