Toxicology Brief: Hydroxyurea toxicosis in dogs and cats

Hydroxyurea is a prescription-only antineoplastic drug—available as 200-, 300-, 400-, or 500-mg capsules—given orally to dogs, cats, and people.1,2 In people, it is given to treat melanoma, resistant chronic myelocytic leukemia, and carcinoma of the ovary and to control primary squamous cell carcinoma of the head and neck. Sometimes, it is also used as an adjunctive therapy for patients with HIV infection or AIDS, psoriasis, or sickle cell anemia.3,4 In dogs and cats, it is indicated for treating polycythemia vera, mastocytomas, and leukemias.2

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Recommended oral dosages to treat various conditions (polycythemia vera, chronic myelogenous leukemia) in dogs include 50 mg/kg three times a week, 30 mg/kg once daily for one week and then 15 mg/kg/day until remission, or 20 to 25 mg/kg twice daily, tapering off to every other day once the hematocrit is < 60%.2 In cats, the oral dosage is 25 mg/kg three times a week or 30 mg/kg once daily for one week, tapering off to 15 mg/kg once daily until remission and then to the lowest effective frequency as determined by monitoring the hematocrit.2

TOXICOKINETICS

Hydroxyurea is well-absorbed orally, with the peak plasma concentration seen within one to four hours after administration. The drug readily crosses the blood-brain barrier and is well-distributed in other body tissues. Protein binding is between 75% and 80%. About 50% of the drug is metabolized in the liver, and the remaining 50% (range = 36% to 62%) is eliminated through the kidneys as unchanged drug and as urea. The reported elimination half-life is two to four and a half hours.1,4

The exact mechanism of action of hydroxyurea is not known, but it appears to interfere with DNA synthesis without interfering with RNA or protein synthesis. It is known to inhibit the conversion of DNA bases by blocking the enzyme ribonucleoside diphosphate reductase, possibly resulting in direct damage to the DNA. Myelosuppression seems to occur as a result of inhibition of DNA synthesis.1,3,4

TOXICITY

Hydroxyurea appears to be well-tolerated in animals, with low acute oral toxicity. The oral LD50 in mice and rats is 7,330 and 5,760 mg/kg, respectively.1 Methemoglobinemia can occur in cats given doses exceeding 500 mg.2

Adverse effects of long-term hydroxyurea use in people include gastrointestinal complications (nausea, vomiting, diarrhea, constipation, mucositis); myelosuppression (leukopenia, thrombocytopenia, anemia); cutaneous effects (rashes, ulcers, melanonychia [black pigmentation of nails]); hepatitis, occasionally; and reversible renal damage.3,4

Onychomadesis (nail shedding) involving several claws on all feet in two dogs receiving long-term hydroxyurea treatment has been described.5 Both dogs recovered, one after the cessation of treatment and the other after the dosage was reduced.5 Acute toxicosis characterized by the development of methemoglobinemia, moderate thrombocytopenia, and mild delayed neutropenia has been reported in one dog that had possibly ingested 200 to 300 mg/kg of hydroxyurea belonging to the owner. The dog made a full recovery with aggressive supportive treatment.1

APCC DATA

A review of the ASPCA Animal Poison Control Center (APCC) toxicology database from 2003 to 2009 found 16 hydroxyurea cases involving 13 dogs and three cats.6 These cases involved exposure to one agent (hydroxyurea) only and were assessed as medium-suspect (history of exposure, some clinical signs consistent with hydroxyurea toxicosis) or high-suspect cases (history of exposure, clinical signs consistent with hydroxyurea toxicosis).

Dogs

One 24.3-lb (11-kg) dog showed signs of vomiting within minutes, lethargy and weakness within two hours of exposure, and hypothermia, muddy mucous membranes (suspected methemoglobinemia), and recumbency within nine hours of exposure after potentially ingesting four 500-mg capsules (approximate dose = 182 mg/kg).6 This dog was euthanized about 10 hours after exposure because of poor response to treatment.

The most commonly reported clinical signs in the 13 dogs were vomiting (six dogs), methemoglobinemia indicated by changes in mucous membrane color (six dogs), cyanosis (five dogs), tachycardia (five dogs), ataxia (four dogs), and weakness or recumbency (two dogs).6 Of the seven dogs with a known outcome, five recovered with treatment and two were euthanized. The onset of clinical signs of the five dogs that recovered was within 30 minutes, and the duration of signs in one dog was two weeks.

Cats

In the three cats, dyspnea was the most common clinical sign (all three cats), followed by methemoglobinemia or changes in mucous membrane color (one cat).6 The minimum dose at which dyspnea was reported in one cat was 79 mg/kg. The final outcome was unknown in all three cats. The clinical signs were noticed within 30 minutes to two hours after exposure. The durations of the clinical signs were unknown.

TREATMENT

If the exposure is within two hours of presentation and no clinical signs are present, induce emesis by using 3% hydrogen peroxide (2.2 ml/kg orally; repeat once in 10 to 15 minutes if no emesis). Alternatively, emesis may be induced in dogs by administering apomorphine (0.03 mg/kg intravenously or dissolving a pill in saline solution and instilling the resulting solution in the conjunctival sac) or in cats by administering xylazine (0.4 to 0.5 mg/kg intramuscularly or intravenously). Any central nervous system or respiratory depression resulting from xylazine administration in cats may be reversed with yohimbine (0.1 mg/kg intravenously). Then administer activated charcoal (1 to 3 g/kg orally, or a labeled dose if using a commercial product) with a cathartic such as sorbitol (70% solution at 1 to 3 ml/kg orally).

The agent of choice for treating methemoglobinemia is 5% N-acetylcysteine at a dosage of 140 mg/kg intravenously or orally followed by 70 mg/kg orally every six to eight hours for five to 15 treatments. To obtain the 5% concentration, dilute in 5% dextrose or sterile water. Methylene blue is not commonly administered anymore because injectable methylene blue is not readily available to veterinarians, but the dosage is 1 to 1.5 mg/kg in a 1% solution or as provided by the manufacturer intravenously, repeated once in 30 minutes if needed in dogs only since cats treated with it can show increased oxidative damage to their red blood cells.

Administer intravenous fluids, oxygen, and whole blood or packed red blood cells to improve oxygen-carrying capacity as needed. Filgrastim (granulocyte colony-stimulating factor [Neupogen—Amgen] 1 to 5 µg/kg subcutaneously once daily) can be administered proactively or if myelosuppression becomes evident.2

MONITORING

Monitor for cyanosis and methemoglobinemia (chocolate-brown mucous membranes, dark-brown blood), which can occur within a few hours after exposure. Also monitor for delayed myelosuppression and thrombocytopenia by performing a baseline complete blood count and serum chemistry profile and then repeating these tests on days 3 and 7 after treatment is initiated. In addition, monitor the patient's hematocrit and liver and kidney function.

CONCLUSION

Acute hydroxyurea toxicosis in animals can result in serious and life-threatening clinical signs of methemoglobinemia and myelosuppression. Prompt and aggressive treatment is indicated to help ensure a successful outcome.

"Toxicology Brief" was contributed by Safdar A. Khan, DVM, MS, PhD, DABVT, ASPCA Animal Poison Control Center, 1717 S. Philo Road, Suite 36, Urbana, IL 61802. The department editor is Petra Volmer, DVM, MS, DABVT, DABT.

REFERENCES

1. Wray JD. Methaemoglobinaemia caused by hydroxycarbamide (hydroxyurea) ingestion in a dog. J Small Animal Pract 2008;49:211-215.

2. Plumb DC. Veterinary drug handbook. 5th edition. Ames: Iowa State University Press, 2005;401-402.

3. Hydroxyurea. In: POISINDEX System [intranet database]. Version 5.1. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc.

4. Hydroxyurea. AHFS Drug Information 2008. American Society of Health-System Pharmacists, American Hospital Formulary Service, 2008;1083-1089.

5. Marconato L, Bonfanti U, Fileccia I. Unusual dermatological toxicity of hydroxyurea in two dogs with spontaneously occurring tumours. J Small Animal Pract 2007;48:514-517.

6. AnTox Database. Urbana, Ill: ASPCA Animal Poison Control Center, 2003-2010.