CHEQUE® DROPSCIIPharmacia & UpjohnEstrous PreventiveMibolerone dropsNADA No.: 102-709Active Ingredient(s): Each mL contains 100 mcg mibolerone and propylene glycol, qs.Indications: CHEQUE® (mibolerone) Drops are administered orally for estrous (heat)prevention in adult female dogs not intended primarily for breeding purposes. CHEQUE®Drops dosage should be discontinued after 24 months of use.CHEQUE® Drops are effective in preventing estrus only when drug administration is initiated30 days prior to the start of the proestrus. It should not be used in an attempt to abbreviate anestrous period. It should not be used in bitches prior to the first estrous period.Pharmacology: CHEQUE® (mibolerone) Drops are 17-b-hydroxy-7a,17-dimethyl-estr-4-en-3-one, generic name mibolerone, a non-progestational steroid. In its pureform, mibolerone is a white crystalline solid. The compound is stable under ordinary conditionsand temperatures.Actions: More than 90 percent of normal, mature cycling bitches did not exhibit estrus whenadministered CHEQUE® (mibolerone) Drops in adequate doses.Mibolerone has been shown to be an anabolic and androgenic steroid in rats. When comparedto methyltestosterone, it is 41 times more potent as an anabolic agent and 16 times more potentas an androgen. Mibolerone has no estrogenic activity in mice when used at levels up to 1.0mg per animal per day. It is antiestrogenic in mice in intravaginal tests at 0.9 mcg and insubcutaneous tests at 10 mcg or less when tested against estradiol.In the bitch, mibolerone has androgenic, anabolic and antigonadotrophic activity. Miboleroneselectively blocks the luteinizing hormone (LH) peak thereby preventing estrual activity. Nosignificant progestational nor estrogenic activity has been demonstrated in the canine.Metabolism: Based on tritium labeled studies in the bitch, approximately equal quantities ofmibolerone were excreted via the urine and feces. Mibolerone was extensively metabolized,being excreted as over 10 metabolites. Mibolerone was present in most tissues with highestconcentrations being in the liver, anal glands and reproductive organs. Significant levels ofradioactivity occurred along the digestive tract.Canine Efficacy: Mibolerone dosage for estrous prevention was evaluated in 13 breeds ofpurebred dogs in kennels. It was also field tested in a substantial number of bitches. Based onkennel trials and in home evaluations for various periods of time, more than 90 percent ofnormal, mature cycling bitches did not exhibit estrus when administered CHEQUE®(mibolerone) Drops in adequate dosage.Drug Interaction: The following classes of drugs have been administered concurrently duringmibolerone therapy without apparent problems being observed: general and local anesthetics,analgesic/antipyretics, anthelmintics-parasitacides, antibacterials-fungicides, corticosteroids andbiologicals. However, dogs administered pharmaceuticals or biologicals concurrent with
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CHEQUE® (mibolerone) Drops should be carefully monitored for possible interactions.Data from a well controlled study support the concurrent uses of mibolerone andstyrylpyridinium chloride-diethylcarbamazine citrate when the latter is used for prevention ofheart worm infections. Concurrent therapy of the pharmaceuticals altered neither the efficacynor safety of mibolerone or of styrylpyridinium chloride-diethylcarbamazine citrate.Seizure activity has been reported in a previously controlled epileptic patient whilesimultaneously receiving mibolerone and diphenylhydantoin.Dosage and Administration: CHEQUE® (mibolerone) Drops dosage is as follows(administer orally once each day by adding to a small amount of food or directly to the mouth):Weight of Bitch (lbs)CHEQUE® Drops Daily DosagemLmcg1 to 250.33026 to 500.66051 to 1001.2120101 and over1.8180German Shepherd Dog or German ShepherdMix (All Weights)1.8180CHEQUE® Drops Dispensed(Bottle Size)Approximate Days of Treatment for Different Dose LevelsDaily Dose (mL).3.61.21.855.0 mL180904530Contraindication(s): CHEQUE® (mibolerone) Drops should not be used in a pregnant bitchor female dogs with perianal adenoma, perianal adenocarcinoma, or other androgen dependentneoplastic conditions. CHEQUE® should not be administered to any animal with a prior historyof liver or kidney disease.Not for use in Bedlington Terriers. A genetic defect (chronic progressive hepatitis) has beenreported to occur in a high percentage of animals of this breed. Thus, irrespective of theexistence or absence of liver disease in a given animal, every Bedlington Terrier should be
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regarded as an animal with such a prior history.Precaution(s): Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].Caution(s): Federal (USA) law restricts this drug to use by or on the order of a licensedveterinarian.Do not administer for more than 24 months. CHEQUE® (mibolerone) Drops should beadministered only to normal, mature, nonpregnant, nonlactating bitches, as directed, and shouldnot be administered to immature bitches, male dogs, puppies or cats. CHEQUE® Drops shouldnot be administered to bitches intended primarily for breeding purposes.CHEQUE® Drops should not be administered to any animal with prior history of liver orkidney disease. Liver serum enzyme elevations may be encountered. Some androgens mayresult in jaundice in particularly sensitive animals. This effect has been observed in a fewanimals administered CHEQUE® Drops at the therapeutic level. If jaundice does occur,CHEQUE® Drops treatment should be discontinued. Periodic liver function tests arerecommended under prolonged administration. SGPT values were evaluated and appear to bean appropriate criterion for monitoring liver changes.CHEQUE® Drops should be used with caution in the younger mature bitch (approximately 7months old or less) in that steroids with androgenic activity can result in early epiphysealclosure. This effect on skeletal development has, however, not been observed with miboleronetreatment. Some immature bitches are especially responsive to the androgenicity ofCHEQUE® Drops with marked clitoral enlargement and low grade vaginitis resulting fromprolonged therapy. Topical antibiotic-corticosteroid ointments for genital application may beused if the irritation results in problem discharges. Failure to respond to topical treatmentindicates the animal is no longer a candidate for CHEQUE® Drops. CHEQUE® Drops shouldbe used with caution in animals with chronic epiphora or other conditions involving the lacrimalapparatus. Testing in Miniature and Toy Poodles has, however, not resulted in detectableaggravation of existing epiphora.If CHEQUE® Drops dosage is started and then the bitch comes into estrus, CHEQUE®Drops may be continued but caution should be taken to prevent breeding. If breeding occurs,CHEQUE® Drops dosage should be stopped until such time as the bitch is determined not tobe pregnant. CHEQUE® Drops should not be used concurrently with or following use of anyprogestational or estrogenic compound until potential clinical abnormalities associated with useof those compounds are eliminated.For use in animals only.Warning(s): Not for human use. One study in humans indicated a potential altered liverfunction that resulted in termination of the study.Toxicology: Beagles treated orally for 28 days with mibolerone at a level of 300 mcg/kg hadno drug related alterations in hematology or blood chemistry and no toxic symptoms wereobserved.In a subsequent test, mibolerone was administered orally to Beagles at the rate of 3,000 to30,000 mcg/kg daily for 28 days. Clinical chemistry, hematology, urinalysis, including urineconcentration test, gross pathology and histopathology showed no drug related toxic effects.The only drug related effects included a reduction of the stainable lipid in the adrenal cortices,enlargement of the clitoris, thickening of the myometrium and endometrium, and inhibition ofspermatogenesis (3,000 mcg/kg level). All treated dogs had periodic episodes of epiphora.There was an apparent drug related increase in renal, uterine, and prostatic weights and adecrease in the ovarian, testicular and thymic weights.
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Beagles, male and female, have been treated with levels of mibolerone of up to 500 mcg perday for 240 days and 200 mcg per day for up to 730 days. The incidence of vaginal irritationand clitoral enlargement was more pronounced in the immature than mature bitch. Othereffects included: (1) blockage of tertiary but not primary or secondary follicular development,(2) maintenance of prepubertal ovarian and uterine-cervical weights in the immature treatedbitches, (3) a slight decrease in adrenal weights without evidence of altered morphology orfunction, (4) an increase in kidney weight without evidence of altered morphology or function,(5) a decrease in prostate weight in high dose immature dogs. Treated males and females hadslight increases in mean SGOT (serum glutamic oxalacetic transaminase, or aspartatetransaminase) and SGPT (serum glutamic pyruvic transaminase or alanine transaminase)without evidence of hepatocellular damage (based on light microscopy) or alteration of hepaticfunction (based on BSP retention and clinical chemistry).After terminating mibolerone treatment, Beagle bitches returned to cyclic estrous activity assoon as 7 days after last treatment with the longest interval being somewhat over 200 days. Ina study involving 96 bitches bred starting their first estrus after the end of miboleronetreatment, bitches had a normal pregnancy and delivery and had normal pups. Miboleronebitches had a lower conception rate for all breedings compared to untreated bitches (76% vs100%). However, percent mibolerone treated bitches whelping of those conceiving (97%) wassimilar to untreated bitches (90%).Weaned Beagle puppies (7-15 weeks of age, averaging 5.36 kg in weight) were treated dailywith levels of mibolerone up to 200,000 mcg per day for 30 days. During the fourth week oftreatment, the animals receiving 200,000 mcg per day showed excessive lacrimation,depression, anorexia, weight loss and myalgia. No gross lesions occurred at necropsy. Anexpected dose related uterotropic response occurred as well as marked increase in prostateweight. A dose related decrease occurred in adrenal weight at 4,000 and 200,000mcg/animal/day. Histologically there was a slight fatty change in the livers of 3 of 4 femalesreceiving 200,000 mcg per day.Mibolerone was administered six times a week for up to 9.6 years (average of 6.1 years) tobitches of seven breeds of dogs. The average age of all dogs at time of their termination was9.7 years. Sixty-three bitches served as nontreated controls, 103 bitches received 30 to 180mcg mibolerone per day to approximate the efficacious dose, and 61 bitches were given 90 to900 mcg mibolerone per day as an exaggerated dose. Study bitches were evaluated withphysical examinations, hematology, and clinical chemistry. Tissues of dogs which died duringthe study and those of dogs killed at study termination were evaluated histopathologically. Dogswere tested also for changes in peripheral circulation concentrations of both cortisol inresponse to ACTH and triiodothyronine and thyroxin to TSH.Chronic oral administration of mibolerone was associated with an increased incidence ofchronic liver disease with controls, 1X, and the exaggerated dose groups showing 57, 91, and93 percent of the dogs with diseased livers, respectively. Drug administration was alsoassociated with cirrhosis with controls, 1X, and exaggerated dose groups having 4, 10, and 28percent of the dogs with cirrhosis, respectively. An increased prevalence of hepatocellularintranuclear crystalline inclusion bodies was found in many treated bitches.Treatment related reproductive tract lesions included ovarian arterial mineralization,endometrial atrophy, endometrial cysts, endocervical cysts, vaginal mucosal atrophy,invaginations and cysts of the vaginal mucosa, vaginitis, clitoral ossification and clitoritis at theefficacious and exaggerated doses. A 10% incidence of ovarian fibroma was found in bitchesgiven the approximate efficacious dose only; an increased incidence of ovarian follicular cystswas found in bitches given the exaggerated dose.Chronic mibolerone exposure was also associated with decreased numbers of corpora lutea
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and vaginal fibromas at the efficacious and exaggerated doses.Treatment related findings from other organs included increased incidences of mineraldeposition in the kidneys, adrenal cortical lipidosis and a reduction in the incidence of mammaryneoplasms and total neoplasms, all at the efficacious and exaggerated doses.The Beagle, but not the other six breeds, appeared to have a reduced response to ACTHchallenge. Epiphora appeared to be mibolerone related in Toy Poodles and Beagles.The therapeutic dose of mibolerone kept females out of heat and did not elicit side effects orclinical health problems that would prevent the animal from being a functional pet. The dogsfed mibolerone at exaggerated doses were not compromised as judged by their fitness to be afunctional pet, based on clinical evaluations.Adult bitches of mixed breeding receiving 60 mcg of mibolerone daily for up to 1,574 daysshowed no signs of toxicity. A drug related increase in clitoral size occurred but it was notdeemed to be objectionable.Adult Beagle bitches were started on mibolerone treatment orally at 20 or 60 mcg per animalper day starting 1, 3 or 6 days after the first two breedings and were continued on treatmentuntil weaning. Conception and implantation were not prevented in bitches started on treatmentafter breeding. Gestation, parturition, and lactation were normal in all bitches. Female pupsfrom the animals receiving mibolerone were masculinized. No other lesions were observed.One study indicated liver tissue changes such as cellular swelling, obliterations of sinusoids,vascular degeneration, leukocyte infiltration and fibrosis.The acute oral LD50 in the rat is greater than 1,600,000 mcg/kg while the intraperitoneal LD50in the mouse is 555,600 mcg/kg.Mibolerone has been well tolerated in rats at levels of 3,000 or 10,000 or 30,000 mcg/kg orallyfor up to 28 days. Changes observed included hypertrophy of the myometrium, reduction of theamount of stainable lipid in all three zones of the adrenal cortices, arrest of spermatogenesisand atrophy of the accessory sex gland of male rats at 3,000 and 10,000 mcg/kg. Treatedanimals ate less than the controls and required more food per unit of body weight gain.The dose of mibolerone was increased at equal increments weekly from 600 mcg/kg the firstweek to 4,800 mcg/kg the fourth week in rats. A reduction in food consumption and areduction in weight gain were noted. Treated males had a leukocytosis. No other toxic effectsor changes in hemotology or in gross or microscopic pathology were observed in either malesor females. Rats exposed under dynamic conditions for one hour to a dust aerosol ofmibolerone at a concentration of 5.03 mg/liter of air did not have any signs of toxicity duringexposure or during a 14 day post treatment observation period.Ointment containing mibolerone at a concentration of 0.25% was applied to abraded andunabraded rabbit skin daily for five days. The ointment was slightly irritating to the unabradedskin of the abdomen while it was not irritating to abraded skin.Side Effects: Some animals, particularly immature females, have shown increased sensitivityto mibolerone. This sensitivity has been expressed by clitoral enlargement and white visciddischarge consisting of leukocytes originating from the clitoral fossa. If irritation of the vaginalvestibule persists some bitches may develop mounting behavior. Occasional bitches have had amusky body odor.In clinical evaluation of CHEQUE® (mibolerone) Drops the following side effects have beenattributed to CHEQUE® at estrus inhibiting doses (listed as a % of total clinical cases
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reporting): Clitoral enlargement (20%); vaginal discharge (10%); riding behavior (1.6%);epiphora (5.6%), objectionable body odor (4.3%). Percent of all reported side effects was45.4. A common finding after prolonged dosage was the presence of small (<1mm diameter)vesicles on the vaginal mucosa posterior to the urethral orifice. The clinical significance ofthese vesicles has not been determined.Since the market introduction of CHEQUE® Drops, certain clinical signs have been reportedas being associated with dogs receiving the drug. The actual role of mibolerone in theelicitation of those signs has not in all cases been determined. In decreasing order offrequency, they are:1. Expression of estrus - generally due to failure to receive proper dose.2. Vaginal/uterine discharge - may lead to diagnostic problems; e.g. mimic heat, confusediagnosis of uterine disease.3. Mating - may occur during estrus break or false estrus due to genital discharge.4. Hepatic dysfunction as evidenced by jaundice, hepatomegaly, cirrhosis, and occasionaldeaths has been reported.5. Increased aggressiveness - a recognizable side effect of androgenic substances.Presentation: CHEQUE® (mibolerone) Drops are available in a bottle of 55 mL fill withgraduated dropper.Disclaimer: Every effort has been made to ensure the accuracy of the information published. However, itremains the responsibility of thereaders to familiarize themselves with the product information contained on the product label or packageinsert. Compendium Code No.:04151777
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