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Introduction

Although many drugs may be used legally in both human and animal patients, certain drugs have unique human toxicities and are approved for use only in non-human species. In some cases, these drugs were approved initially for use in humans but withdrawn after serious adverse effects emerged. In other cases, these drugs were identified as toxic to humans early in development and never approved for human use.

Given that pharmacists are the only health care professionals expected by society to provide pharmaceutical care for all species, it is highly likely that pharmacists will encounter prescriptions for veterinary-only medications. Accordingly, it is critically important that pharmacists possess a working knowledge of the names, mechanisms of action, indications, dosing, adverse effects, safety profiles, and counseling points for drugs that may belong to similar therapeutic classes as those used in humans but may cause serious adverse effects if dispensed to a human accidentally. Even more important, because medication administration to animals by necessity involves a human, pharmacists must be able to advise human caregivers about possible risks from veterinary drugs.

More than 1,400 drugs are approved by the Food and Drug Administration (FDA) Center for Veterinary Medicine. Modules 5 and 6 focus on the 25 veterinary drugs most likely to be encountered by community pharmacists. (Because of the sheer number of parasiticides available, the modules do not address flea and tick products, heartworm preventatives, or anthelmintics.)

Module 5 covered antimicrobial agents and nonsteroidal anti-inflammatory drugs (NSAIDs). This module covers hormonal drugs and selected other individual agents.

Hormonal Drugs

The veterinary hormonal drugs most likely to be encountered by community pharmacists are diethylstilbestrol and estriol.

Diethylstilbestrol

Diethylstilbestrol (die-ETH-il-still-BES-tral)—often referred to by the initials DES—is a synthetic estrogen that increases the responsiveness of urethral smooth muscle to nervous (norepinephrine) control, thereby increasing muscle tone in the bladder neck and urethra.

DES had been approved for use in humans, but it was withdrawn from marketing in 1975 for safety reasons after it was linked to cancers and birth defects in treated women and their offspring. DES appears on the list of drugs that cannot be compounded for humans. Use in food-producing animals also is banned.

No dosage forms are commercially available for use in animals. DES typically is compounded in patient-specific gelatin capsules.

Information about dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Diethylstilbestrol Summary.

Indications. DES is approved for the treatment of (1) estrogen-responsive urinary incontinence in female dogs and (2) benign prostatic hypertrophy in male dogs.

Although estriol also is FDA-approved for estrogen-responsive urinary incontinence, many veterinarians prefer to continue using DES.

Dosage. DES is administered by mouth. The initial dosage in dogs is 0.02 mg/kg (not to exceed 1 mg per dog) every 24 hours for 3–5 days. The dosing frequency is then tapered to every other day. Ultimately, dosing is tapered to the longest interval that controls incontinence—a frequency of once weekly for most dogs. Pet owners should be cautioned not to increase the dose or dosing frequency without consulting a veterinarian.

Pharmacokinetics. DES is well absorbed and widely distributed following oral administration. It is metabolized primarily through conjugation with glucuronide and undergoes enterohepatic recycling. DES is eliminated in bile and feces.

Adverse Effects. Estrogens (including DES) cause a dose-related myelosuppression in dogs that may progress to a fatal aplastic anemia. As a precaution, no dog should receive a total daily DES dose greater than 1 mg. All dogs treated with DES should be observed for signs of myelosuppression (abnormal bruising, bleeding, lethargy, fever, infection).

Estrogens (including DES) may cause uterine, cervical, and mammary neoplasia in female dogs.

Other adverse effects include reversible alopecia in male or female dogs and feminization of male dogs. Some spayed females will exhibit estrus-like behavior (i.e., signs of being in heat).

Use of DES is contraindicated in cats. Possible consequences of DES exposure include anorexia, progressive weight loss, jaundice, and death.¹

Monitoring. Dogs treated with DES should have CBC and serum chemistries performed at baseline, 1 month, and then every 3–6 months to monitor for myelosuppression. Dogs also should be observed for clinical signs of toxicity.

Safety Considerations for Humans. DES is carcinogenic in humans. Women who took DES during pregnancy have a higher rate of breast cancer than the general population.² Female offspring exposed to DES in utero (“DES daughters”) have a substantially increased risk of developing clear cell adenocarcinoma of the vagina and cervix.² Male offspring exposed to DES in utero (“DES sons”) may have an increased risk of testicular and prostate cancer.²

DES also is teratogenic. DES daughters and sons have a high rate of structural reproductive tract abnormalities that can contribute to infertility.² For example, female offspring may have a T-shaped uterus; male offspring may have epididymal cysts or undescended testes.

To the extent possible, humans should avoid contact with DES. Pregnant women (or women who are trying to conceive) are cautioned to avoid any contact with DES. Pharmacists who compound DES capsules should wear proper personal protective garb and work in appropriate containment hoods.

Pharmacist Scenario Example: Diethylstilbestrol The owner of a 10-kg female Beagle presents a prescription for diethylstilbestrol 0.2 mg capsules, quantity 30. The instructions are to administer one capsule by mouth every 24 hours for 5 days, then one capsule every 48 hours for 5 days, then one capsule every 2–3 days as needed to control urinary incontinence. You verify the weight-based dose and ask if there are any girls or women in the household who are pregnant or attempting to become pregnant (the answer is no). You don protective garb and prepare 30 capsules in the containment hood. When the dog owner returns, you counsel him to watch the Beagle for tiredness, bruising, bleeding, fever, or other signs of myelosuppression.

Estriol (Incurin)

Estriol (ESS-tree-ol) is a synthetic estrogen that increases the responsiveness of urethral smooth muscle to nervous (norepinephrine) control, thereby increasing muscle tone in the bladder neck and urethra.

Estriol is not approved for use in humans in the United States. It is possible that some people might attempt to obtain veterinary estriol tablets for personal use.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Estriol Summary.

Indications. Estriol is approved for the control of estrogen-responsive urinary incontinence in ovariohysterectomized (spayed) female dogs.

Dosage. Estriol is administered by mouth. The dose is tapered according to the following schedule:

• 2 mg every 24 hours for the first 14 days.
• 1 mg every 24 hours for 7 days.
• 0.5 mg every 24 hours for 7 days.

Once the lowest effective dose is determined, the frequency of administration can be decreased to every 48 hours, or as infrequently as possible to control incontinence. Pet owners should be cautioned not to increase the dose or dosing frequency without consulting a veterinarian.

Estriol is available commercially as scored tablets. If an alternate dosage form must be compounded, the commercially available tablets—not bulk drug substance—should be used as the source of active ingredient.³

Pharmacokinetics. Estriol is well absorbed and widely distributed following oral administration. It is metabolized primarily through conjugation with glucuronide and undergoes enterohepatic recycling. Estriol is eliminated in bile and feces.

Adverse Effects. Estrogens (including estriol) have been associated with bone marrow changes (dose-related myelosuppression that may progress to a fatal aplastic anemia) and an increased risk of mammary tumors. Targeted animal safety study results and foreign postmarketing pharmacovigilance data for estriol tablets show that dogs are at low risk of developing these conditions.⁴ Nonetheless, dogs treated with estriol should be observed for signs of myelosuppression (abnormal bruising, bleeding, lethargy, fever, infection).

Some spayed female dogs treated with estriol may develop a swollen vulva and exhibit estrus-like behavior (i.e., signs of being in heat). They also may become sexually attractive to male dogs.

Other adverse effects include reversible alopecia, gastrointestinal effects such as anorexia or vomiting, hypersalivation, polydipsia, anxiety, and somnolence.

The safe use of estriol has not been evaluated in intact female dogs, pregnant or lactating dogs, male dogs, or dogs younger than 1 year of age.

Use of estriol is contraindicated in cats.

Monitoring. Dogs treated with DES should have CBC and serum chemistries performed at baseline, 1 month, and then every 3–6 months to monitor for myelosuppression. Dogs also should be observed for clinical signs of toxicity.

Safety Considerations for Humans. Estriol is produced naturally by human females and is used commonly in bioidentical hormone replacement in perimenopausal women. Estriol may be administered by the transdermal route in women, so female pet owners should wash their hands thoroughly after administering estriol to dogs. Women who are of child-bearing age or currently breastfeeding should avoid contact with estriol if possible, or use caution when handling.

Individual Agents

The veterinary drugs discussed in the remainder of this module represent various drug classes and indications.

Phenylpropanolamine (Proin)

Phenylpropanolamine (fen-il-PROPE-a-NOLE-a-meen) is an α-adrenergic agonist that has been reported to increase urethral tone in dogs. Its mechanism of action is not well established. Phenylpropanolamine is believed to stimulate norepinephrine release by acting indirectly on both α-adrenergic and β-adrenergic receptors of smooth muscle, resulting in increased tone of the urethra, bladder neck, and internal urethral sphincter.

Although phenylpropanolamine was approved for use in humans as an anorectic and decongestant, it has not been available since 2005, when the FDA reclassified phenylpropanolamine as “not generally recognized as safe and effective” (see Safety Considerations for Humans section). Phenylpropanolamine also has been used in the illegal production of methamphetamine; the Combat Methamphetamine Epidemic Act of 2005 further limited the distribution of phenylpropanolamine by designating it as a List I chemical. Pharmacists still are able to obtain bulk phenylpropanolamine after completing extensive paperwork, but Proin is the only commercially available product. It is possible that some people might attempt to obtain veterinary phenylpropanolamine tablets for personal use or misuse.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Phenylpropanolamine Summary.

Indications. Phenylpropanolamine is indicated for the control of urinary incontinence due to urethral sphincter hypotonus in dogs. It sometimes is used off-label for the same indication in cats, but this use is not recommended.

Dosage. Phenylpropanolamine is administered by mouth. The usual dosage in dogs is 2 mg/kg every 8–24 hours. It may take several days before therapeutic effects are evident and incontinence is controlled.

When phenylpropanolamine is used to treat cats, the usual dosage is 1–2.2 mg/kg orally every 8–24 hours.

Phenylpropanolamine is available commercially as chewable liver-flavored tablets. If an alternate dosage form must be compounded, the commercially available tablets—not bulk drug substance—should be used as the source of active ingredient.³ The commercially available tablets should not be used to compound dosage forms for dogs allergic to liver.

Pharmacokinetics. Absorption of phenylpropanolamine is rapid and complete (98% bioavailability) when administered orally to fasted dogs. Food delays the rate but not the extent of absorption.

Phenylpropanolamine is widely distributed into various tissues and body fluids, including the cerebrospinal fluid and brain.

Phenylpropanolamine undergoes minor hydroxylation. Most (80%–90%) of an administered dose is excreted unchanged in the urine.

Adverse Effects. Phenylpropanolamine can cause an increase in thirst. Dogs treated with phenylpropanolamine should have plenty of fresh drinking water available.

Many common adverse effects are associated with sympathetic activity; they include hypertension, anorexia, weight loss, and anxiety or behavior change. Phenylpropanolamine also can cause vomiting, diarrhea, and proteinuria.

Monitoring. Dogs treated with phenylpropanolamine should undergo regular physical examination to monitor for the development of hypertension.

Safety Considerations for Humans. Phenylpropanolamine was used widely in humans until 2000, when results of the Hemorrhagic Stroke Project showed it to be an independent risk factor for hemorrhagic stroke.⁵ The FDA took steps to remove phenylpropanolamine from all drug products and asked all drug companies to discontinue marketing products containing phenylpropanolamine. Pharmacists are advised to observe refill patterns to guard against human abuse or misuse of veterinary phenylpropanolamine (for example, as a weight loss aid or for the manufacture of methamphetamine).

Pharmacist Scenario Example: Phenylpropanolamine A veterinarian calls you regarding a canine patient that is very sensitive to phenylpropanolamine and requires an unusually small dose (4–5 mg). You recommend compounding capsules containing 4 mg or 5 mg of phenylpropanolamine, using the Proin® liver-flavored tablets as a starting ingredient.

Trilostane (Vetoryl)

Trilostane (try-LOW-stain)—a synthetic steroid analogue—is a competitive inhibitor of 3-β-hydroxysteroid dehydrogenase in the adrenal cortex. It inhibits the conversion of pregnenolone to progesterone, thereby blocking synthesis of cortisol, progesterone, estrogens, and androgens.

Trilostane was marketed for use in humans as Modrastane until it was withdrawn for safety reasons (see Safety Considerations for Humans section) in 1994.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Trilostane Summary.

Indications. Trilostane is approved for the treatment of pituitary-dependent hyperadrenocorticism in dogs and hyperadrenocorticism caused by adrenal tumors in dogs. It has been used off-label to treat Alopecia X, a disease that affects Nordic breeds, Poodles, and Pomeranians.

Trilostane also has been used to treat hyperadrenocorticism in cats and pituitary pars intermedia dysfunction (PPID, also referred to as Equine Cushing’s Disease) in horses.^6,7 Trilostane has no effect on the pituitary gland and is unlikely to be effective in horses with pituitary-dependent PPID.⁷

Dosage. Trilostane is administered by mouth. The labeled dosage for dogs with hyperadrenocorticism is 2.2–6.7 mg/kg every 24 hours. However, veterinary endocrinologists typically recommend starting therapy at a dosage of approximately 1 mg/kg every 12 hours to avoid adverse effects.⁸ When used to treat Alopecia X, the dosage is 3 mg/kg every 12 hours for 4–6 months.⁹

In cats, the usual dosage of trilostane for the treatment of hyperadrenocorticism is 0.5–12 mg/kg every 12 hours or every 24 hours.⁶

In horses, the usual dosage of trilostane for the treatment of PPID is 120–240 mg every 24 hours (dosing is not weight-based).⁷

Trilostane is available commercially as capsules. If an alternate dosage form must be compounded—for example, an oral suspension for a small dog—the commercially available capsule (not bulk drug substance) should be used as the source of active ingredient.¹⁰

Pharmacokinetics. Trilostane is absorbed rapidly but erratically when administered orally. Distribution in dogs has not been characterized; trilostane has a low volume of distribution in monkeys and rats.

Trilostane is metabolized via hydroxylation and glucuronidation to several active metabolites, including ketotrilostane. Metabolites are excreted primarily in the urine.

Adverse Effects. Adverse effects reported most commonly during trilostane therapy include poor or reduced appetite, vomiting, lethargy or dullness, diarrhea, and weakness. Less common but more serious reactions include severe depression, hemorrhagic diarrhea, collapse, hypoadrenocortical crisis, and adrenal necrosis or rupture. These reactions can occur without warning and have resulted in animal death in some cases.

Both intolerance to trilostane therapy and overdosage can result in hypoadrenocorticism (Addison’s disease). Adrenal function may return slowly; some dogs never regain adequate adrenal function.

Some dogs experience a corticosteroid withdrawal syndrome when therapy is initiated, characterized by weakness, lethargy, anorexia, and weight loss. Serum electrolytes should be measured to rule out hypoadrenocorticism. If symptoms are severe, trilostane can be withdrawn and then restarted at a lower dose when symptoms resolve.

Monitoring. When trilostane therapy is initiated, pet owners should monitor the animal’s water consumption (ideally <80 mL/kg/day) and urine production for evidence that the drug is working.

Animals treated with trilostane should be observed for signs of corticosteroid withdrawal or hypoadrenocorticism. Owners should contact a veterinarian immediately if their pet develops vomiting, diarrhea, lethargy, poor or reduced appetite, weakness, or collapse.

An adrenocorticotropic hormone (ACTH) stimulation test should be performed 2 weeks after trilostane therapy is initiated, as well as 2 weeks after any dosage adjustment. Once an effective trilostane dosage has been achieved, a physical examination, ACTH stimulation test, and serum chemistries and electrolytes should be performed at 30 days, 60 days, and then every 3 months. The importance of honoring recheck appointments for laboratory tests and physical examination should be emphasized to pet owners.

Safety Considerations for Humans. Trilostane had been approved for use in humans, but it was withdrawn from marketing in 1994. Because it inhibits 3-β-hydroxysteroid dehydrogenase, trilostane also inhibits the formation of progesterone, estrogens, androgens, glucocorticoids, and mineralocorticoids. Trilostane causes miscarriage through inhibition of progesterone formation. Women who are pregnant (or intending to become pregnant) should avoid any contact with trilostane.

Pharmacist Scenario Example: Trilostane A veterinarian requires the ability to adjust trilostane doses in 1-mg increments for a 1-kg Chihuahua with Cushing’s disease. You offer to compound either a 10 mg/mL oral suspension or gelatin capsules containing trilostane 1 mg, using the commercially available product as the source of the active ingredient. The veterinarian consults with the pet owner and asks you to prepare the oral suspension.

Pergolide Mesylate (Prascend)

Pergolide mesylate (PURR-go-lide MEH-sill-ate)—a synthetic ergot derivative—is a potent dopamine receptor agonist. It exerts negative feedback on the pituitary gland to halt production of ACTH, pro-opiomelanocortin (POMC), and other hormonally active substances responsible for the clinical signs of PPID in horses.

Pergolide was approved for the treatment of Parkinson’s disease in humans but was withdrawn from the market in 2007 for safety reasons (see Safety Considerations for Humans section).

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Pergolide Mesylate Summary.

Indications. Pergolide is indicated for the control of clinical signs associated with PPID in horses. It is the therapy of choice for PPID.

Dosage. Pergolide is administered by mouth. The usual dosage in horses is 2–4 µg/kg every 24 hours, rounded to the nearest 0.5 mg (½ tablet). Clinical response may not be apparent for several weeks.

If an alternate dosage form must be compounded, the commercially available tablet—not bulk drug substance—should be used as the source of active ingredient.¹¹ USP has developed a validated compounded preparation monograph for pergolide 1 mg/mL oral suspension.

Pharmacokinetics. Pergolide is rapidly and completely absorbed following oral administration. It is widely distributed with high protein binding.

Pergolide is metabolized extensively to at least 10 active metabolites. Excretion is primarily via the urine.

Adverse Effects. The most common adverse effect of pergolide therapy is inappetance. Horses treated with pergolide also may experience abnormal weight loss, lethargy, colic, or diarrhea or loose stools. Lameness and heart murmur have been reported.

Monitoring. Horses treated with pergolide should be observed for clinical signs of efficacy, such as improved haircoat and decreased thirst and urination. A dexamethasone suppression test, fasting serum insulin measurement, or both should be performed 4–8 weeks after therapy is initiated as well as 4–8 weeks after any dosage adjustment. A complete physical examination, CBC, and serum chemistries should be performed periodically during therapy.

Safety Considerations for Humans. Pergolide had been approved for the treatment of Parkinson’s disease in humans but was withdrawn from marketing in 2007 following association with valve regurgitation, valvular vegetative lesions, and cardiac lesions. These lesions have not been observed in horses receiving pergolide, although 8.2% of horses in a field study of pergolide developed heart murmurs.¹² Pergolide must be administered for the duration of the horse’s life; human caregivers should guard against exposure. Women who are pregnant or lactating should wear gloves when administering this product. Humans with ergot allergies should avoid contact with pergolide.

Although the commercially available tablets are scored and the package labeling indicates rounding doses to the nearest half tablet, there have been reports of headache, eye irritation, and an irritating smell after the tablets were split or crushed. The tablets ideally should not be crushed by caregivers because of the potential for increased human exposure; caregivers should be cautious when splitting tablets. Pharmacists who must crush the tablets to prepare compounded suspensions should don appropriate protective apparel (including a face mask).

Pharmacist Scenario Example: Pergolide Mesylate Pharmacists may be asked to compound flavored oral suspensions of pergolide mesylate. The commercially available tablets—not the bulk drug substance—should be used as the source of active ingredient. USP has developed a validated compounded preparation monograph for pergolide oral suspension 1 mg/mL.

Domperidone (Equidone)

Domperidone (dohm-PARE-i-dohne) is a dopamine receptor (D2) antagonist. Dopamine inhibits prolactin secretion. By binding to dopamine receptors, domperidone prevents that inhibition.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Domperidone Summary.

Indications. Domperidone is approved for the prevention of fescue toxicosis in periparturient mares. Fescue toxicosis is a clinical syndrome that may occur when pregnant mares ingest tall fescue grass that has gone to seed and is infested with a specific endophyte fungus, Neotyphodium coenophialum (formerly Acremonium coenophialum). The fungus produces ergovaline, which has dopaminergic activity and suppresses prolactin secretion. Clinical signs associated with fescue toxicosis include lack of milk production, prolonged gestation, thickened fetal membranes, premature separation of the placenta, retained fetal membranes, abortion, dystocia, reduced fertility, and increased neonatal mortality.

Domperidone also has been used off-label as a diagnostic tool for horses with PPID, and to induce lactation in non-pregnant mares for adoption of orphaned foals.

Domperidone has been administered as a prokinetic agent in dogs and cats but has not demonstrated efficacy for this use.

Dosage. Domperidone is administered to horses by mouth. The usual dosage for the prevention of fescue toxicosis in periparturient mares is 1.1 mg/kg every 24 hours, starting 10–15 days before the expected foaling date. (Domperidone must not be administered more than 15 days before the expected foaling date because of the possibility of premature birth, low birthweight foals, or foal morbidity.) Treatment may be continued for up to 5 days after foaling if mares are not producing adequate milk.

Pharmacists who dispense domperidone should demonstrate proper use of the multi-dose dosing syringe, including how to set the dial ring for accurate dosing after the first dose.

When domperidone is used to diagnose PPID, a single 2.5 mg/kg dose is administered by mouth, and the ACTH level is measured 4 hours after the dose.

Pharmacokinetics. Domperidone is absorbed rapidly following oral administration. It undergoes significant first pass metabolism; oral bioavailability is approximately 20% in most species. Domperidone is widely distributed in all tissues, but it does not cross the blood–brain barrier readily.

Domperidone is metabolized extensively in the liver by hydroxylation and n-dealkylation. The main metabolic pathway is through CYP3A4. It is eliminated primarily in feces, with small amounts eliminated in the urine.

Adverse Effects. The most common adverse reactions during domperidone therapy are diarrhea, premature leakage of milk from the teats before foaling, and failure of passive transfer (i.e., failure to transfer antibodies from the mare to the foal through the mare’s milk).

Monitoring. All foals born to mares treated with domperidone should be tested for serum immunoglobulin (IgG) concentrations.

Safety Considerations for Humans. Domperidone has never been approved for use in humans in the United States. Several studies have indicated that domperidone is torsadogenic; the FDA Pharmacy Compounding Advisory Committee voted in October 2015 to add domperidone to the list of drugs that may not be compounded for humans, based on the risk of sudden death from prolongation of the QT interval. It is possible that women seeking to increase lactation may attempt to obtain domperidone for personal use.

Oclacitinib Maleate (Apoquel)

Oclacitinib maleate (oak-lah-SIT-a-nib MAL-ee-ate) is a Janus kinase (JAK) inihibitor. It inhibits the function of pruritogenic cytokines and pro-inflammatory cytokines that are dependent on JAK1 and JAK3 enzyme activity. Oclacitinib has minimal effect on JAK2-mediated hematopoiesis.

Oclacitinib is a relatively new drug. Because supplies are limited, distribution periodically is restricted to board-certified veterinary dermatologists. Pharmacists have been approached by veterinarians who are not dermatologists to compound oclacitinib maleate for their canine patients.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Oclacitinib Maleate Summary.¹³

Indications. Oclacitinib is indicated for the control of (1) pruritus associated with allergic dermatitis and (2) atopic dermatitis in dogs at least 12 months of age.

Oclacitinib may be used off-label in cats for the treatment of non-flea, non–food-induced dermatitis.¹⁴

Dosage. Oclacitinib is administered by mouth. The recommended dosage is 0.4–0.6 mg/kg every 12 hours for 14 days, then every 24 hours for the duration of therapy. In practice, the reduction in frequency often is accomplished by administering half of the daily dose in the morning and half in the evening (not the entire dose once daily). Veterinarians often find that the full initial dosage (0.4–0.6 mg/kg every 12 hours) must be continued as maintenance therapy in some dogs that experience therapeutic failure when the dosage is reduced.

When oclacitinib is used to treat dermatitis in cats, the usual dosage is 0.4–0.6 mg/kg every 12 hours.¹⁴

It is important to note that oclacitinib is available commercially as the maleate salt. There are anecdotal reports of therapeutic failure following use of compounded dosage forms that were prepared using oclacitinib base or the citrate salt.

Pharmacokinetics. Oclacitinib is absorbed rapidly and almost completely (bioavailability ~90%) when administered by the oral route, with low protein binding. It is metabolized extensively via oxidation to several metabolites. Less than 4% of an administered dose is excreted unchanged in the urine.

Adverse Effects. The most common adverse effects during treatment with oclacitinib are vomiting, diarrhea, anorexia, and lethargy. Administering doses with food may help to alleviate gastrointestinal upset.

An increased risk of infection (including demodicosis), increased lymphocytes, neoplasia, and papillomas also were reported during field studies. Oclacitinib should not be administered to dogs with serious infections or neoplasia. Pet owners should contact a veterinarian immediately if they notice signs of infection or skin growths.

Monitoring. Dogs treated with oclacitinib should be monitored with periodic CBC and serum chemistries. Dogs also should be observed for signs of infection and abnormal skin growths.

Safety Considerations for Humans. Oclacitinib is a strong eye irritant. Caregivers should wash their hands thoroughly after administering oclacitinib and avoid crushing tablets. In case of accidental eye contact, the eyes should be rinsed with water or saline for 15 minutes, and the affected person should seek medical attention.

Little else is known about human exposure to oclacitinib. Data from laboratory animal studies suggest a low potential for acute oral or dermal toxicity. Oclacitinib does not appear to be a skin irritant or sensitizer.

Pharmacist Scenario Example: Oclacitinib Maleate A dog owner whose pet is being treated with oclacitinib mentions that the dog seems to be developing growths that look like warts. She wonders if the growths could be caused by the drug. You inform the dog owner that skin growths are indeed a serious adverse effect of oclacitinib therapy; you advise her to consult the veterinarian or a veterinary dermatologist immediately.

Maropitant (Cerenia)

Maropitant (ma-RAHP-i-tent) is a neurokinin-1 (NK1) receptor antagonist that blocks the action of Substance P in the central nervous system (CNS). Substance P is the primary CNS mediator of vomiting.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Maropitant Summary.

Indications. Maropitant is indicated for the prevention of (1) acute vomiting and (2) vomiting due to motion sickness in dogs and cats.

Dosage. Maropitant is administered by mouth or by subcutaneous or intravenous injection. When administered to dogs to control acute vomiting, the dosage is 2 mg/kg every 24 hours for oral administration and 1 mg/kg every 24 hours for parenteral administration.

When used to prevent motion sickness in dogs, the dosage is 8 mg/kg orally every 24 hours for a total of two doses. The dog must be fasted 1 hour before administration, and administration must occur 2 hours before travel. Pet owners should be advised to feed the dog a small amount of food 3 hours before travel, then withdraw food until after travel is complete.

The usual dosage in cats is 1 mg/kg every 24 hours by subcutaneous or intravenous injection.

A 50% dosage reduction is recommended for animals with hepatic insufficiency (see Pharmacokinetics section).

Pharmacokinetics. Maropitant is rapidly and completely absorbed following subcutaneous administration. High first-pass metabolism results in an oral bioavailability of only 24%–37%.

Distribution of maropitant is limited. It crosses the blood–brain-barrier and exhibits concentrations nearly 4 times higher in brain than plasma at 8 hours.

Maropitant undergoes extensive hepatic metabolism through CYP2D15 and CYP3A12. Saturation of these enzymes causes dose-related nonlinear pharmacokinetics. Maropitant should be used with caution in animals with compromised hepatic function; a 50% dosage reduction is recommended for animals with hepatic insufficiency.

The original package insert warned veterinarians not to administer maropitant for more than 5 consecutive days to avoid potential drug accumulation, and to have at least a 2-day drug vacation between 5-day intervals. However, postmarketing clinical use has not revealed any risk of drug accumulation after chronic use, and the warning was removed from the package insert in 2015.

Less than 1% of an administered dose of maropitant is eliminated via the urine.

Adverse Effects. Maropitant may cause pain when administered by subcutaneous injection in dogs and cats. Refrigerating the solution reportedly decreases pain and stinging on administration¹⁵; this may be because cyclodextrin used to solubilize maropitant binds strongly to maropitant at lower temperatures.

Adverse reactions reported during field studies of maropitant or post-approval experience include drowsiness, lethargy, anorexia, and diarrhea. Vomiting and hypersalivation are possible at the higher motion sickness dose.

Maropitant causes prolongation of the QT interval.¹⁶ Safe use of maropitant in animals with underlying cardiac disease has not been studied. Maropitant should be used with caution in animals that have pre-existing cardiovascular disease or require concomitant therapy with drugs that prolong the QT interval.

Some animals treated with maropitant have experienced ataxia, seizures, and anaphylaxis or anaphylactoid reactions (including swelling of the head and face). Dogs or cats that exhibit any of these symptoms require immediate veterinary care.

Monitoring. Dogs and cats treated with maropitant should be monitored for efficacy (cessation

of nausea and vomiting). Animals also should be observed for signs of serious adverse effects (anaphylaxis/anaphylactoid reactions, including swelling of the head or face; ataxia; seizures) that require immediate veterinary attention.

Safety Considerations for Humans. Maropitant has never been approved for use in humans. It is a strong contact irritant and eye irritant. Pet owners should wash their hands thoroughly after handling maropitant. In case of accidental eye contact, the eyes should be flushed with water for 15 minutes, and the affected person should seek medical attention.

Pharmacist Scenario Example: Maropitant A veterinary oncologist has prescribed 14 days of consecutive maropitant therapy for a dog undergoing chemotherapy for canine lymphoma. While searching the Internet for additional information about miropitant, the dog owner discovered information stating that maropitant should be used for no more than 5 consecutive days. He is concerned about this information and asks what he should do. You tell the dog owner that this warning was removed from the package insert in 2015; you also explain that the risk of breakthrough vomiting during chemotherapy from skipping doses of maropitant outweighs any risk associated with accumulation of the drug.

Cisapride

Cisapride (SIS-a-pride) is a serotonin 5HT4 receptor antagonist that causes release of acetylcholine at the myenteric plexus.

Cisapride was marketed for use in humans as Propulsid until 2000, when it was withdrawn from active marketing following reports of serious cardiac arrhythmias and fatalities. Although cisapride remains available through an investigational limited access program, it must be compounded for veterinary use. USP has developed validated compounded preparation monographs for cisapride oral suspension 10 mg/mL and cisapride injection3 mg/mL.

Information about dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Cisapride Summary.^17,18

Indications. Cisapride is a prokinetic drug used to manage gastrointestinal paresis, esophageal reflux, esophagitis, megacolon, and constipation.

Dosage. Cisapride is administered by mouth or by intravenous injection. The dosage varies by species (see Cisapride Summary).^17-19

Rectal administration of cisapride suspension in horses is not effective.¹⁹

Pharmacokinetics. Cisapride is absorbed rapidly and distributed widely. Oral bioavailability is low (30%–40%). Cisapride is highly protein bound (97%).

Cisapride undergoes extensive hepatic metabolism through CYP3A4 .

Adverse Effects. The most common adverse effects associated with cisapride therapy are diarrhea, abdominal pain and cramping, and nausea. Headache was a commonly reported adverse effect in humans.

Arrhythmias have not been reported in animals but may be possible, especially if cisapride is administered concurrently with other drugs known to prolong the QT interval (e.g., maropitant).

Monitoring. Animals treated with cisapride should be observed for signs of gastrointestinal obstruction (cisapride is contraindicated in gastrointestinal obstruction). Animals with cardiovascular conditions should be monitored for arrhythmias.

Cats being treated for megacolon or constipation should be observed for straining, painful defecation, or blood in the stool. Early intervention is most likely to avoid fecal impaction. Cats with megacolon should be examined frequently to ensure that they do not become obstructed.

Safety Considerations for Humans. Cisapride was removed from the human market in 2000 after more than 300 cases of serious cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation. Those cases resulted in 80 deaths. Most of the deaths were caused by increased blood levels of cisapride resulting from drug interactions.

Human caregivers should exercise caution when handling cisapride and avoid exposure to the extent possible.

Pharmacist Scenario Example: Cisapride The owner of a 6-kg cat diagnosed with megacolon presents a prescription for cisapride 5 mg by mouth every 12 hours for 30 days. She requests a liquid formulation. You consult the USP Compounding Compendium and identify a standardized formula for cisapride 10 mg/mL oral suspension. You confirm with the veterinarian that this formulation is appropriate for the cat, and you prepare and dispense a 30-day supply.

Potassium Bromide

Potassium bromide (po-TASS-ee-um BROE-mide) raises the seizure threshold by competing with chloride ions across neuronal membranes. The overall result is hyperpolarization of neuronal cell membranes and depression of neuron excitability.

Bromides had been approved for use in humans. They were withdrawn from marketing in 1975 because humans are at particular risk for bromide toxicity (bromism; see Adverse Effects section).

No manufactured versions of potassium bromide are approved by the FDA, so there are no legally available commercial products. The widely marketed KBroVet bears the federal prescription drug legend and has an NDC number, but it is not approved by the FDA fully, conditionally, or under any terms of the Minor Use and Minor Species Act. Accordingly, the most legally correct approach is to compound potassium bromide for veterinary use.

USP has developed a validated compounded preparation monograph for potassium bromide oral solution 250 mg/mL. The solution should be clear, with no visible particles. Concentrations greater than 250 mg/mL are not recommended because of a higher likelihood of precipitation, especially when refrigerated. Caregivers should be warned not to administer solution with evidence of crystals; doing so could result in bromide toxicity.

Information about dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Potassium Bromide Summary.

Indications. Potassium bromide is indicated for the management of epilepsy in dogs, either as monotherapy or as an adjunct to other neuroleptic drugs.

Use in cats is not recommended. Potassium bromide can cause serious lower respiratory adverse effects in cats, including cough, dyspnea, and eosinophilic bronchitis. Although these effects usually are reversible when therapy is discontinued, they also can be fatal.

Dosage. Potassium bromide is administered by mouth. Because potassium bromide has a very long half-life in dogs (days, not hours; see Potassium Bromide Summary) and takes a very long time to reach steady state, many veterinarians initiate therapy with a loading dose of 400–600 mg/kg, administered as several divided doses over 1–5 days.

The usual maintenance dosage of potassium bromide is 30–35 mg/kg every 24 hours. The daily dose also can be divided into two equal doses.

Administering doses with food helps to decrease gastrointestinal upset and erosion.

Pharmacokinetics. Potassium bromide is well absorbed from the small intestine following oral administration. Oral biovailability in dogs is approximately 46%.

Potassium bromide is distributed primarily in the CNS and extracellular fluid. It is eliminated almost exclusively in the urine, as unchanged drug.

Adverse Effects. Symptoms of gastrointestinal upset—nausea, vomiting, and diarrhea—are the most common adverse effects during potassium bromide therapy. Polyphagia, polydipsia, and polyuria also may occur. Dogs treated with potassium bromide should have easy access to water and ample opportunities to go outside to urinate, especially when therapy is initiated.

Sedation accompanied by vomiting is possible when loading doses of potassium bromide are administered to dogs. Each dose should be given with food to lessen gastrointestinal upset, and food bowls should be elevated to prevent aspiration of food into the lungs if vomiting occurs while sedated.

Bromide toxicity (bromism) may occur at blood levels exceeding 2.5 mg/mL. It is manifested by neurological signs such as deep sedation, stupor, ataxia, coma, and mydriasis. Bromism can be treated on an inpatient basis with intravenous administration of sodium chloride.

Bromides compete with chloride at the neuronal membrane, as well as for renal tubular reabsorption. Chloride intake from all sources—e.g., dietary salt, sea water, swimming pool water—should be regulated carefully in dogs receiving bromides to avoid loss of seizure control. If potassium bromide is administered with food, the chloride content of the food should be consistent from dose to dose. Excessively salty foods and treats should be avoided.

As mentioned earlier, potassium bromide can cause potentially serious lower respiratory adverse effects in cats, including cough, dyspnea, and eosinophilic bronchitis. Many veterinarians consider potassium bromide to be contraindicated in cats, using it only as a treatment of last resort.

Monitoring. Bromide blood levels should be measured 1 month after initiation of therapy and then again 8–12 weeks later. The therapeutic blood level target range is 1–3 mg/mL, although many clinicians prefer that blood levels not exceed 2 mg/mL because of the risk of bromism.

Animals treated with potassium bromide should undergo physical examination and have routine serum chemistries performed every 6 months. They also should be observed for signs of bromism (deep sedation, stupor, ataxia, coma) or subtherapeutic dosing (breakthrough seizures). Dogs that display signs of either bromism or breakthrough seizures should receive immediate veterinary care.

When used as a treatment of last resort in cats, the animal should be monitored closely for development of respiratory signs (cough, dyspnea). Cats that display these signs should receive immediate veterinary care.

Safety Considerations in Humans. Given the risk of bromism, caregivers should take precautions to avoid exposure to potassium bromide. Direct skin contact in particular should be avoided; rash is common after contact. Caregivers should wash their hands thoroughly after administering potassium bromide to pets.

Pharmacist Scenario Example: Potassium Bromide You receive a prescription to compound potassium bromide solution 500 mg/mL for a large dog. You become concerned that this high concentration may result in bromide precipitation, especially if flavorings and other excipients are used. You contact the veterinarian to make sure that the formulation specified in the USP compounded preparation monograph (250 mg/mL) will work for this patient.

Pimobendan (Vetmedin)

Pimobendan (pi-moe-BEN-den) is a negative inotrope that decreases heart rate by inhibiting phosphodiesterase enzyme type 3 (PDE3) and increasing intracellular calcium channel sensitivity.

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Pimobendan Summary.

Indications. Pimobendan is indicated for the management of mild, moderate, or severe congestive heart failure in dogs.

Pimobendan also is used off-label in cats to manage congestive heart failure.

Dosage. Pimobendan is administered by mouth. The commercially available tablets are formulated with ingredients designed to facilitate oral absorption.

The approved dosage for dogs is 0.25 mg/kg every 12 hours. However, the effective dosage recommended by an American College of Veterinary Internal Medicine Specialty of Cardiology consensus panel convened to formulate guidelines for the diagnosis and treatment of chronic valvular heart disease in dogs is 0.3 mg/kg every 8 hours.²⁰

When pimobendan is used in cats, the dosage is 0.25 mg/kg every 12 hours. This usually translates into individual doses of 1.25 mg per cat every 12 hours.

Commercially available pimobendan tablets are large and oblong, and they can be difficult to administer to some animals (especially cats). Tablets may be fractionated and hidden in empty gelatin capsules for cats and dogs that refuse the intact tablets.

Pharmacokinetics. Pimobendan is readily absorbed following oral administration. Although food can decrease the bioavailability of oral solutions of pimobendan, the effect of food on absorption from the tablet formulation has not been studied.

Pimodendan is widely distributed, with a high volume of distribution. It undergoes hepatic demethylation with subsequent conjugation with sulfate or glucuronide. Active metabolites contribute to the duration of action.

Excretion of pimobendan is mainly in feces.

Adverse Effects. The most common adverse effects associated with pimobendan therapy are gastrointestinal upset, inappetance, cough, dyspnea, and lethargy. Arrhythmias also have been reported.

Monitoring. Animals treated with pimobendan should be observed for evidence of clinical efficacy and signs of disease progression. Pet owners should monitor the animal’s heart rate, respiratory rate, body weight, appetite, and medication adherence and keep written documentation for evaluation by the veterinarian at recheck appointments. Recheck appointments also will include monitoring of renal function and blood work; the importance of honoring these appointments should be emphasized to pet owners.

Safety Considerations for Humans. Although pimobendan has been studied in multiple clinical trials for use in humans with congestive heart failure, it is not approved for human use in the United States. The pimobendan Safety Data Sheet indicates little likelihood of human hazard through contact (it is not an eye, skin, or respiratory irritant) but does advise caregivers to wash their hands after handling the product.

Pharmacist Scenario Example: Pimobendan A cat owner has struggled to administer a 1.25-mg tablet of Vetmedin to her cat twice daily. She asks if you have any suggestions for administering the tablet successfully. You recommend that she try splitting the tablet into smaller pieces and placing the pieces in an empty gelatin capsule, then coating the capsule with something the cat likes (for example, tuna oil or anchovy paste) to increase acceptance. The cat owner agrees to give this a try; you provide her with the empty gelatin capsules.

Clenbuterol (Ventipulmin)

Clenbuterol (klen-BYOO-ter-ol) is a β2-adrenergic receptor agonist that causes bronchodilation through production of cyclic AMP. It is more specific for smooth muscle relaxation (β2) in the bronchi, uterus, and blood vessels than for cardiac muscle relaxation (β1). Its bronchodilatory actions are blocked by β-adrenergic antagonists (β-blockers).

Information about available dosage forms, dosage by species, pharmacokinetic parameters, contraindications, use in pregnancy, drug interactions, storage, and regulatory considerations is provided in the Clenbuterol Summary.

Indications. Clenbuterol is indicated for the management of horses affected with airway obstruction, such as occurs in chronic obstructive pulmonary disease (COPD) or heaves (recurrent airway obstruction). Efficacy is increased if caregivers can decrease airborne irritants from bedding, feedstuffs, or straw. Soiled bedding should be removed to minimize airway irritation.

The product labeling states that clenbuterol should not be used in pregnant mares near term, because the drug antagonizes the effects of prostaglandin F2α and oxytocin (and thus inhibits uterine contractions). However, because clenbuterol has specific smooth muscle relaxation properties on the uterus, it sometimes is given to mares with dystocia (obstructed labor) to relax the uterus and facilitate in utero repositioning or delivery of foals.

Clenbuterol is not used in dogs or cats because of cardiotoxicity.

Dosage. Clenbuterol is administered by mouth. The usual dosage for the treatment of horses with airway obstruction is 0.8 µg/kg every 12 hours.

When used in mares with dystocia, clenbuterol is administered as a single 10-mL dose.

Pharmacokinetics. Clenbuterol is well absorbed following oral administration; bioavailability in horses is 84%. It is widely distributed.

Clenbuterol is excreted primarily as unchanged drug in the urine. Unchanged drug persists in urine for 12 days following the last dose.

Adverse Effects. The most common adverse effects during treatment with clenbuterol— primarily during the first few days of therapy—are mild sweating, muscle tremor, restlessness, urticaria, and tachycardia. Severe ataxia was observed in some horses during field studies.

Sweating in horses is mediated through β2-adrenergic receptors. Long-term use of clenbuterol may reduce ability to sweat over time. If this occurs, the horse should be examined by a veterinarian.

Recent investigations suggest that prolonged continuous exposure to clenbuterol (>2–3 weeks) may result in decreased bronchodilatory effects.²¹ Periodic drug vacations may help to delay tolerance to clenbuterol.

Clenbuterol may cause elevated creatine kinase (CK) serum levels.

Monitoring. Horses should be observed for evidence of clenbuterol tolerance. If tolerance is suspected, a brief drug vacation should be considered.

Safety Considerations for Humans. Clenbuterol is not approved for use in humans. Adverse effects include tachycardia, cardiomyopathy, and hypertension, possibly leading to myocardial infarction.

Because of its anabolic properties, clenbuterol is a target of drug-seeking athletes, body builders, and others who seek to lose body fat rapidly. It is known on the street as the “Size 0 Drug” or “Clen.” Clenbuterol use is banned by both the International Olympic Committee and the World Anti-Doping Agency.

Clenbuterol also recently has become popular as an adulterant for heroin.

Pharmacists should be vigilant for attempts by drug seekers to obtain clenbuterol illegally for human use. Suspected fraudulent prescriptions should be brought to the attention of veterinarians.

References

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2. Schrager S, Potter BE. Diethylstilbestrol exposure. Am Fam Phys. 2004;69(10):2395-400.
3. U.S. Food and Drug Administration. Incurin (estriol) tablets and Proin (phenylpropanolamine hydrochloride) chewable tablets—veterinarians. Issued April 20, 2012. Reissued February 25, 2016. Available at: http://www.fda.gov/animalveterinary/safetyhealth/productsafetyinformation/ucm277198.htm. Accessed September 1, 2016.
4. Incurin [package insert]. Madison, NJ: Merck Animal Health; 2011.
5. Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med. 2000;343:1826-32.
6. Valentin SY, Cortright CC, Nelson RW, et al. Clinical findings, diagnostic test results, and treatment outcome in cats with spontaneous hyperadrenocorticism: 30 cases. J Vet Intern Med. 2014;28(2):481-7.
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9. Leone F, Cerundolo R, Vercelli A, et al. The use of trilostane for the treatment of alopecia X in Alaskan malamutes. J Am Anim Hosp Assoc. 2005;41:336-42.
10. U.S. Food and Drug Administration. Vetoryl (trilostane) capsules—veterinarians. Issued September 11, 2009. Reissued February 25, 2016. Available at: http://www.fda.gov/animalveterinary/safetyhealth/productsafetyinformation/ucm182038.htm. Accessed September 1, 2016.
11. FDA Center for Veterinary Medicine. Prascend (pergolide mesylate) tablets—veterinarians. Issued April 20, 2012. Reissued March 2, 2016. Available at: http://www.fda.gov/animalveterinary/safetyhealth/productsafetyinformation/ucm277207.htm. Accessed September 1, 2016.
12. Prascend (package insert). St. Joseph, MO: Boehringer Ingelheim Vetmedica, Inc.; July 2011.
13. European Medicines Agency. Apoquel European public assessment report—product information. Published October 15, 2013. Updated May 19, 2015. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/veterinary/002688/WC500152091.pdf. Accessed September 1, 2016.
14. Ortalda C, Noli C, Colombo S, et al. Oclacitinib in feline nonflea-, nonfood-induced hypersensitivity dermatitis: results of a small prospective pilot study of client-owned cats. Vet Dermatol. 2015;26(4):235-e52.
15. Narishetty ST, Galvan B, Coscarelli E, et al. Effect of refrigeration of the antiemetic Cerenia (maropitant) on pain on injection. Vet Ther. 2009;10(3):93-102.
16. Kukanich B. Geriatric veterinary pharmacology. Vet Clin North Am Small Anim Pract. 42(4): 631-42.
17. Steel CM, Bolton JR, Preechagoon Y, et al. Pharmacokinetics of cisapride in the horse. J Vet Pharmacol Ther. 1998;21(6):433-6.
18. Adamcak A, Otten B. Rodent therapeutics. Vet Clin North Am Exot Anim Pract. 2000;3(1):221-37.
19. Cook G, Papich MG, Roberts MC, et al. Pharmacokinetics of cisapride in horses after intravenous and rectal administration. Am J Vet Res. 1997;58(12):1427-30.
20. Atkins C, Bonagura J, Ettinger S, et al. Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. J Vet Intern Med. 2009;23(6):1142-50.
21. Read JR, Boston RC, Abraham G, et al. Effect of prolonged administration of clenbuterol on airway reactivity and sweating in horses with inflammatory airway disease. Am J Vet Res. 2012;73(1):140-5.

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