Cyclophosphamide intoxication because of pharmacy error in two dogs

• Autores: Jennifer E. Wells
• Localización: JAVMA: Journal of the American Veterinary Medical Association, ISSN-e 0003-1488, Vol. 245, Nº. 2, 2014, págs. 222-226
• Idioma: inglés
• Texto completo no disponible (Saber más ...)
• Resumen

  • Case Description—An 8-year-old spayed female Yorkshire Terrier and 5-year-old castrated male West Highland White Terrier were evaluated because of cyclophosphamide intoxication subsequent to pharmacy error. Both dogs received cumulative doses of approximately 1,080 mg of cyclophosphamide/m2 after cyclophosphamide was erroneously dispensed instead of cyclosporine by different pharmacies.

    Clinical Findings—Both dogs became lethargic, and 1 dog also had anorexia, vomiting, and diarrhea within 2 days after initiation of cyclophosphamide administration. The other dog developed anorexia on the seventh day after initiation of cyclophosphamide administration. The dogs were evaluated by their primary-care veterinarians 9 and 11 days after administration of the first dose of cyclophosphamide, and both had severe leukopenia and thrombocytopenia.

    Treatment and Outcome—One dog was treated on an outpatient basis with broad-spectrum antimicrobials, granulocyte colony-stimulating factor, and an appetite stimulant. The other dog was more severely affected and was hospitalized for 7 days, during which it was treated with broad-spectrum antimicrobials, gastroprotectants, granulocyte colony-stimulating factor, and cryopreserved platelet and packed RBC transfusions. Both dogs fully recovered after treatment.

    Clinical Relevance—This was the first report of survival for dogs with inadvertent prolonged cyclophosphamide intoxication subsequent to pharmacy error. Although the 2 dogs had similar clinical signs and clinicopathologic findings, the severity of disease and treatment required differed for each dog. Dogs can recover from prolonged cyclophosphamide intoxication provided appropriate supportive care is administered.

    An 8-year-old 4.2-kg (9.2-lb) spayed female Yorkshire Terrier (dog 1) was evaluated after being administered 25 mg of cyclophosphamide daily for 11 days, which was consistent with a daily dose of 98 mg of cyclophosphamide/m2 and a cumulative dose of 1,078 mg of cyclophosphamide/m2. The dog had been treated for > 1 year with a brand-name cyclosporinea for atopic dermatitis. Because of a manufacturing shortage of the brand-name cyclosporine, the veterinarian prescribed 25-mg capsules of a generic cyclosporine for the dog through a local community pharmacy. The pharmacy erroneously dispensed 50-mg tablets of cyclophosphamide with instructions to give the dog half a tablet daily.

    The owner noticed that the dog had become lethargic within 2 days after initiation of cyclophosphamide administration, and the lethargy progressed daily. The dog became anorexic 7 days after initiation of cyclophosphamide administration and was evaluated by its primary-care veterinarian 4 days later (ie, 11 days after initiation of cyclophosphamide administration), at which time the pharmacy mistake was identified. The dog was referred to the University of Tennessee Veterinary Medical Center for further evaluation.

    During initial evaluation at the university hospital, the dog was hyperthermic (39.66°C [103.4°F]; reference interval, 37.5° to 39.16°C [99.5° to 102.5°F]) and was hyperactive with signs of extreme anxiety. No other abnormalities were identified during physical examination. Results of a CBC revealed leukopenia (800 leukocytes/μL; reference interval, 5,100 to 14,000 leukocytes/μL), neutropenia (260 neutrophils/μL; reference interval, 2,650 to 9,800 neutrophils/μL), lymphopenia (400 lymphocytes/μL; reference interval, 1,100 to 4,600 lymphocytes/μL), monocytopenia (70 monocytes/μL; reference interval, 165 to 850 monocytes/μL), and thrombocytopenia (25,000 platelets/μL; reference interval, 147,000 to 423,000 platelets/μL). The Hct was 44.8% (reference interval, 41% to 60%), and total protein concentration was 7.7 g/dL (reference interval, 5.7 to 7.9 g/dL). A serum biochemical analysis revealed no clinically important abnormalities. A urinalysis was not performed because the dog did not urinate when walked, and a cystocentesis was not performed because of the severe thrombocytopenia.

    The dog was not hospitalized because of its apparent stability at home and concerns regarding its severe anxiety and susceptibility to nosocomial infection. Medications prescribed were mirtazapine (0.83 mg/kg [0.38 mg/lb], PO, q 24 h) to stimulate appetite, amoxicillin trihydrate (23 mg/kg [10.5 mg/lb], PO, q 12 h) and enrofloxacin (8 mg/kg [3.6 mg/lb], PO, q 12 h) as prophylaxis against a secondary bacterial infection subsequent to neutropenia, and G-CSF (5 μg/kg [2.3 μg/lb], SC, q 12 h) to stimulate neutrophil production.

    The dog was reevaluated 4 days after the initial evaluation, at which time the owner reported a slight improvement in the dog's lethargy and hyporexia. The only pertinent physical examination findings were hyperthermia (39.94°C [103.9°F]) and signs of anxiety. Abnormal CBC findings were leukopenia (2,700 leukocytes/μL), neutropenia (1,240 neutrophils/μL), and thrombocytopenia (16,000 platelets/μL); the Hct was 47.7%, and total protein concentration was 7.8 g/dL. The dog was discharged to the owner with instructions to continue the medications as previously prescribed.

    Eleven days after the initial evaluation, the physical examination findings remained unchanged with hyperthermia (40.16°C [104.3°F]) and signs of anxiety. The owner reported that the dog's lethargy and hyporexia had resolved and that it had been clinically normal for 48 hours prior to reevaluation. Pertinent CBC findings were leukocytosis (37,000 leukocytes/μL), neutrophilia (28,490 neutrophils/μL) with band neutrophils (3,300 band neutrophils/μL; reference interval, 0 to 300 band neutrophils/μL), and thrombocytopenia (65,000 platelets/μL); the Hct was 43.8%, and total protein concentration was 8.1 g/dL. All medications were discontinued.

    The dog was reevaluated for the last time 25 days after the initial evaluation. The owner reported that the dog was clinically normal. Physical examination findings remained unchanged; the dog was hyperthermic (40.16°C) and had signs of marked anxiety. Results of a CBC revealed that the leukocyte (12,400 leukocytes/μL), neutrophil (7,440 neutrophils/μL), and platelet (299,000 platelets/μL) counts had returned to within reference limits. The Hct was 46.8%, and the total protein concentration was undeterminable because of lipemia.

    A 5-year-old 9.4-kg (20.7-lb) castrated male West Highland White Terrier (dog 2) was evaluated after being administered 50 mg of cyclophosphamide daily for 9 days, which was consistent with a daily dose of 120 mg of cyclophosphamide/m2 and a cumulative dose of 1,080 mg of cyclophosphamide/m2. The dog was being treated with cyclosporine for atopic dermatitis, and cyclophosphamide instead of cyclosporine was inadvertently dispensed by a community pharmacy.

    Two days after the first dose of cyclophosphamide was administered, the dog developed anorexia, lethargy, and diarrhea, which continued until the dog was evaluated by its primary-care veterinarian 9 days after cyclophosphamide administration was initiated. The pharmacy mistake was identified, and the dog was referred to the University of Tennessee Veterinary Medical Center.

    During initial examination at the university hospital, the dog was hyperthermic (39.66°C [103.4°F]), and had a grade 3 of 6 left-sided systolic heart murmur, pale pink and tacky mucous membranes (estimated dehydration, 7%), and diarrhea. Results of a CBC revealed severe leukopenia (500 leukocytes/μL), neutropenia (140 neutrophils/μL), lymphopenia (300 lymphocytes/μL), monocytopenia (30 monocytes/μL), and thrombocytopenia (9,000 platelets/μL). The Hct was 44.7%, and the total protein concentration was 6.0 g/dL. Serum biochemical analysis revealed hypoalbuminemia (2.2 μg/dL; reference interval, 3.2 to 4.1 μg/dL), hyperglobulinemia (3.5 g/dL; reference interval, 2 to 3.2 g/dL), hyperglycemia (138 mg/dL; reference interval, 84 to 120 mg/dL), and hypokalemia (2.8 mEq/L; reference interval, 3.1 to 4.8 mEq/L). Urinalysis revealed no hematuria or active sediment and, despite clinical dehydration, a urine specific gravity of 1.010; however, the urine sample was obtained after initiation of IV fluid therapy and administration of furosemide.

    The dog was hospitalized and treated with an electrolyte solutionb (4.8 mL/kg/h [2.2 mL/lb/h], IV) for dehydration; G-CSF (5 μg/kg, SC, q 12 h) to stimulate neutrophil production; ampicillin sodium (21 mg/kg [9.5 mg/lb], IV, q 8 h), enrofloxacin (10 mg/kg [4.5 mg/lb], IV, q 24 h), and metronidazole (10 mg/kg, IV, q 12 h) as prophylaxis against secondary bacterial infection subsequent to neutropenia; and furosemide (2 mg/kg [0.9 mg/lb], IV, q 12 h) as prophylaxis against hemorrhagic cystitis. After 2 days of hospitalization, the dog was normothermic (38.33°C [101°F]) and rehydrated but remained anorexic and lethargic and had developed epistaxis and melena. Results of a CBC indicated leukopenia (500 leukocytes/μL), neutropenia (120 neutrophils/μL), lymphopenia (300 lymphocytes/μL), monocytopenia (30 monocytes/μL), thrombocytopenia (9,000 platelets/μL), and nonregenerative anemia (Hct, 31.1%; reticulocyte count, 3,500 reticulocytes/μL; reference interval, 12,500 to 93,000 reticulocytes/μL) with a total protein concentration of 6.0 g/dL. The dog was administered a cryopreserved platelet concentrate transfusion (100 mL, IV) and dolasetron mesylate (0.6 mg/kg [0.27 mg/lb], IV, q 24 h) in addition to continued administration of G-CSF, ampicillin, enrofloxacin, metronidazole, and furosemide.

    On the third day of hospitalization, the dog began eating well and remained normothermic (38.94°C [102.1°F]); however, it still had epistaxis and melena, and hemorrhage was observed at the sites where the G-CSF was injected SC. In the morning, the PCV was 24% and the total protein concentration was 5.2 g/dL; both increased throughout the day, and by evening, the PCV was 29% and the total protein concentration was 6.2 g/dL. Because the dog was eating and its heart and respiratory rates were within reference limits, a blood transfusion was not administered. Owing to evidence of continued hemorrhage, the dog was premedicated with diphenhydramine hydrochloridec (2.6 mg/kg [1.2 mg/lb], PO) and administered a second platelet concentrate transfusion (100 mL, IV).

    On the fourth day of hospitalization, the dog became hyperthermic (39.8°C [103.8°F]) and the melena and epistaxis continued. The PCV had stabilized at 27%, and the total protein concentration was 6.2 mg/dL. The medications administered were continued unchanged, and the dog was administered a third platelet concentrate transfusion (100 mL, IV).

    The dog was much less lethargic and continued to eat well on the fifth day of hospitalization. The melena persisted but was less frequent, and the epistaxis was noted only when the dog became excited. Because the anemia had worsened (PCV, 18%; total protein concentration, 6.0 g/dL), 125 mL of packed RBCs was administered IV. After the RBC transfusion, the PCV was 34% and the total protein concentration was 6.8 g/dL.

    On the seventh day of hospitalization, the dog was no longer lethargic and continued to eat well despite being hyperthermic (40.16°C [104.3°F]). The dog still had epistaxis and melena, although the frequency of each had decreased from that during the earlier stages of hospitalization. Results of a CBC revealed leukopenia (600 leukocytes/μL), neutropenia (200 neutrophils/μL), lymphopenia (400 lymphocytes/μL), monocytopenia (20 monocytes/μL), thrombocytopenia (5,000 platelets/μL), and anemia (Hct, 31.6%). Because the dog had improved clinically and peripheral venous access could no longer be achieved, it was discharged for continued treatment at home. The owner was instructed to measure the dog's rectal temperature once daily and administer enrofloxacin (10.8 mg/kg [4.9 mg/lb], PO, q 24 h), amoxicillin with clavulanic acidd (26.5 mg/kg [12.0 mg/lb], PO, q 12 h), metronidazole (13.3 mg/kg [6.0 mg/lb], PO, q 12 h), furosemidee (2 mg/kg, PO, q 12 h), and G-CSF (5 μg/kg, SC, q 12 h).

    The dog was reevaluated 3 days after discharge from the hospital. The owner reported that the dog had remained normothermic (mean temperature, 38.9°C [102°F]) and was hyporexic at home; no epistaxis or hematuria was observed, and melena, which was observed when the dog initially went home, had resolved. Physical examination revealed that the dog's temperature (39°C [102.2°F]) and heart and respiratory rates were within reference limits, and no melena was detected during rectal examination. The dog had bruises at previous SC injection sites. Results of a CBC indicated that the leukocyte (8,700 leukocytes/μL), neutrophil (7,310 neutrophils/μL), band neutrophil (260 band neutrophils/μL), and monocyte (260 monocytes/μL) counts were all within their respective reference limits, despite persistent lymphopenia (870 lymphocytes/μL), thrombocytopenia (14,000 platelets/μL), and anemia (PCV, 36.7%; total protein concentration, 7.5 g/dL). Abnormalities detected on serum biochemical analysis included hypoalbuminemia (2.7 g/dL), hyperglobulinemia (4.4 g/dL), and high alkaline phosphatase activity (408 U/L, reference interval, 15 to 164 U/L). Administration of enrofloxacin was discontinued at this time.

    On the seventh day after discharge from the hospital, the owner reported that the dog's activity and appetite had returned to levels similar to those prior to the intoxication. The bruises that were detected during the previous examination were resolving, and the grade 3 of 6 heart murmur that was detected during the initial physical examination was no longer present. Findings of a CBC included leukocytosis (38,100 leukocytes/μL), neutrophilia (35,811 neutrophils/μL) with a left shift (760 band neutrophils/μL), thrombocytopenia (29,000 platelets/μL), and regenerative anemia (Hct, 37.3%; reticulocyte count, 133,200 reticulocytes/μL; total protein concentration, 6.7 g/dL). Administration of amoxicillin with clavulanic acid and G-CSF was discontinued, but administration of furosemide was continued.

    During reevaluation 14 days after discharge from the hospital, the owner reported that the dog was clinically normal at home. Physical examination revealed no abnormalities, and the previously noted bruises at the injection sites had almost completely resolved. Results of a CBC revealed leukocyte (9,100 leukocytes/μL), neutrophil (7,700 neutrophils/μL), lymphocyte (730 lymphocytes/μL), and monocyte (640 monocytes/μL) counts within their respective reference limits and thrombocytopenia (66,000 platelets/μL) and anemia (Hct, 32.3%; total protein concentration, 6.4 g/dL). Results of a CBC performed 24 days after discharge from the hospital indicated that all cell counts were within their respective reference limits except for the platelet count, which was slightly low (135,000 platelets/μL).

    The dog was examined for the final time 34 days after discharge from the hospital. The owner reported that the dog was clinically normal, and physical examination findings were unremarkable. Results of a CBC revealed that the leukocyte (7,000 leukocytes/μL), neutrophil (5,740 neutrophils/μL), lymphocyte (840 lymphocytes/μL), monocyte (280 monocytes/μL), and platelet (211,000 platelets/μL) counts and Hct (49.9%) were within their respective reference limits. Results of a serum biochemical analysis were all within reference limits except for the presence of mild hyperglycemia (122 mg/dL). Urinalysis revealed a urine specific gravity of 1.029 and inactive sediment.