ProHeart 6 (Canada)

1. Shake microspheres vial to break up aggregates prior to constitution.

2. Using a 18G or 20G needle and sterile syringe withdraw 17 mL of the unique vehicle from the vial. There is slightly more vehicle supplied than the 17 mL required.

3. Insert the enclosed 25G vent needle into the microsphere vial.

4. Transfer the vehicle into the microsphere vial through the stopper using the transfer needle and syringe.

5. Once the vehicle has been added, remove the vent and transfer needles from the microsphere vial. Discard unused vehicle and needles.

6. Shake the microsphere vial vigorously until a thoroughly mixed suspension is produced.

7. Allow suspension to stand for at least 30 minutes to allow large air bubbles to dissipate.

8. Record the date of mixing on the microsphere vial.

9. Before every use, gently swirl the mixture to achieve uniform suspension. The microspheres and vehicle will gradually separate on standing.

10. Use a 1 mL or 3 mL syringe and a 18G or 20G needle for dosing. Dose promptly after drawing into dosing syringe. If necessary when administration is delayed, gently roll the dosing syringe prior to injection to maintain a uniform suspension and accurate dosing.

11. Refrigerate the unused product. The constituted product remains stable for eight weeks in a refrigerator. Avoid direct sunlight.

Administration And Dosage

Swirl gently to uniformly resuspend microspheres in the constituted product before withdrawing 0.05 mL of the suspension/kg body weight into an appropriate size syringe fitted with a 18G or 20G hypodermic needle. Inject the product subcutaneously in the dorsum of the neck cranial to the scapula, at a rate of 0.05 mL of suspension per kg of body weight as soon as possible. ProHeart 6 can be administered to dogs 6 months of age and older. For growing dogs, dose to the average weight during the 6 month effective period.

Recommended Dosage Chart

Dog Weight (kg)	Dosage (ml/dog)	Dog Weight (kg)	Dosage (ml/dog)
5	0.25	35	1.75
10	0.50	40	2.00
15	0.75	45	2.25
20	1.00	50	2.50
25	1.25	55	2.75
30	1.50	60	3.00

Adverse Reactions

Adverse Drug Reaction Overview

Post-market experience with ProHeart 6 has identified a number of safety concerns associated with the use of this drug. The most frequently reported adverse events requiring clinical intervention have been allergic in nature. These reactions appear to be idiosyncratic, with no identifiable risk factors such as health status, age, sex, or breed. Anaphylaxis is the most clinically significant serious allergic event. The great majority of these adverse events have occurred at the labeled dose. Vomiting, lethargy and injection site reactions are other reported adverse events. Standard therapeutic intervention should be administered as appropriate. Consult a veterinarian immediately if any adverse reaction is suspected.

Field Trial Adverse Drug Reactions

Because field trials are conducted under carefully controlled conditions, the adverse drug reaction rates observed in field trials may not reflect the rates observed in practice. In the four ProHeart 6 18-month long field trial studies, mild, transient swelling of injection sites for approximately 1-8 weeks have been observed further to the administration of the product per label recommendation. Other reactions observed at various times during the field testing program included diarrhea, vomiting, pruritus, weight loss, listlessness, seizures and increased body temperature.

The various adverse events reported during field trial studies with the recommended dose of ProHeart 6 are provided in the following table.

Percentage Of Dogs With Abnormal Health

Observations Reported In Field Trial Studies (n = 280)*

Observation	Percentage Of Proheart 6-treated Dogs (# Cases)
Vomiting	1.07 (3)
Injection Site Pruritus	1.07 (3)
Weight Loss	0.71 (2)
Diarrhea	0.71 (2)
Listlessness	0.36 (1)
Elevated Body Temperature	0.36 (1)
Seizures	0.36 (1)

*Data taken from the US FDA Center for Veterinary Medicine Freedom of Information Summary for ProHeart 6 (moxidectin) Sustained Release Injectable for Dogs, NADA 141-189.

Adverse reactions, other than injection site swellings, have not been observed in margin of safety studies in which dogs were administered ProHeart 6 at dosages up to five times the recommended dose level.

Post-approval Experience

Although all adverse reactions are not reported, the following adverse reaction information is based on voluntary post-approval adverse drug experience reporting. It is generally recognized that this method of reporting results in significant under-reporting of adverse drug reactions. In order of decreasing frequency, the adverse reactions reported to Health Canada through 2005 include, facial edema, anaphylaxis, vomiting, injection site reports, lethargy, urticaria, pruritus, diarrhea, anorexia, pain, liver disease and seizures. Allergic reactions represent the most common serious events reported. The post-approval experience in Europe is comparable to that of Canada in that reported events are similar in nature.

The following adverse reaction reports are based on voluntary post-approval reporting to the Center for Veterinary Medicine in the United States*. For each body system, adverse reactions are listed in decreasing order of frequency.

Gastrointestinal

vomiting, diarrhea, anorexia, hypersalivation, dehydration, abdominal pain, elevated pancreatic enzymes, hematochezia, incontinence, gastrointestinal lesion, abdominal distension, pancreatitis, gastroenteritis, nausea, dysphagia, peritoneal effusion, tenesmus, gingivitis, polyphagia, tongue edema, constipation, pharyngitis, esophageal lesion, oral lesion, mesenteric lesion, tongue ulcer, gastrointestinal volvulus, borborygmi, esophageal obstruction, pica, prolapsed rectum, abnormal stool, esophageal dilatation, halitosis

Endocrine

hyperglycemia, hypercalcemia, hypoglycemia, hypothyroidism, hyperphosphatemia glucosuria, diabetes, hypoadrenocorticism, adrenal lesion, hyperadrenocorticism, parathyroid lesion

Hepatic

elevated liver enzymes, hypoalbuminemia, liver lesion, hypoproteinemia, icterus, hypercholesterolemia, abnormal hepatic ultrasound, low BUN, ascites, bilirubinuria, hepatomegaly, elevated lipids, hepatitis, liver failure, low fibrinogen

Neurologic

seizure, ataxia, paresis, nystagmus, proprioceptive deficit, blindness, head tilt, mydriasis, circling, neck pain, staring, vestibular disease, miosis, opisthotonos, pupillary areflexia, deafness, back pain, meningeal lesion, anisocoria, CSF abnormality, hyperesthesia, uveitis, hyphema, facial nerve paralysis, paralysis, brain lesion, paddling, encephalopathy, glaucoma, head pressing, retinal abnormality, strabismus, CNS infarct, dementia, head bobbing, inflammation of the iris, corneal opacity, prolapsed disc, prolapsed eyelid, neck torsion, corneal ulcer, blepharospasm, epiphora, Horner’s, keratoconjunctivitis, neuritis, photophobia, spinal cord lesion

Urinary

elevated BUN, elevated creatinine, hematuria, polydipsia, renal failure, proteinuria, adipsia, polyuria, hypokalemia, low specific gravity, hyponatremia, hypochloremia, UTI, bladder lesion, azotemia, crystalluria, abnormal kidney function test, electrolyte abnormalities, nephritis, stranguria, acidosis, casts, anuria, nephrotic calculi, cystitis, dysuria, oliguria

Behavioural

depression, lethargy, recumbency, trembling, nervousness, confusion, hyperactivity, vocalization, abnormal behaviour, aggression, unconsciousness, pacing, insomnia, fly biting, hallucination

Hematologic

elevated WBC, anemia, thrombocytopenia, autoimmune hemolytic anemia, neutrophilia, polycythemia, low WBC, petechia, monocytosis, lymphopenia, epistaxis, eosinophilia, DIC, bone marrow lesion, aplastic anemia, monocytopenia, reticulocytosis, basophilia, eosinopenia, pancytopenia, hemaglobinuria, clotting problem

Dermatologic/musculoskeletal

injection site swelling, pain on injection, alopecia, lameness, pain, skin lesion, abscess, twitching, stiffness, ecchymosis, dermatitis, conjunctivitis, locomotary disorder, otitis, arthritis, seborrhea, shedding, skin necrosis/ulceration, scleral injection, granuloma, hyperpigmentation, cellulitus, dermal mass, hyperkeratosis, erythema multiforme, myositis, bone lesion, muscle lesion, leukoderm, tail disorder, tetany

Immunologic

anaphylaxis, urticaria, facial edema, edema, pruritus, lymphadenopathy, hyperglobulinemia, splenic lesion, Coomb’s positive, splenomegaly, ANA positive, purpura, thymic lesion

Cardiopulmonary

dyspnea, polypnea, pallor, coughing, bradycardia, cardiac arrest, weak pulse, cyanosis, heart murmur, cardiopulmonary lesion, pulmonary congestion, exercise intolerance, apnea, nasal discharge, pleural effusion, ECG abnormality, syncope, arrhythmia, cardiomegaly, hypertension, sneezing, pericardial effusion, pneumonia, bronchitis, emphysema, tachycardia

Generalized

fever, weight loss, hypothermia, muscle atrophy, hyperemia, sepsis, weight gain

Neoplastic

neoplasm, injection site neoplasm, lymphoma, skin neoplasia, abdominal mass, liver neoplasm, brain neoplasia, bone neoplasm, multiple organ neoplasm, pancreatic neoplasm, splenic neoplasm

Reproductive

vaginal bleeding, prostatomegaly, birth defect, abortion, vulvular discharge, vulvular edema, abnormal estrus, scrotal erythema/edema, metritis, prepucial edema, testicular edema

In rare situations, death has been associated with some of the adverse reactions listed above.

*Taken from the US FDA Center for Veterinary Medicine’s July, 2004 Cumulative ADE Summary.

Animal Safety

ProHeart 6 has been safely administered to a wide variety of dog breeds. The target animal safety testing program for ProHeart 6 included field tests at the recommended dose level, a margin of safety study, tests with ivermectin-sensitive collie dogs, tests with dogs known to have patent heartworm infections, and reproductive studies with breeding bitches and stud dogs. The results of these studies showed that ProHeart 6 was safe at all doses tested in target animals six months of age and older, including administration at five times the recommended dose level.

As part of the field-testing program, ProHeart 6 was safely used in conjunction with a variety of veterinary products commonly used in dogs. These products included vaccines, vitamins and nutritional supplements, steroid and antibiotic medications, anesthesia, tranquilizers, sedatives, nonsteroidal anti-inflammatory products, shampoos, dips, and other ectoparasite treatments.

Warning

KEEP THIS AND ALL DRUGS OUT OF REACH OF CHILDREN. In case of human consumption, contact a Poison Control Center or a physician immediately.

How Supplied

ProHeart 6 (moxidectin) Sustained Release Injectable Suspension for Dogs comes in a twin vial pack.

5-pack

17 mL vial product: 5 - 10% moxidectin microspheres - 598 mg/vial, 5 - constitution vehicle - 17 mL/vial

Storage

Store the unconstituted product at 25°C or lower. Do not expose to light for extended periods of time. After constitution, the product is stable for 8 weeks stored under refrigeration at 2° to 8°C.

Wyeth Animal Health, Division of Wyeth Canada, Guelph, Ontario N1K 1E4

Trademarks used under license

00326

C3670C

Nac No.

11984211