Equine & Livestock

Altren ® (altrenogest) SOLUTION 0.22% (2.2 mg/mL) CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian. DESCRIPTION: Altren ® (altrenogest) Solution 0.22% contains the active synthetic progestin, altrenogest. The chemical name is 17α-allyl-17β- hydroxyestra-4,9,11-trien-3-one. The CAS Registry Number is 850-52-2. The chemical structure is: Each mL of Altren ® (altrenogest) Solution 0.22% contains 2.2 mg of altrenogest in an oil solution. ACTIONS: Altren ® (altrenogest) Solution 0.22% produces a progestational effect in mares. INDICATIONS: Altren ® (altrenogest) Solution 0.22% is indicated to suppress estrus in mares. Suppression of estrus allows for a predictable occurrence of estrus following drug withdrawal. This facilitates the attainment of regular cyclicity during the transition from winter anestrus to the physiological breeding season. Suppression of estrus will also facilitate management of prolonged estrus conditions. Suppression of estrus may be used to facilitate scheduled breeding during the physiological breeding season. CONTRAINDICATIONS: Altren ® (altrenogest) Solution 0.22% is contraindicated for use in mares having a previous or current history of uterine inflammation (i.e., acute, subacute, or chronic endometritis). Natural or synthetic gestagen therapy may exacerbate existing low-grade or "smoldering" uterine inflammation into a fulminating uterine infection in some instances. PRECAUTIONS: Various synthetic progestins, including altrenogest, when administered to rats during the embryogenic stage of pregnancy at doses manyfold greater than the recommended equine dose caused fetal anomalies, specifically masculinization of the female genitalia. DOSAGE AND DIRECTIONS: While wearing protective gloves, remove shipping cap and seal; replace with enclosed plastic dispensing cap. Remove cover from bottle dispensing tip and connect luer lock syringe (without needle). Draw out appropriate volume of Altren ® solution. (Note: Do not remove syringe while bottle is inverted as spillage may result.) Detach syringe and administer solution orally at the rate of 1 mL per 110 pounds of body weight (0.044 mg/kg) once daily for 15 consecutive days. Administer solution directly on the base of the mare's tongue or on the mare's usual grain ration. Replace cover on bottle dispensing tip to prevent leakage. Excessive use of a syringe may cause the syringe to stick; therefore, replace syringe as necessary. DOSAGE CHART: Approximate Weight Dose in Pounds in mL 770 7 880 8 990 9 1100 10 1210 11 1320 12 WHICH MARES WILL RESPOND TO ALTREN ® (altrenogest) SOLUTION 0.22%: Extensive clinical trials have demonstrated that estrus will be suppressed in approximately 95% of the mares within three days; however, the post-treatment response depended on the level of ovarian activity when treatment was initiated. Estrus in mares exhibiting regular estrus cycles during the breeding season will be suppressed during treatment; these mares return to estrus four to five days following treatment and continue to cycle normally. Mares in winter anestrus with small follicles continued in anestrus and failed to exhibit normal estrus following withdrawal. Response in mares in the transition phase between winter anestrus and the summer breeding season depended on the degree of follicular activity. Mares with inactive ovaries and small follicles failed to respond with normal cycles post-treatment, whereas a higher proportion of mares with ovarian follicles 20 mm or greater in diameter exhibited normal estrus cycles post-treatment. Altrenogest Solution 0.22% was very effective for suppressing the prolonged estrus behavior frequently observed in mares during the transition period (February, March and April). In addition, a high proportion of these mares responded with regular estrus cycles post-treatment. SPECIFIC USES FOR ALTREN ® (altrenogest) SOLUTION 0.22%: SUPPRESSION OF ESTRUS TO: 1. Facilitate attainment of regular cycles during the transition period from winter anestrus to the physiological breeding season. To facilitate attainment of regular cycles during the transition phase, mares should be examined to determine the degree of ovarian activity. Estrus in mares with inactive ovaries (no follicles greater than 20 mm in diameter) will be suppressed but these mares may not begin regular cycles following treatment. However, mares with active ovaries (follicles greater than 20 mm in diameter) frequently respond with regular post-treatment estrus cycles. 2. Facilitate management of the mare exhibiting prolonged estrus during the transition period. Estrus will be suppressed in mares exhibiting prolonged behavioral estrus either early or late during the transition period. Again, the post-treatment response depends on the level of ovarian activity. The mares with greater ovarian activity initiate regular cycles and conceive sooner than the inactive mares. Altren ® (altrenogest) Solution 0.22% may be administered early in the transition period to suppress estrus in mares with inactive ovaries to aid in the management of these mares or to mares later in the transition period with active ovaries to prepare and schedule the mare for breeding. 3. Permit scheduled breeding of mares during the physiological breeding season. To permit scheduled breeding, mares which are regularly cycling or which have active ovarian function should be given Altren ® (altrenogest) Solution 0.22% daily for 15 consecutive days beginning 20 days before the date of the planned estrus. Ovulation will occur 5 to 7 days following the onset of estrus as expected for non-treated mares. Breeding should follow usual procedures for mares in estrus. Mares may be regulated and scheduled either individually or in groups. ADDITIONAL INFORMATION: A 3-year well controlled reproductive safety study was conducted in 27 pregnant mares, and compared with 24 untreated control mares. Treated mares received 2 mL altrenogest solution 0.22%/110 lb body weight (2x dosage recommended for estrus suppression) from day 20 to day 325 of gestation. This study provided the following data: 1. In filly offspring (all ages) of treated mares, clitoral size was increased. 2. Filly offspring from treated mares had shorter interval from Feb. 1 to first ovulation than fillies from their untreated mare counterparts. 3. There were no significant differences in reproductive performance between treated and untreated animals (mares & their respective offspring) measuring the following parameters: • interval from Feb. 1 to first ovulation, in mares only. • mean interovulatory interval from first to second cycle and second to third cycle, mares only. • follicle size, mares only. • at 50 days gestation, pregnancy rate in treated mares was 81.8% (9/11) and untreated mares was 100% (4/4). • after 3 cycles, 11/12 treated mares were pregnant (91.7%) and 4/4 untreated mares were pregnant (100%). • colt offspring of treated and control mares reached puberty at approximately the same age (82 & 84 weeks respectively). • stallion offspring from treated and control mares showed no differences in seminal volume, spermatozoal concentration, spermatozoal motility, and total sperm per ejaculate. • stallion offspring from treated and control mares showed no difference in sexual behavior. • testicular characteristics (scrotal width, testis weight, paren- chymal weight, epididymal weight and height, testicular height, width & length) were the same between stallion offspring of treated and control mares. REFERENCES: Shoemaker, C.F., E.L. Squires, and R.K. Shideler, 1989. Safety of Altrenogest in Pregnant Mares and on Health and Development of Offspring. Eq. Vet. Sci. (9); No. 2: 69–72. Squires, E.L., R.K. Shideler, and A.O. McKinnon. 1989. Reproductive Performance of Offspring from Mares Administered Altrenogest During Gestation. Eq. Vet. Sci. (9); No. 2: 73–76. WARNING: For oral use in horses only. Keep this and all other medications out of the reach of children. Do not use in horses intended for human consumption. HUMAN WARNINGS: Skin contact must be avoided as Altren ® (altrenogest) Solution 0.22% is readily absorbed through unbroken skin. Protective gloves must be worn by all persons handling this product. Preg- nant women or women who suspect they are pregnant should not handle Altren ® (altrenogest) Solution 0.22%. Women of child bearing age should exercise extreme caution when handling this product. Accidental absorption could lead to a disruption of the menstrual cycle or prolongation of pregnancy. Direct contact with the skin should therefore be avoided. Accidental spillage on the skin should be washed off immediately with soap and water. INFORMATION FOR HANDLERS: WARNING: Altren ® (altrenogest) Solution 0.22% is readily absorbed by the skin. Skin contact must be avoided; protective gloves must be worn when handling this product. Effects of Overexposure There has been no human use of this specific product. The information contained in this section is extrapolated from data available on other products of the same pharmacological class that have been used in humans. Effects anticipated are due to the progestational activity of altrenogest. Acute effects after a single exposure are possible; however, continued daily exposure has the potential for more untoward effects such as disruption of the menstrual cycle, uterine or abdominal cramping, increased or decreased uterine bleeding, prolongation of pregnancy and headaches. The oil base may also cause complications if swallowed. In addition, the list of people who should not handle this product (see below) is based upon the known effects of progestins used in humans on a chronic basis. PEOPLE WHO SHOULD NOT HANDLE THIS PRODUCT: 1. Women who are or suspect they are pregnant. 2. Anyone with thrombophlebitis or thromboembolic disorders or with a history of these events. 3. Anyone with cerebral-vascular or coronary-artery disease. 4. Women with known or suspected carcinoma of the breast. 5. People with known or suspected estrogen-dependent neoplasia. 6. Women with undiagnosed vaginal bleeding. 7. People with benign or malignant tumors which developed during the use of oral contraceptives or other estrogen-containing products. 8. Anyone with liver dysfunction or disease. Accidental Exposure Altrenogest is readily absorbed from contact with the skin. In addition, this oil based product can penetrate porous gloves. Altrenogest should not penetrate intact rubber or impervious gloves; however, if there is leakage (i.e., pinhole, spillage, etc.), the contaminated area covered by such occlusive materials may have increased absorption. The following measures are recommended in case of accidental exposure. Skin Exposure: Wash immediately with soap and water. Eye Exposure: Immediately flush with plenty of water for 15 minutes. Get medical attention. If Swallowed: Do not induce vomiting. Altren ® (altrenogest) Solution 0.22% contains an oil. Call a physician. Vomiting should be supervised by a physician because of possible pulmonary damage via aspiration of the oil base. If possible, bring the container and labeling to the physician. Store at or below 25° C (77° F). Reclose tightly. HOW SUPPLIED: Altren ® (altrenogest) Solution 0.22% (2.2 mg/mL). Each mL contains 2.2 mg altrenogest in an oil solution. Available in 1000 mL and 150 mL plastic bottles. Manufactured by: Aurora Pharmaceutical, Inc. Northfield, Minnesota 55057 Approved by FDA under ANADA # 200-620 04/2019 EQUISUL - SDT ® (Sulfadiazine/Trimethoprim) Oral Suspension For use in horses only. Approved by FDA under NADA # 141-360 CAUTION Federal law (USA) restricts this drug to use by or on the order of a licensed veterinarian. DESCRIPTION EQUISUL-SDT is a broad-spectrum antimicrobial from the potentiated sulfonamide class of chemotherapeutic agents. These two drugs block different sequential steps in the biosynthesis of nucleic acids. Sulfadi- azine inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid. Trimethoprim blocks the production of tetrahy- drofolic acid from dihydrofolic acid by reversibly inhibiting dihydrofolate reductase. The effect of the dual action is to reduce the minimum inhibitory concentration of each agent (synergism) and to convert a bacteriostatic action to a bactericidal action. Sulfadiazine is the non-proprietary name for 4-amino-N-2-pyrimidinylbenzenesulfonamide. Trimethoprim is the non-proprietary name for 5-[(3,4,5¬trimethoxyphe- nyl)methyl]-2,4-pyrimidinediamine. Figure 1. Structure of sulfadiazine Figure 2. Structure of trimethoprim Each mL of EQUISUL-SDT contains 400 mg combined active ingredients (333 mg sulfadiazine and 67 mg trimethoprim) in an aqueous suspension. INDICATION EQUISUL-SDT is indicated for the treatment of lower respiratory tract infections in horses caused by susceptible strains of Streptococcus equi subsp. zooepidemicus. DOSAGE AND ADMINISTRATION Shake well before use. Administer EQUISUL-SDT orally at the dosage of 24 mg combined active ingredients per kilogram body weight (10.9 mg/lb) twice daily for 10 days. EQUISUL-SDT can be administered by volume at 2.7 mL per 45.4 kg (2.7 mL/100 lb) body weight. CONTRAINDICATIONS EQUISUL-SDT is contraindicated in horses with a known allergy to sulfadiazine, sulfonamide class antimicrobials, or trimethoprim. WARNING Do not use in horses intended for human consumption. HUMAN WARNINGS Not for use in humans. For use in animals only. Keep this and all drugs out of the reach of children. Consult a physician in the case of accidental human exposure. Antimicrobial drugs, including sulfonamides, can cause mild to severe allergic reactions in some individuals. Avoid direct contact of the product with the skin, eyes, mouth, and clothing. Persons with a known sensitivity to sulfonamides or trimethoprim should avoid exposure to this product. If an allergic reaction occurs (e.g., skin rash, hives, difficulty breathing, facial swelling) seek medical attention. PRECAUTIONS Prescribing antibacterial drugs in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to treated animals and may increase the risk of development of drug-resistant animal pathogens. The administration of antimicrobials, including sulfadiazine and trimethoprim, to horses under conditions of stress may be associated with acute diarrhea that can be fatal. If acute diarrhea or persistent changes in fecal consistency are observed, additional doses of EQUISUL-SDT should not be administered and appropriate therapy should be initiated. The safe use of EQUISUL-SDT has not been evaluated in breeding, pregnant, or lactating horses. Potentiated sulfonamides should only be used in pregnant or lactating mares when the benefits to the mare justify the risks to the fetus. Use of potentiated sulfonamides during pregnancy has been associated with an increased risk of congenital abnormalities that may be related to folate deficiency. In humans, sulfonamides pass through the placenta, are excreted in milk, and may cause hyperbilirubinemia-induced neurotoxicity in nursing neonates. Decreased hematopoetic activity and blood dyscrasias have been associated with the use of elevated doses and/or prolonged administration of potentiated sulfonamides. EQUISUL-SDT should be discontinued if prolonged clotting times, or decreased platelet, white blood cell or red blood cell counts are observed. Sulfonamides should be used with caution in horses with impaired hepatic function. Although rare, sulfonamide use has been associated with fulminant hepatic necrosis in humans. Neurologic abnormalities have been reported in several species follow- ing administration of potentiated sulfonamides. In horses, potentiated sulfonamides have been associated with gait alterations and behavior changes that resolved after discontinuation of the drug. The safe use of EQUISUL-SDT has not been evaluated in horses less than 1 year of age. ADVERSE REACTIONS Adverse reactions reported during a field study of 270 horses of various breeds, ranging from 1 to 25 years of age, which had been treated with either EQUISUL-SDT (n = 182) or with a saline control (n = 88) are summarized in Table 1. At least one episode of loose stool of varying severity was observed in 69 of 182 (38%) of the EQUISUL-SDT-treated horses, and 29 of 88 (33%) saline control horses. Of those animals experiencing loose stool, 2 of 182 (1.1%) of the EQUISUL-SDT-treated horses and 0 of 88 (0%) placebo-treated horses were removed from the study due to diarrhea (defined as at least one episode of watery stool). Both cases of diarrhea in this study were self-limiting and resolved without treatment within 5–10 days after discontinuation of EQUISUL-SDT. Table 1. Number of Horses with Adverse Reactions During the Field Study with EQUISUL-SDT Adverse Reactions Equisul-SDT (n=182) Saline control (n=88) Loose stool (including diarrhea) 69 (38%) 29 (33%) Colic 3 (1.6%) 2 (2.2%) Diarrhea 2 (1.1%) 0 (0%) To report suspected adverse events, for technical assistance or to obtain a copy of the SDS, contact Aurora Pharmaceutical, Inc. at 888-215-1256 or www.aurorapharmaceutical.com. For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at www.fda.gov/ reportanimalae. CLINICAL PHARMACOLOGY Following oral administration, EQUISUL-SDT is rapidly absorbed and widely distributed throughout body tissues. Sulfadiazine levels are usual- ly highest in the kidney, while the tissue concentration in other tissues is only slightly lower than plasma concentrations. Concentrations of trimethoprim are usually higher in the lungs, kidney, and liver than in the blood. Sulfadiazine and trimethoprim are both eliminated primarily by renal excretion, both by glomerular filtration and tubular secretion. Urine concentrations of both sulfadiazine and trimethoprim are several-fold higher than blood concentrations. 1 Sulfadiazine and trimethoprim are 20% and 35% bound to plasma protein, respectively. Administration of sulfadi- azine and trimethoprim with food has no apparent effect on the absorption of sulfadiazine but the absorption of trimethoprim is decreased. Based on a study in fed horses, trimethoprim concentrations following repeat oral administration of 24 mg/kg EQUISUL-SDT to 6 horses reached peak concentration in 0.5 to 12.0 hours. The median plasma elimination half-life was 3 hours, with a range of 2.31 to 4.96 hours. Peak sulfadiazine concentrations were reached within 1.0 to 12.0 hours in the same study. The median plasma elimination half-life for sulfadiazine was approximately 7.80 hours, with a range of 6.78 to 10.39 hours. Only minor accumulation of both drugs was observed following repeat oral administration of EQUISUL-SDT and both drugs reached steady state by day 3. Sulfadiazine and trimethoprim key steady state parameters associated with administration in 6 fed horses over a period of 7 days are found in Table 2. Table 2. Median (Range) of sulfadiazine and trimethoprim pharmacokinetics parameters following repeat dosing of 24 mg/kg bid EQUISUL-SDT for 7 days to six horses in fed condition Drug Sulfadiazine Trimethoprim Tmax (hr) 4.75 (1.00–12.00) 8.50 (0.50–12.00) Cmax (µg/mL) 17.63 (10.10–31.15) 0.78 (0.60–1.14) AUC 0–12 (last dose) (hr*µg/mL) 159.35 (73.90–282.54) 5.47 (3.31–10.91) T 1/2 (hr) 7.80 (6.78–10.39) 3.00 (2.31–4.96) MICROBIOLOGY EQUISUL-SDT is the combination of the sulfonamide sulfadiazine and trimethoprim. These two drugs block sequential steps in nucleic acids biosynthesis. Sulfadiazine inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid. Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by reversibly inhibiting dihydrofolate reductase. The two drugs act syner- gistically, reducing the minimum inhibitory concentration of each, while enhancing the bacteriostatic action of each separately to a bactericidal action when combined. EQUISUL-SDT administered as a combined sulfadiazine-trimethoprim dose of 24 mg/kg body weight twice daily for 7 days provided concentrations of sulfadiazine and trimethoprim with T>MIC90 (%T) values of 100% and 98% respectively. The minimum inhibitory concen- tration (MIC) values for EQUISUL-SDT against indicated pathogens isolated from lower respiratory tract infections in horses enrolled in a 2010–2011 effectiveness field study are presented in Table 3. All MICs were determined in accordance with the Clinical and Laboratory Standards Institute (CLSI) Approved Standard M31-A3 using a broth microdilution system and 3% lysed horse blood. Table 3. Trimethoprim/sulfadiazine minimum inhibitory concentra- tion (MIC) values a of isolates recovered from horses with lower respiratory infection caused by Streptococcus equi subsp. zooep- idemicus treated with EQUISUL-SDT in the U.S. (2010–2011) Treatment Outcome Success Failure Number of Isolates 65 c 46 Time of Sample Collection Pre-Treatment Pre-Treatment MIC 50 b (µg/mL) 0.25/4.75 0.25/4.75 MIC 90 b (µg/mL) 0.25/4.75 0.25/4.75 MIC Range (µg/mL) 0.12/2.4 to 0.5/9.5 0.12/2.4 to 0.5/9.5 a The correlation between in vitro susceptibility data and clinical effectiveness is unknown. b The lowest MIC to encompass 50% and 90% of the most suscepti- ble isolates, respectively. c One isolate of S. equi subsp. zooepidemicus was not tested. EFFECTIVENESS A negative control, randomized, masked, field study evaluated the effec- tiveness of EQUISUL-SDT administered at 24 mg/kg body weight, orally, twice daily for 10 days for the treatment of lower respiratory tract infections in horses caused by Streptococcus equi subsp. zooepidemicus. In this study, a total of 182 horses were treated with EQUISUL-SDT, and 88 horses were treated with saline. One hundred seventy-three horses (112 EQUISUL-SDT and 61 saline) were included in the statistical analysis. Therapeutic success was characterized by absence of fever and no worsening of clinical signs at Day 5 and Day 10, and significant clinical im- provement or resolution of clinical signs of lower respiratory tract infection by Day 17. The observed success rates are 58.9% (66/112) and 14.8% (9/61) for the EQUISUL-SDT and saline-treated groups, respectively. Table 4 summarizes the statistical analysis results on the overall success rate. Table 4. Overall Clinical Effectiveness Results Equisul-SDT Saline P-value* Least Square Means 61% 13.1% 0.0123 * P-value and estimated success rates are based on back-transformed mean estimates from the statistical analysis. ANIMAL SAFETY In a target animal safety study, EQUISUL-SDT was administered orally to 32 healthy adult horses at 0 (0X), 24 (1X), 72 (3X), or 120 (5X mg/kg twice daily for 30 days. Loose stool was the most common abnormal observation. Observations of loose stool (pellets with liquid or unformed/ cowpile stool) occurred more often in horses treated with EQUISUL-SDT with the incidence of loose stool increasing in a dose related manner. All incidents of loose stool were self-limiting and resolved without treatment. Horses in all EQUISUL-SDT groups demonstrated statistically signifi- cantly higher mean serum creatinine concentrations, and those in the 3X and 5X groups demonstrated statistically significantly higher mean serum albumin concentrations. Statistically higher mean neutrophil counts and mean serum gamma glutamyl transferase (GGT) activity were seen in the 1X and 5X groups. Individual animal creatinine, GGT, and albumin concentrations remained within the reference range. Individual animal elevations in absolute neutrophil counts ranged up to 7.09 x 10 3 /mcL (reference range: 1.96-5.31 x 10 3 /mcL). Based upon blood concentrations obtained during the study, it was noted that the sulfadiazine and trimethoprim plasma concentrations did not increase in proportion to dose. For sulfadiazine, a 3X and 5X dose resulted in an average exposure of 2.0X and 2.6X the concentrations observed following a 1X dose. For trimethoprim, the corresponding values were 2.5X and 3.5X as compared to the 1X dose. Furthermore, marked intersubject variability, particularly with sulfadiazine, resulted in substantial overlap of individual subject blood levels across the three dosing groups. STORAGE CONDITIONS Store at 59°– 86° F (15°– 30° C). Brief periods up to 104° F (40° C) are permitted. Protect from freezing. HOW SUPPLIED EQUISUL-SDT is available in the following package sizes: 135 mL 280 mL 560 mL 900 mL [footnote] 1 Kahn CM, Line S, eds. The Merck Veterinary Manual. 10th Ed. Merck & Co. 2010. 08/2019

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