Allopurinol (Zyloprim)

By | 2013-06-08

Xanthine Oxidase Inhibitor; Purine Analog

Highlights Of Prescribing Information

Used as a uric acid reducer in dogs, cats, reptiles & birds & as an alternative treatment Leishmaniasis &Trypanosomiasis in dogs

Use with caution (dosage adjustment may be required) in patients with renal or hepatic dysfunction

Contraindicated in red-tailed hawks & should be used with caution, if at all, in other raptors

Diet may need to be adjusted to lower purine

GI effects are most likely adverse effects, but hypersensitivity, hepatic & renal effects can occur

Many potential drug interactions

What Is Allopurinol Used For?

The principle veterinary uses for allopurinol are for the prophylactic treatment of recurrent uric acid uroliths and hyperuricosuric calcium oxalate uroliths in small animals. It has also been used in an attempt to treat gout in pet birds and reptiles.

Allopurinol has been recommended as an alternative treatment for canine Leishmaniasis. Although it appears to have clinical efficacy, it does not apparently clear the parasite in most dogs at usual dosages. Allopurinol may also be useful for American Trypanosomiasis.

Pharmacology/Actions

Allopurinol and its metabolite, oxypurinol, inhibit the enzyme xanthine oxidase. Xanthine oxidase is responsible for the conversion of oxypurines (e.g., hypoxanthine, xanthine) to uric acid. Hepatic microsomal enzymes may also be inhibited by allopurinol. It does not increase the renal excretion of uric acid nor does it possess any antiinflammatory or analgesic activity.

Allopurinol is metabolized by Leishmania into an inactive form of inosine that is incorporated into the organism’s RNA leading to faulty protein and RNA synthesis.

Allopurinol, by inhibiting xanthine oxidase, can inhibit the formation of superoxide anion radicals, thereby providing protection against hemorrhagic shock and myocardial ischemia in laboratory conditions. The clinical use of the drug for these indications requires further study.

Pharmacokinetics

In Dalmatians, absorption rates were variable between subjects. Peak levels occur within 1-3 hours after oral dosing. Elimination half-life is about 2.7 hours. In dogs (not necessarily Dalmatians), the serum half-life of allopurinol is approximately 2 hours and for oxipurinol, 4 hours. Food does not appear to alter the absorption of allopurinol in dogs.

In horses, oral bioavailability of allopurinol is low (approximately 15%). Allopurinol is rapidly converted to oxypurinol in the horse as the elimination half-life of allopurinol is approximately 5 – 6 minutes. Oxypurinol has an elimination half-life of about 1.1 hours in the horse.

In humans, allopurinol is approximately 90% absorbed from the GI tract after oral dosing. Peak levels after oral allopurinol administration occur 1.5 and 4.5 hours later, for allopurinol and oxypurinol, respectively.

Allopurinol is distributed in total body tissue water but levels in the CNS are only about 50% of those found elsewhere. Neither allopurinol nor oxypurinol are bound to plasma proteins, but both drugs are excreted into milk.

Xanthine oxidase metabolizes allopurinol to oxypurinol. In humans, the serum half-life for allopurinol is 1-3 hours and for oxypurinol, 18-30 hours. Half-lives are increased in patients with diminished renal function. Both allopurinol and oxypurinol are dia-lyzable.

Before you take Allopurinol

Contraindications / Precautions / Warnings

Allopurinol is contraindicated in patients who are hypersensitive to it or have previously developed a severe reaction to it. It should be used cautiously and with intensified monitoring in patients with impaired hepatic or renal function. When used in patients with renal insufficiency, dosage reductions and increased monitoring are usually warranted.

Red-tailed hawks appear to be sensitive to the effects of allopurinol. Doses at 50 mg/kg PO once daily caused clinical signs of vomiting and hyperuricemia with renal dysfunction. Doses of 25 mg/kg PO once daily were safe but not effective in reducing plasma uric acid.

Adverse Effects

Adverse effects in dogs are apparently uncommon with allopurinol when fed low purine diets. There has been one report of a dog developing hemolytic anemia and trigeminal neuropathy while receiving allopurinol. Xanthine coatings have formed around ammonium urate uroliths in dogs that have been fed diets containing purine. If the drug is required for chronic therapy, reduction of purine precursors in the diet with dosage reduction should be considered.

Several adverse effects have been reported in humans including GI distress, bone marrow suppression, skin rashes, hepatitis, and vasculitis. Human patients with renal dysfunction are at risk for further decreases in renal function and other severe adverse effects unless dosages are reduced. Until further studies are performed in dogs with decreased renal function, the drug should be used with caution and at reduced dosages.

Reproductive / Nursing Safety

While the safe use of allopurinol during pregnancy has not been established, dosages of up to 20 times normal in rodents have not demonstrated decreases in fertility. Infertility in males (humans) has been reported with the drug, but a causal effect has not been firmly established. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, hut there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.)

Allopurinol and oxypurinol may be excreted into milk; use caution when allopurinol is administered to a nursing dam.

Overdosage / Acute Toxicity

Vomiting is common in dogs at doses >100 mg/kg per the APCC database. A human ingesting 22.5 grams did not develop serious toxicity. The oral LD50 in mice is 78 mg/kg.

There were 27 exposures to allopurinol reported to the ASPCA Animal Poison Control Center (APCC; www.apcc.aspca.org) during 2005-2006. In these cases 25 were dogs with 2 showing clinical signs; the remaining 2 reported cases were cats that showed no clinical signs. Common findings recorded in decreasing frequency included vomiting and tachycardia.

How to use Allopurinol

Allopurinol dosage for dogs:

For urate uroliths:

a) 7-10 mg/kg PO three times daily for both dissolution and prevention. Goal is to reduce urine uratexreatinine ratio by 50%. ()

b) For dissolution: 15 mg/kg PO q12h; only in conjunction with low purine foods.

For prevention: 10-20 mg/kg/day; because prolonged high doses of allopurinol may result in xanthine uroliths, it may be preferable to minimize recurrence with dietary therapy, with the option of treating infrequent episodes of urate urolith formation with dissolution protocols. ()

c) Alkalinize urine to a pH of 6.5-7 (see sodium bicarbonate monograph), give low purine diet and eliminate any UTI. Allopurinol at 10 mg/kg three times daily for the first month, then 10 mg/kg once daily thereafter. Reduce dose in patients with renal failure. ()

For Leishmaniasis:

a) 15 mg/kg PO twice daily for months ()

b) If possible use with meglumine antimoniate, if not, use allopurinol alone at 10 mg/kg PO twice daily. If animal has renal insufficiency, use at 5 mg/kg PO twice daily. ()

c) Meglumine antimoniate (100 mg/kg/day SQ) until resolution, with allopurinol at 20 mg/kg PO q12h for 9 months.

An alternate protocol using allopurinol alone: allopurinol 10 mg/kg PO q8h or 10-20 mg/kg PO q12h for 1-4 months. ()

Allopurinol dosage for cats:

For urate uroliths:

a) 9 mg/kg PO per day ()

Allopurinol dosage for birds:

For gout:

a) In budgies and cockatiels: Crush one 100 mg tablet into 10 mL of water. Add 20 drops of this solution to one ounce of drinking water. ()

b) For parakeets: Crush one 100 mg tablet into 10 mL of water. Add 20 drops of this solution to one ounce of drinking water or give 1 drop 4 times daily. ()

Allopurinol dosage for reptiles:

a) For elevated uric acid levels in renal disease in lizards: 20 mg/ kg PO once daily ()

b) For gout: 20 mg/kg PO once daily. Suggested dosage based upon human data as dose is not established for reptiles. ()

Monitoring

■ Urine uric acid (for urolithiasis)

■ Adverse effects

■ Periodic CBC, liver and renal function tests (e.g., BUN, Creatinine, liver enzymes); especially early in therapy

Client Information

■ Unless otherwise directed, administer after meals (usually 1 hour or so). Notify veterinarian if animal develops a rash, becomes lethargic or ill.

Chemistry / Synonyms

A xanthine oxidase inhibitor, allopurinol occurs as a tasteless, fluffy white to off-white powder with a slight odor. It melts above 300° with decomposition and has an apparent pKa of 9.4. Oxypurinol (aka oxipurinol, alloxanthine), its active metabolite, has a pKa of 7.7. Allopurinol is only very slightly soluble in both water and alcohol.

Allopurinol may also be known as: allopurinolum, BW-56-158, HPP, or NSC-1390; many trade names are available.

Storage / Stability/Compatibility

Allopurinol tablets should be stored at room temperature in well-closed containers. The drug is stated to be stable in both light and air. The powder for injection should be stored at 25°C; may be exposed to 15-30°C. Once diluted to a concentration < 6 mg/mL, store at room temperature and use within 10 hours; do not refrigerate. Compatible IV solutions include D5W and normal saline.

An extemporaneously prepared suspension containing 20 mg/ mL allopurinol for oral use can be prepared from the commercially available tablets. Tablets are crushed and mixed with an amount of Cologel suspending agent equal to V3 the final volume. A mixture of simple syrup and wild cherry syrup at a ratio of 2:1 is added to produce the final volume. This preparation has been reported to be stable for at least 14 days when stored in an amber bottle at either room temperature or when refrigerated.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

Human-Labeled Products:

Allopurinol Tablets: 100 mg & 300 mg; Zyloprim (GlaxoWell-come); generic; (Rx)

Allopurinol Powder for Injection: 500 mg preservative-free in 30 mL vials; Aloprim (Nabi); Allopurinol Sodium (Bedford Labs); (Rx)