Allopurinol: A Comprehensive Guide for Patients

Allopurinol is a medication widely prescribed to manage gout and other conditions caused by high uric acid levels in the body. This article provides a comprehensive overview of allopurinol, its uses, how to take it, potential side effects, and other important information to help patients understand and manage their treatment effectively.

Introduction to Allopurinol

Allopurinol belongs to a class of medications called xanthine oxidase inhibitors. It functions by reducing the production of uric acid in the body. Allopurinol is used to treat gout (a type of arthritis in which uric acid, a naturally occurring substance in the body, builds up in the joints and causes sudden attacks of redness, swelling, pain, and heat in one or more joints). Allopurinol is also used to treat high levels of uric acid that builds up in the blood as tumors break down in people with certain types of cancer who are being treated with chemotherapy medications. It is also used to treat kidney stones that have come back in people who have high levels of uric acid in their urine.

What is Gout?

Gout is a type of arthritis caused by the buildup of uric acid crystals in the joints. This accumulation leads to sudden, severe attacks of pain, swelling, redness, and heat in the affected joints.

How Allopurinol Works

Allopurinol works by inhibiting xanthine oxidase, an enzyme responsible for converting hypoxanthine to xanthine and then to uric acid. By blocking this enzyme, allopurinol reduces the amount of uric acid produced in the body, helping to prevent gout attacks and other complications of high uric acid levels.

Uses of Allopurinol

Allopurinol is FDA approved for managing gout, preventing tumor lysis syndrome, and preventing recurrent calcium nephrolithiasis in patients with hyperuricosuria. Other non-FDA-approved indications include Lesch-Nyhan syndrome-associated hyperuricemia and the prevention of recurrent uric acid nephrolithiasis. It is important to note that asymptomatic hyperuricemia is not an indication of allopurinol or any urate-lowering therapy.

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Gout Prevention: Allopurinol is primarily used to prevent gout attacks, not to treat them once they occur. It helps to lower uric acid levels in the blood, reducing the risk of crystal formation and subsequent joint inflammation.
Management of High Uric Acid Levels: Allopurinol is effective in treating high levels of uric acid that accumulate in the blood due to the breakdown of tumors in cancer patients undergoing chemotherapy.
Kidney Stones: It is also used to treat kidney stones that have come back in people who have high levels of uric acid in their urine.
Other uses: Allopurinol has also been studied for treating inflammatory bowel disease and fibromyalgia.

Situations for initiating allopurinol

American College of Rheumatology recommends initiating urate-lowering therapy such as allopurinol in patients with an established diagnosis of gouty arthritis in the following situations:

Frequent attacks of acute gouty arthritis, defined as equal to or more than two attacks per year
Chronic kidney disease stage 2 or worse
Presence of tophi or tophus on clinical exam or imaging
History of nephrolithiasis

Dosage and Administration

Allopurinol comes as a tablet to take by mouth. It is usually taken once or twice a day, preferably after a meal. To help you remember to take allopurinol, take it around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take allopurinol exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Typical Dosage

The correct dose of allopurinol is one that causes serum uric acid (sUA) level to drop below 6.0 mg/dL. This dose varies from patient to patient. The minimum or maximum dose for each person is not predictable by the patient’s size, gender or age. The American College of Rheumatology recommends that all people with gout start allopurinol at a low dose and gradually build the dose until the levels in the blood reaches the target. For most people, the starting dose of allopurinol tablets is 100 mg daily. For those with significant kidney health issues, the initial dose should be lower. The average dose of allopurinol needed to get an sUA level to target in patients with gout is about 400 mg per day.

Proper Use

Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand and to provide medical advice. Do not stop taking allopurinol without talking to your doctor. As with other drugs, keep allopurinol in the container it came in so you have access to the drug information. Be sure to store allopurinol tightly closed at room temperature away from moisture and out of reach of children.

How and When to Take Allopurinol

Take your allopurinol for gout around the same time every day, as directed by your doctor. Since allopurinol may not stop gout attacks at first, continue to take the medicine even if you experience a flare. It may be many months to a couple of years before all of your gout symptoms disappear after starting allopurinol. Your doctor may start you on a low dose (100 mg daily) and gradually increase it over time in order to lower your uric acid levels and prevent a future gout attack.

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Missed Dose

The tablet should be taken around the same time every day, as directed by your doctor. If the time you usually take allopurinol passes and you miss a dose, take your usual dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Be sure to tell your doctor if you skip the missed dose, and how often you have a missed dose. Do not take a double dose to make up for a missed one. Take your next dose as usual.

Duration of Treatment

It may take several months or longer before you feel the full benefit of allopurinol. Allopurinol may increase the number of gout attacks during the first few months that you take it, although it will eventually prevent attacks. Your doctor may prescribe another medication such as colchicine to prevent gout attacks for the first few months you take allopurinol. Continue to take allopurinol even if you feel well. Do not stop taking allopurinol without talking to your doctor.

Additional Considerations

Drink at least eight 8-ounce (240-milliliter) cups of water or other liquids each day while taking allopurinol unless directed to do otherwise by your doctor.
You may need to follow a special diet to help prevent kidney stones. Follow all instructions of your doctor or dietitian.

Potential Side Effects

Allopurinol can lower blood cells that help your body fight infections. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. Your blood may need to be tested often. In rare cases, allopurinol may cause a severe allergic reaction. Allopurinol may impair your thinking or reactions. Avoid driving or hazardous activity until you know how allopurinol will affect you.

Common Side Effects

Allopurinol is generally well tolerated. There are some possible side effects that you should be aware of and tell your doctor if you are taking allopurinol. However, allopurinol use does not cause unusual tiredness. Most important of these is the development of a rash. If a rash occurs, you should stop the medication immediately and contact your doctor.

Common side effects of allopurinol include:

Skin rash
Change in taste
Diarrhea
Nausea, stomach pain, or indigestion
Changes in liver function test results
Initial gout flares

Management of Side Effects

Taking allopurinol after you eat meals helps reduce the chance of other side effects, such as stomach pain.
While allopurinol is meant to lower uric acid, you may experience more gout attacks and joint pain during the first few months as uric acid levels regulate. Your doctor may prescribe colchicine or other pain management options along with allopurinol to control your gout symptoms and further attacks.
Mild side effects should subside within a few days, or up to a couple of weeks. Developing a new rash, whether a mild or severe reaction, after starting allopurinol should lead to immediate discontinuation of the drug and you should call your doctor immediately.

Serious Side Effects

Rare, but serious symptoms include:

Serious allergic reaction
Severe skin rash - itchy hives, red- or purple-colored spots, scaly skin reactions
Fever, chills or trouble breathing
Swelling of your face or throat
Liver injury - tiredness, lack of appetite, weight loss, upper abdominal pain or discomfort, jaundice (dark urine or yellowing of your skin or whites of your eyes)

Allopurinol Hypersensitivity Syndrome (AHS)

Allopurinol hypersensitivity syndrome (AHS) is a rare severe adverse effect of allopurinol with an incidence of about 1 in 1000, with a high mortality rate of 20% to 25%. The mechanism is a T-cell-mediated immune reaction to oxypurinol. The highest risk is in the first few months of therapy, especially with higher starting doses of allopurinol. Concurrent diuretics, especially thiazide use, renal insufficiency stage 3, or higher, are major risk factors. Patients of Korean, Han Chinese, and Thai descent with HLA-B*5801 genotype are at a very high risk of AHS. Clinical features of AHS include Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, hepatocellular injury, acute kidney injury, fever, leukocytosis, and eosinophilia. Management is supportive. Lowering the starting dose of allopurinol to less than 100 mg daily in all patients and less than 50 mg daily in patients with chronic kidney disease stage 3 or worse can lower the risk of AHS.

What to do if you experience side effects

Talk to your doctor if you experience any serious side effects, such as allergic reactions. If you develop a skin rash, tell your doctor or pharmacist right away, as you may be asked to discontinue using allopurinol. A serious allergic reaction could mean you have allopurinol hypersensitivity syndrome, which is rare-only 1 in 1,000 patient cases. Patient populations with increased risk - including people who are Han Chinese or Southeast Asian, and Koreans with kidney disease - can be screened for a genetic marker (HLA-B5801) that can predict this allergic reaction as one of the side effects of taking allopurinol. To determine any allergic reactions, doctors will start you on a low dose with a plan to increase the allopurinol to the optimal medication dose. If you have kidney or liver disease, your health care professional can help advise on whether medications like allopurinol are your best treatment option.

Precautions

Allopurinol may harm an unborn baby. Tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking allopurinol, call your doctor.

Before Taking Allopurinol

Before taking allopurinol, tell your doctor and pharmacist if you are allergic to allopurinol, any other medications, or any of the ingredients in allopurinol tablets. Ask your pharmacist for a list of the ingredients.

Also, tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking while you are taking allopurinol. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.

Medical Conditions

Tell your doctor if you have or have ever had high blood pressure, diabetes, kidney or liver disease, or heart failure.

Lifestyle Considerations

You should know that allopurinol may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
Ask your doctor about the safe use of alcoholic beverages while you are taking allopurinol. Avoid drinking alcohol. It can make your condition worse.
Avoid driving or hazardous activity until you know how allopurinol will affect you.

Drug Interactions

Other drugs can affect allopurinol and interact with it, reducing its effectiveness. They specifically can interact with blood thinners, also known as anticoagulants or antiplatelet drugs, which are prescribed to prevent blood clots or keep existing clots from getting larger, ultimately reducing the risk of stroke or heart attack.

Medications to Disclose

Be sure to mention any of the following other drugs to your doctor to prevent other medicines from interacting with the allopurinol:

Antibiotics such as amoxicillin (Amoxil, Trimox), ampicillin (Polycillin, Principen)
Cancer treatments and other medicines that suppress the immune system such as cyclophosphamide (Cytoxan), mercaptopurine (Purinethol), and azathioprine (Imuran)
Chlorpropamide (Diabinese) to treat diabetes
Diuretics (known as “water pills”) for high blood pressure
Heparin or warfarin, which is also called by the brand name Coumadin®, are anticoagulants.
Aspirin is a type of anti-platelet drug.

Management of Interactions

Your doctor may need to change the doses of your other medicines or monitor you carefully for side effects.

Contraindications

The presence of the HLA-B5801 genotype in patients of Korean descent with chronic kidney disease stage 3 or worse, or in patients of Han Chinese or Thai descent irrespective of renal function, is an especially high risk of AHS (hazard ratio of several hundred). American College of Rheumatology recommends screening this population for HLA-B5801 genotype using the polymerase chain reaction (PCR) testing before initiating allopurinol and, if positive, using an alternative urate-lowering therapy. However, universal HLA-B5801 allopurinol screening is not recommended, given the significantly lower HLA-B5801 prevalence and hazard ratio in other populations.

When to avoid Allopurinol

If you are allergic to this drug; any part of this drug; or any other drugs, foods, or substances.
If you are breast-feeding.

Monitoring

It is very important that your doctor check your or your child's progress at regular visits to make sure that this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Regular Check-ups

Complete blood count, liver function tests, renal function, and serum uric acid levels shall be measured every 2 to 5 weeks while titrating the dose until achieving the target serum uric acid level and every six months thereafter.

Patient Counseling

Patients need counseling about the signs and symptoms of AHS with a recommendation to discontinue allopurinol promptly if they develop skin rash concerning AHS, especially early in therapy.

Storage and Disposal

Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Proper Disposal

Dispose of unneeded medications in a way so that pets, children, and other people cannot take them. Do not flush this medication down the toilet. Use a medicine take-back program. Talk to your pharmacist about take-back programs in your community.

Safety Measures

Always lock safety caps. Place the medication in a safe location - one that is up and away and out of their sight and reach.

Addressing Allopurinol Failure

Allopurinol is the most widely used urate-lowering medication worldwide. However, allopurinol failure is frequently observed in clinical practice. In this review, we provide a framework for assessing allopurinol failure, which includes failure of allopurinol to control serum urate concentrations, failure of allopurinol to control clinical symptoms, and failure of allopurinol due to an adverse drug reaction. Understanding the causes of allopurinol failure underpins the approach required to turn failure into success in gout management.

What do allopurinol success and failure look like?

According to Collins Dictionary, “Something that is successful achieves what it was intended to achieve.” When defining “success” of ULT, it is important to consider clinical outcomes and not just SU. Although achieving target SU has been the main focus for defining “success” in most gout clinical trials, it is meaningful only if there are associated clinical improvements. Ideally in gout, the clinical improvement would be disease remission, which has been preliminarily defined as absence of gout flares, SU < 0.36 mmol/L, absence of tophi, pain due to gout < 2 and patient global assessment of gout disease activity < 2 on a 10 cm visual analog scale, and the absence of adverse effects.

Drug failure can be considered if the expected effects do not occur with a prescribed pharmacological treatment. This could include failing to achieve the desired treatment target or clinical outcome, or occurrence of an adverse drug reaction requiring treatment cessation. In the case of allopurinol, “failure” can therefore be defined as (1) failure to achieve target SU, (2) failure to achieve the desired clinical outcomes, or (3) an adverse reaction requiring cessation, such as allopurinol hypersensitivity syndrome (AHS). The reasons for drug failure are complex and can occur at any point in the therapeutic chain, which is “the process describing the life of medicines in a community”

Failure of allopurinol to achieve target SU

Failure of allopurinol to achieve target SU may be related to (1) allopurinol manufacture, (2) allopurinol dosing, (3) adherence and persistence with allopurinol, or (4) true nonresponse.

Allopurinol manufacture

Counterfeit medicines are on the rise globally and although there are no specific reports of counterfeit allopurinol, it would be naive to presume it did not exist. Even though we might perceive that the high/middle-income countries are immune to these substandard and/or falsified medicines, the World Health Organization has estimated that 50% of the medicines for sale on the internet are fake, even if the online providers look legitimate. In addition, the Alliance for Safe Online Prescribing 2021 survey of Americans’ perceptions and use of online pharmacies identified that nearly half of Americans were purchasing medications online because of perceived benefits of cost and convenience. Although these substandard or fake medicines may cause adverse reactions, it is far more likely that they contain little or no active ingredient. In the case of allopurinol, substandard or fake versions should be easy to identify as one would anticipate little reduction in SU.

If target SU is not achieved, practitioners should ask where medicines are being sourced.

Allopurinol dosing

Two of the most common reasons for allopurinol failure are underdosing and lack of regular prescribing by healthcare professionals. Restricting the dose of allopurinol is undeniably associated with not achieving target SU. Further, 300 mg daily, which is often considered the standard dose, is ineffective in achieving target SU in the majority of patients.

Allopurinol dose escalation to achieve target SU is safe and effective even in those with renal impairment. It is recommended that allopurinol is commenced at a low dose (eg, 50-100 mg daily depending on renal function) to minimize the risk of the rare but potentially life-threatening AHS. The dose of allopurinol should then be gradually increased in 50 mg to 100 mg increments to achieve target SU. Multiple studies have shown that target SU can be achieved in the vast majority of people with gout with this approach.

If SU is not achieved with low-dose allopurinol, the dose should be systematically up-titrated until SU is achieved or to the maximum approved or tolerated dose.

Allopurinol adherence and persistence

Irregular allopurinol prescribing is a barrier to treatment success. Health system factors, healthcare provider (HCP) factors, and patient factors all contribute to low rates of allopurinol persistence. Practitioners need systems to ensure regular prescribing of allopurinol for people with gout, and build understanding about gout as a chronic disease of MSU crystal deposition that can be treated with long-term ULT.

Nonresponse to allopurinol

There is only a very small subgroup of people with gout who do not achieve target SU despite taking regular allopurinol at a dose that would be expected to result in a reduction in SU. If allopurinol is dose escalated and the SU does not reduce as expected, the most likely reason is low adherence. In this setting, an open and nonjudgmental discussion about allopurinol adherence is required prior to assuming nonresponse and changing to another urate-lowering medication.

Failure to achieve the desired clinical outcomes despite reducing the SU to target

Some patients may continue to experience clinical symptoms despite allopurinol reducing the SU to target. This may be due to (1) incorrect diagnosis, (2) gout flares occurring early in the course of treatment, or (3) high MSU crystal burden.

Lifestyle modifications

Taking uric acid-lowering medications, like allopurinol, for gout can help to avoid serious symptoms, like gout attacks. This is because lower uric acid levels reduce the chances of uric acid crystals forming. While taking steps, such as following a healthy, balanced diet, staying hydrated, and getting regular exercise, research has shown that these lifestyle changes can only lower serum uric acid by so much. Making healthy dietary changes or weight loss has been shown to lower uric acid levels by only 1.0 to 2.0 mg/dL, which is insufficient to reach a health target for gout sufferers. While healthy lifestyle changes are important for anyone who has or who is at risk, taking daily medications-like allopurinol for gout-as prescribed by a doctor, is one of the best ways to reduce levels of uric acid to less than 6.0 mg/dL or lower, depending on the doctor’s recommendations.

Enhancing Healthcare Team Outcomes

Allopurinol is a relatively safe drug that has been used for over half a century. Still, recent studies in gout have shown significant underutilization of this agent and suboptimal dose use, insufficient to reach target serum uric acid concentrations in a considerable proportion of gout patients. A problem with allopurinol treatment for gout is therapy adherence. Contrary to the common belief, recent studies have shown that allopurinol is safe in severe chronic kidney disease and can impede the progression of renal disease in patients with gout and chronic kidney disease. Using allopurinol in patients with gout is also associated with lower all-cause mortality and other adverse cardiovascular events, including readmissions due to congestive heart failure.

The use of allopurinol requires management by an interprofessional healthcare team that includes clinicians (MDs, DOs, NPs, PAs), nurses, and pharmacists. Clinicians initiating allopurinol therapy should ensure no drug interactions and that xanthine oxidase inhibitor therapy is the optimal choice; if necessary, a pharmacist consult can assist in this evaluation. Pharmacists can also verify dosing and provide additional patient counsel regarding how to take the drug. The nursing team shall assist with verifying patient adherence and helping to monitor for adverse events and therapeutic effectiveness. All team members should document their observations in the patient's permanent health record, and be prepared to reach out to other team members when necessary, so alterations to the therapeutic regimen can be made. The best chance for allopurinol to have therapeutic success with minimal adverse events is via an interprofessional team approach.

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