Safety of Urate-Lowering Therapies




Gout is a metabolic disorder of purine metabolism and uric acid elimination. Over time, acute gout can develop into a chronic, disabling arthropathy, often associated with multiple comorbidities. Gout patients have often been undertreated, partly because of the clinician’s perceived risks of a therapy outweighing its potential benefits. The approval of new therapies to treat hyperuricemia in gout has led to a new understanding of gout management and medication safety regarding new and old therapies. This review focuses on potential safety issues of currently available urate-lowering therapies and outlines strategies to minimize risks so their benefits can be reached.








  • Safe use of urate-lowering therapy in patients with gout with multiple comorbidities can be a challenge for the clinician.



  • Potential drug-drug interactions between traditional urate-lowering therapies and frequently prescribed medications are more common than usually appreciated, but can be appropriately managed in most patients.



  • Allopurinol and other urate-lowering therapies can be safely used in patients with renal disease and other comorbidities.



  • New therapies have provided additional options for patients with gout that may allow for safer and better management of their disease.



Key Points


Introduction


Gout is the most common inflammatory arthropathy affecting more than 8 million adults in the United States alone. The prevalence of gout continues to increase in the United States as well as abroad. Gout affects more than 6 million men and more than 2 million women, and the rising incidence parallels with conditions such as cardiovascular (CV) disease, metabolic syndrome, chronic kidney disease (CKD), and an aging population. This association is unlikely coincidental, as there is accumulating evidence suggestive of gout potentially contributing to a number of the aforementioned comorbidities. Regardless of whether or not gout plays a causative role, the fact patients with gout frequently have multiple comorbidities is undisputable.


With the increase in the incidence and prevalence of gout, new urate-lowering therapies (ULT) have become available and a renaissance of interest in gout has occurred. Forty years after the introduction of allopurinol (Aloprim; Zyloprim) and 50 years after probenecid (Benemid), febuxostat (Uloric) and pegloticase (Krystexxa) have been added to the arsenal against gout. Yet despite the surge in gout interest and new therapies, there is substantial evidence that quality of gout care continues to be inadequate. Patients with gout have been repeatedly shown to have greater morbidity compared with their counterparts without gout. In some patients, hyperuricemia and gout may be simply a prelude for impending illnesses; but often, by the time a patient is diagnosed with gout, comorbidities are well established and are being treated with multiple medications.


Managing gout is intrinsically straightforward. The goal is to reduce and maintain serum urate (SU) levels well below that of physiologic supersaturation (6.8 mg/dL). Maintaining SU levels below this level allows for the mobilization of monosodium urate crystals out of joints and soft tissue, eventually eliminating the nidus of acute and chronic inflammation. As lower SU levels directly correlate with an increased rate by which tophi resolve, using a target goal of less than 6 mg/dL as a starting point can decrease and ideally eliminate the crystal burden, thereby eradicating tophi and future flares. With appropriate therapy and compliance, most patients with gout should be able to achieve full remission. Challenges arise when clinicians and patients are faced with potential adverse drug reactions (ADRs) owing to decreased renal clearance, hepatic impairment, drug-drug interactions, or simply, intolerance.


All Food and Drug Administration (FDA)-approved medications have risks and benefits. It is paramount to consider potential pitfalls and benedictions of a therapy before its use. Both the provider and the patient must balance a medication’s risks and benefits to determine if it is the safest and most efficacious option. It is also important to understand the risk of any therapy for an individual patient is not static; rather it is a dynamic process that involves pharmacokinetics, pharmacodynamics (PD), and drug-drug interactions. This article reviews the safety of current ULT indicated for the use of chronic gout, including allopurinol, febuxostat, pegloticase, and probenecid. Monitoring practices and strategies to decrease the risk of potential adverse effects in clinical practice are also reviewed.




Burden of gout and adverse drug reactions


The cost of ADRs caused by all medications is estimated to account for 5% to 9% of all inpatient costs. There is little data regarding the impact of gout therapy–specific ADRs on patient disability and health care costs. Conversely, it has been shown that inadequately treated patients with gout have a poorer quality of life versus their age-matched and comorbidity-matched peers. Also, the annual direct and indirect costs of having gout are estimated to range from $800 to $10,000. The impact of gout on the quality of life and potential economic burden emphasizes the importance of treating these patients appropriately and safely.




Burden of gout and adverse drug reactions


The cost of ADRs caused by all medications is estimated to account for 5% to 9% of all inpatient costs. There is little data regarding the impact of gout therapy–specific ADRs on patient disability and health care costs. Conversely, it has been shown that inadequately treated patients with gout have a poorer quality of life versus their age-matched and comorbidity-matched peers. Also, the annual direct and indirect costs of having gout are estimated to range from $800 to $10,000. The impact of gout on the quality of life and potential economic burden emphasizes the importance of treating these patients appropriately and safely.




Xanthine oxidase inhibitors


Allopurinol


There has been a renewed surge in the medical management of chronic gout with the development of several new therapies. Even in this light, allopurinol has seemed to have a rebirth of its own. Initially developed as an antineoplastic agent in the mid-1950s, allopurinol is a purine analog, an isomer of hypoxanthine, which inhibits xanthine oxidase. Allopurinol is the most commonly prescribed ULT, and continues to be the foundation and benchmark for chronic gout therapy since its approval by the FDA in 1966. The half-life of allopurinol in the blood is short (1.1 ± 0.3 hour), and is rapidly metabolized to its active metabolite, oxypurinol. In contrast to allopurinol, oxypurinol has a relatively long half-life (23 ± 7 hours), and is largely responsible for urate reduction. Given its long half-life and noncompetitive inhibition of xanthine oxidase, oxypurinol has been deemed the perpetrator of intolerance and ADRs associated with allopurinol use.


Drug-drug interactions


Both allopurinol and oxypurinol inhibit xanthine oxidase, therefore concomitant use of medications such as azathioprine and mercaptopurine, which are also metabolized by xanthine oxidase or inhibit xanthine oxidase, should be used with caution. There are several known allopurinol-drug interactions of which the clinician should be aware when making therapeutic decisions ( Table 1 ). There have been case reports suggesting interactions between allopurinol and some classes of antihypertensive medications, including angiotensin-converting enzyme inhibitors and diuretics (see later in this article), but a causal relationship has not been proven.



Table 1

ULT-drug interactions



















































































































































Drug Risk Rating Risk Reliability Rating
Allopurinol-Drug Interaction
ACE inhibitors D Possible increased risk of allergy/hypersensitivity Fair
Amoxicillin/ampicillin C Possible increased risk of allergy/hypersensitivity Fair
Antacids a D Decrease absorption of allopurinol Good
Azathioprine D Accumulation of mercaptopurine/increased risk of toxicity/bone marrow suppression Fair
Mercaptopurine D Accumulation of mercaptopurine/increased risk of toxicity/bone marrow suppression Fair
Phenytoin C Increased serum levels of phenytoin Fair
Carbamazepine C Increased serum levels of carbamazepine Fair
Cyclophosphamide C Increased cyclophosphamide levels/Increased risk of bone marrow suppression Good
Cyclosporine D Increased cyclosporine levels/Increased risk of bone marrow suppression Poor
Didanosine X Increased didanosine levels and toxicity Good
Loop diuretics C Possible increased risk of allergy/hypersensitivity b Fair
Thiazide diuretics C Possible increased risk of allergy/hypersensitivity b Fair
Theophylline derivatives C Increased levels of theophylline Good
Warfarin D May enhance anticoagulant effect of warfarin and other vitamin K antagonists Good
Febuxostat-Drug Interaction
Azathioprine X Accumulation of mercaptopurine/increased risk of toxicity/bone marrow suppression Fair
Mercaptopurine X Accumulation of mercaptopurine/increased risk of toxicity/bone marrow suppression Fair
Didanosine X Increased didanosine levels and toxicity Fair
Theophylline derivatives C Increased levels of theophylline metabolite Fair
Pegloticase-Drug Interaction
Pegylated drug products C Possibly diminish clinical response to pegylated drug if used together Poor
Other urate-lowering therapy X May lower serum urate level in patient NOT responding to pegloticase, which increases the risk for infusion reaction or anaphylaxis Fair
Probenecid-Drug Interaction
Methotrexate D May increase serum concentration of methotrexate Excellent
Mycophenolate mofetil D May increase levels of mycophenolate and increase risk of toxicity Fair
Nonsteroidal anti-inflammatory agents C May increase the serum concentration of nonsteroidals Good
Salicylates May diminish therapeutic effect of probenecid Excellent
Penicillin C May increase effects of penicillins; consider avoiding use in renal insufficiency Excellent
Zidovudine C May decrease metabolism of zidovudine and increase risk for toxicity Excellent

Risk Rating : C, Monitor Therapy: The benefits of concomitant use of these 2 medications usually outweigh the risks. An appropriate monitoring plan should be implemented to identify potential negative effects. Dosage adjustments of 1 or both agents may be needed in a minority of patients.

D, Consider Therapy Modification: Patient-specific assessment must be conducted to determine whether the benefits of concomitant therapy outweigh the risks. Specific actions must be taken to realize the benefits and/or minimize the toxicity resulting from concomitant use. Aggressive monitoring, empiric dosage changes, choosing alternative agents, may be indicated.

X, Avoid Combination: The risks associated with concomitant use of these agents usually outweigh the benefits. These agents are generally considered contraindicated with concomitant use.

Reliability Rating : Poor, < 2 case reports with no other supporting data or theoretical. Fair, > 2 case reports; or <2 case reports with other supporting data. Good, single randomized, controlled clinical trial (RCT). Excellent, multiple RCTs; or single RCT plus >2 case reports.

Abbreviation: ACE, angiotensin-converting enzyme.

Adapted from Refs.

a Except sodium bicarbonate.


b See text.



Adverse drug reactions


Allopurinol is generally well tolerated, but up to 5% of patients stop the medication because of any ADR. Common side effects include gout flares, nausea, diarrhea, pruritis, and approximately 2% of patients develop a mild rash. Less commonly, allopurinol can cause vomiting, hepatitis, agranulocytosis, and headache. When starting any ULT, the risk of flares should be discussed with the patient, and appropriate prophylaxis should be started 1 to 2 weeks before initiating therapy (eg, colchicine, nonsteroidal anti-inflammatories [NSAIDs]) ( Table 2 ).



Table 2

Urate-lowering therapy cautions, contraindications, and prevention


































Indication Caution Risk Prevention Contraindication
Allopurinol Management of hyperuricemia in patients with gout Acute gout flare; Renal insufficiency a ;
Hepatic impairment
Prophylactic therapy (eg, colchicine), initiate 1–2 wk prior; Start at low dose and titrate up; monitor CBC, hepatic function every 4–8 wk Hypersensitivity; Concomitant use with azathioprine, mercaptopurine
Febuxostat Management of hyperuricemia in patients with gout Acute gout flare; History of CVD a ; Hepatic impairment Prophylactic therapy (eg, colchicine), initiate 1–2 wk prior; Start at low dose; monitor CBC, hepatic function every 8–12 wk Hypersensitivity; Concomitant use with azathioprine, mercaptopurine
Pegloticase Refractory chronic gout Acute gout flare; Heart failure a ;
Infusion reaction; Owing to premedication with corticosteroids, caution should be used in diabetes mellitus, heart failure a
Prophylactic therapy (eg, colchicine), initiate 1–2 wk prior; ensure heart failure is compensated; monitor SU levels <24–48 h before second and subsequent infusions; [monitor and/or have patients adjust diabetes medications as needed] G6PD deficiency; Uncompensated heart failure (uncontrolled CVD); 1 or 2 consecutive SU levels >6 mg/dL; Hypersensitivity reaction a ; concomitant use of other ULT
Probenecid Management of hyperuricemia in patients with gout Acute gout flares; renal insufficiency; history of urate stones; G6PD deficiency Prophylactic therapy (eg, colchicine), initiate 1–2 wk prior; Start low dose and titrate up slowly; monitor CBC, renal function every 4–6 wk Hypersensitivity; blood dyscrasias, chronic urate stones

Abbreviations: CBC, complete blood count; CVD, cardiovascular disease; G6PD, glucose-6-phosphate dehydrogenase deficiency; SU, serum urate; ULT, urate-lowering therapy.

a See text.



The side-effect profile is no worse than most medications prescribed on a regular basis by clinicians, but there is still reluctance to use allopurinol, especially at dosages appropriate to decrease SU levels below the limit of solubility (and therefore prevent further formation and facilitate dissolution of tophi). The basis of this reluctancy is because of a rare, but potentially fatal, ADR known as allopurinol hypersensitivity syndrome (AHS). The estimated incidence of AHS is 0.1% to 0.4%, and the mortality rate is 5% to 30%, depending on the severity. This rare, but potentially lethal, syndrome is characterized by a constellation of signs and symptoms ( Box 1 ).



Box 1




  • 1.

    Clear history of exposure to allopurinol


  • 2.

    Clinical presentation including



    • a.

      At least 2 of the following major criteria



      • i.

        Renal failure


      • ii.

        Acute hepatocellular injury


      • iii.

        Severe rash (Stevens Johnson syndrome, toxic epidermal necrolysis, or a diffuse exanthematous or exfoliative dermatitis




    • Or


    • b.

      1 of the major criteria plus at least 1 of the following minor criteria:



      • i.

        Fever


      • ii.

        Eosinophilia


      • iii.

        Leukocytosis




  • 3.

    No history of exposure to another drug that may cause a similar clinical presentation



Allopurinol hypersensitivity syndrome: criteria and clinical manifestations

Data from Khoo BP, Leow YH. A review of inpatients with adverse drug reactions to allopurinol. Singapore Med J 2000;41:156–60.


Risk factors for AHS include female sex, age, genetic disposition, recent commencement of allopurinol, diuretic use, and renal impairment. ADRs and AHS usually occur within days to weeks after initiation of allopurinol, with a median of approximately 30 days and 90% occurring within 180 days. As more men are prescribed allopurinol, most AHS cases have been male, but multiple analyses have shown women may be more at risk than men. Age may also increase the risk of AHA, especially mortality associated with AHA. This is thought to be because of several factors, including decreased renal clearance, increased diuretic use, and comorbidities.


There is a growing body of evidence that genetics plays a significant role in severe drug reactions. The role of the major histocompatibility complex type I allele, HLA-B*5801, has been shown in several studies to increase the risk for AHS. In a case-control analysis of Han Chinese, 100% of patients with AHS carried the allele versus 15% of patients who tolerated the medication, resulting in an odds ratio of 580 (95% confidence interval, 34–9780). Hung and colleagues suggested that the HLA-B*5801 allele was necessary, but not sufficient for AHS to occur. Similarly, in a recent analysis in a Thai population, 100% of patients with AHS carried HLA-B*5801, whereas only 13% of the control patients carried it, yielding an odds ratio of 348 (95% confidence interval, 19–6336).


Although HLA-B*5801 is most prevalent in East Asia, a study of European patients found a similar association. HLA-B genotyping was performed on 150 patients enrolled in the European Study of Severe Cutaneous Adverse Reactions Registry (RegiSCAR). Even with an HLA-B*5801 frequency of 0.008 in the European population, the study found 31 patients with allopurinol-induced Stevens Johnson syndrome/toxic epidermal necrolysis or 61% carried the HLA-B*5801 allele. In contrast to the Hung and colleagues’ study, the investigators concluded that HLA-B*5801 is a strong risk factor but neither sufficient nor necessary for the development of AHS. Whether HLA-B*5801 can be considered as a good marker for reducing the risk of AHS needs further analyses. As a result of the very low frequency of this allele in the non-Asian population, and the disease could be linked to other more prevalent and yet undetermined alleles in both populations, HLA testing is not currently recommended nor readily available in clinical practice.


Diuretics, such as hydrochlorothiazide and furosemide, have long been implicated as contributors to gout and hyperuricemia. Diuretics increase serum uric acid (SUA) levels by increasing UA reabsorption in the proximal tubule of the kidney. This effect occurs relatively quickly after the initiation of the diuretic and lasts throughout its use. Diuretic use has been implicated in AHS and other ADRs as a result of decreased excretion of oxypurinol. Understandably, if oxypurinol levels do contribute to ADRs, it would be prudent to minimize the levels. Clinically, one would expect the increase in oxypurinol levels caused by the diuretic to counter or eventually overcome the diuretic’s hyperuricemic effect, yet this has been shown not to be the case. This conundrum should cause the clinician to pause and evaluate the use of diuretics with allopurinol in patients, regardless of whether or not increases in oxypurinol occur.


In patients with renal insufficiency, it has been customary for clinicians to adjust or limit the maximum dose of allopurinol. Dose reduction in renal impairment is based on the reported relationship between “high-dose” allopurinol (>300 mg/d) in these patients and development of AHS. Hande and colleagues reported a case series of 6 patients with existing renal impairment in addition to 72 patients they found in a literature search, many of whom had existing renal impairment and were on diuretics as well. They concluded that AHS was caused by decreased renal clearance of oxypurinol, and therefore proposed renally adjusted dosing guidelines ( Table 3 ). Based on their findings, Hande and colleagues recommended that dosing should be modified to maintain oxypurinol levels between 20 and 100 μmol/L. Unfortunately, this dosing of allopurinol and level of oxypurinol may lead to undertreatment. A recent PD study found that to achieve an SUA lower than 6 mg/dL in at least 75% of subjects, serum oxypurinol levels higher than 100 μmol/L were required. Additionally, no study has shown that dose reduction of allopurinol in CKD decreases the risk of AHS.


Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Safety of Urate-Lowering Therapies
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