Four cats/sex/group in the 1.1 and 3.2 mg/kg groups were dosed topically to the inner pinna of the ear, alternating between right and left ears. Eight cats/sex/group in the 0 and 5.3 mg/kg groups were dosed topically to the inner pinna of the ear, splitting the dose between both ears. Four cats/sex/group in the 0 and 5.3 mg/kg groups were maintained and monitored during a 4-week recovery period.
6 Week Dosing Period
Application of mirtazapine and vehicle control was associated with ear flicking, head shaking, pulling away/flinching and infrequently with struggling/fractious behavior, and hypersalivation. Inner and outer pinna erythema, flaking, alopecia, and thickening were observed in all cats in all groups. Erythema, crusting, alopecia, and scabbing of the skin, mostly around the head and neck, was frequently observed in all groups and occasionally affected the tail, tarsi or carpi, likely due to spread of the ointment to these areas by self-grooming.
Mirtazapine administration resulted in increased vocalization, hyperactivity, attention-seeking behaviors, and tremors in all mirtazapine dose groups. Frank blood in the stool was infrequently observed in the vehicle control, 3.2, and 5.3 mg/kg groups. Polyuria was observed in all groups. Polydipsia was observed in one cat in the 5.3 mg/kg group. Three cats (one from each mirtazapine dose group) were isosthenuric. Eight cats developed cystitis with or without urethral obstruction throughout the study in all groups. One cat each from the vehicle control and 3.2 mg/kg group were euthanized early on Day 35 due to urethral obstruction.
Two cats from the 1.1 mg/kg group had either ventricular premature contractions (VPC) or tall R waves, and one cat from the 5.3 mg/kg group had both VPC and a right axis deviation.
Eosinophilia was noted sporadically in the vehicle control, 1.1, and 5.3 mg/kg groups. Mild elevations in ALT values were noted sporadically in vehicle control, 3.2, and 5.3 mg/kg groups. On Day 15, one cat in the 3.2 mg/kg group demonstrated a marked ALT elevation of 3397 U/L, with concurrent elevations in AST and GGT. By Day 42, the ALT declined to 109 U/L and the AST and GGT returned to within normal limits.
Gross pathology findings, confirmed with histopathology, were hyperplastic dermatitis (alopecia, hyperkeratosis, thickening, and ceruminous gland secretion) of the pinnae in all cats and findings consistent with cystitis (mucosal urinary bladder hemorrhage, mottled-dark red appearance, and irregular contour) in four male cats (two vehicle control, one 3.2 mg/kg and one 5.3 mg/kg). Additional histopathologic findings included pyelonephritis (two vehicle control and one 5.3 mg/kg), nephrocalcinosis (three vehicle control, one 1.1 mg/kg, three 3.2 mg/kg, and one 5.3 mg/kg), necrosis of the kidneys (one vehicle control and one 3.2 mg/kg), unilateral hypoplasia of the thyroid gland (two 5.3 mg/kg), and unilateral hypertrophy of the thyroid gland (one 5.3 mg/kg).
4 Week Recovery Period
Following a 4-week recovery period, ALT elevations resolved. Polyuria was reduced and only occurred in two cats in the 5.3 mg/kg group. Pinnal lesions (erythema and flaking) completely resolved in the vehicle control and improved in the 5.3 mg/kg groups. Ear thickening improved in both groups.
Pilot Safety Studies:
In six pilot studies (five laboratory and one clinical study) utilizing the final market formulation of Mirataz™, and one laboratory study that utilized non-final market formulation, a total of 76 cats were administered mirtazapine. Five studies administered mirtazapine ointment topically (0.5-5.3 mg/kg), one study administered mirtazapine topically and orally (0.5 mg/kg), and one study administered mirtazapine orally (10.6 mg/cat).
The most common observations were ear pinnae reactions (erythema with or without blood and flaking), mild behavioral observations (vocalization and tremors), vomiting, and diarrhea.
One study reported six cats with blood in the stool. Two studies reported one cat each showing aggression. One study reported polyuria in one cat; another study reported stranguria and possible urinary tract infection in one cat. Two studies reported cardiac abnormalities, including sinus tachycardia not present at baseline, development of a grade 3/6 heart murmur, tall QRS complexes, and left or right axis deviation. One study reported one cat with ataxia. In the studies that administered mirtazapine orally, salivation and lip licking were frequently observed.
In the terminal study administering 5.3 mg/kg mirtazapine topically, histopathology showed chronic hyperplastic dermatitis at the application site.
Store below 25°C (77°F). Multi-use tube. Discard within 30 days of first use.
Mirataz™ is supplied in a 5 gram aluminum tube.
1. Laimer, M., Kramer-Reinstadler, K., Rauchenzauner, M., Lechner-Schoner, T., Strauss, R., Engl, J., & Ebenbichler, C. F. (2006). Effect of mirtazapine treatment on body composition and metabolism. The Journal of clinical psychiatry, 67(3), 421-424.
2. Kraus, T., Haack, M., Schuld, A., Hinze-Selch, D., Koethe, D., & Pollmächer, T. (2002). Body weight, the tumor necrosis factor system, and leptin production during treatment with mirtazapine or venlafaxine. Pharmacopsychiatry, 35(06), 220-225.
3. Fernstrom, M. H. (1995). Drugs that cause weight gain. Obesity research, 3(S4), 435S-439S.
NADA 141-481, Approved by FDA
REG-007 Rev. 11/17
Kindred Biosciences, Inc.
1555 Bayshore Highway, suite 200
Burlingame, CA 94010
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Mirataz™ is a trademark of Kindred Biosciences, Inc.
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