General

All dogs with heartworm disease are at risk for post-treatment pulmonary thromboembolism (death of worms which may result in fever, weakness, and  coughing), though dogs with severe pulmonary arterial disease have an increased risk and may exhibit more severe signs (dyspnea, hemoptysis, right heart failure and possibly death). Dogs  should be restricted from light to heavy exercise post-treatment depending on the severity of their heartworm disease.
Studies in healthy (heartworm negative) dogs indicate that adverse reactions may occur after the  second injection in the series even if no problems were encountered with the first injection. All  patients should be closely during treatment and for up to 24 hours after the last injection.

Studies in Healthy (Heartworm Negative) Dogs

The safety of melarsomine dihydrochloride was studied in 24 healthy beagle dogs. Drug was administered
at 0, 2.5, 5.0, and 7.5 mg/kg for 6 consecutive days (0, 1, 2, and 3 times the recommended dosage). Clinical observations included tremors, lethargy,  unsteadiness/ ataxia, restlessness, panting, shallow and labored respiration, and/or rales. These
signs were seen in all groups treated with melarsomine dihydrochloride with frequency and intensity
increasing with increasing dosage. Death or euthanasia in a moribund state occurred in 3/6 dogs in
the 7.5 mg/kg (3X) group. The signs exhibited by these dogs, in addition to the signs described
above, included collapse, severe salivation, vomiting, respiratory distress, cyanosis, stupor, and
death within 4 hours of the first dose in two dogs and within 20 hours of the second dose in one  dog.

Body weights, water consumption, hematology and urine parameters were comparable to controls.
Decreased food consumption occurred sporadically in the two high dose groups. Elevations, up to
25-fold,  in creatinine kinase (CK) and elevations, up to 7-fold, in aspartate aminotransferase
(AST) were observed and related grossly and histologically to muscle damage at the injection sites. Up to 2-fold
elevations in alanine aminotransferase (ALT) were also noted. Gross and microscopic pathology
revealed no organ-related toxicity other than edema and acute inflammation in the lungs and pleural
effusion in the 3 dogs that died at the 7.5 mg/kg dose. Injection site irritation was observed in the skeletal muscles at all dose levels.
At 5.0 mg/kg an injection site abscess was observed in one dog.

A separate study was conducted to examine the inten- sity and duration of injection site reactions.
The dogs were dosed at 2.5 and 5.0 mg/kg (1X and 2X the recommended dose) twice 24 hours apart.
This treat- ment series was repeated 4 months later. One group received the second treatment series
after 1 month to mimic the alternate dosing regime. Swelling, which occurred within 7 days of
injection and persisted from 1 to 72 days (average 30 days), was the most common clinical
observation. A small, firm nodule in the lumbar region of one dog in the 1X group appeared during
the first month of the study and persisted for 41 days. Pain at or following injection was not observed in this study. Elevations of the same magnitude as in  the previous study and again related to muscle damage were observed in CK and AST within 8 hours of
injection. The values approached pretest levels by 72 hours and were within the normal range established by control animals by
1 month post-injection.

Gross and microscopic evidence of injection site irritation (cellular infiltrate, fibrosis,
necrosis, and hemorrhage) was still evident in the muscles 1 month post-injection in dogs at both
dose levels. By 3 months post-injection, resolution (healing) was evident micro- scopically in the
skeletal muscles at the 2.5 mg/kg dose level. One dog treated at the 2X dose had extension of
treatment-related injection site inflammation into deeper tissues (i.e., abdominal cavity) as evidenced by an adhesion between the spleen and mesentery.

Other Reactions

Coughing/gagging, depression/lethargy, anorexia/inappetence, fever, lung congestion, and vomiting were the most common reactions
observed in dogs treated with melarsomine dihydrochloride. Hypersalivation and panting occurred
rarely in clinical trials (1.9% and 1.6%, respectively); however, these signs may occur within
30 minutes of injection and may be severe. One dog vomited after each injection of melarsomine
dihydrochloride, despite pretreatment with anti-emetics. All adverse reactions resolved with time
or treatment with the exception of a limited number of injection site reac- tions (persistent
nodules, (see Table: Average Onset Time and Duration (with Ranges) of the Most Common Reactions in Clinical Trials) and a low number of posttreatment deaths (see Mortality).

Prevalence of Clinical Observations/Adverse Reactions Reported in Clinical Field Trials

Prevalence of Clinical Observations/Adverse Reactions Reported in Clinical Field Trials: The following table enumerates adverse events that occurred in 1.5% or more of dogs with Class 1, 2, and 3 heartworm disease treated with melarsomine
dihydrochloride in clinical field trials. Comparison is made with the same adverse events reported
in dogs treated with placebo. Some of the following clinical observations/adverse reactions seen in
dogs treated with melarsomine dihydrochloride may be directly attributable to the drug or they may be secondary to worm death and/or the underlying heartwormdisease process.

.

Clinical observations/adverse reactions occurring in
less than 1.5% of the dogs treated with melarsomine dihydrochloride include: abdominal hemorrhage,
abdominal pain, bloody stool/diarrhea, colitis, gingivitis, pancreatitis, anemia, DIC,
hemoglobinemia, icterus (mucous membranes), discolored urine, hematuria, inappropriate urination,
low specific gravity, polyuria, pyuria, bronchitis, miscellaneous respiratory problem, pneumonia,
tachypnea, tracheobronchitis, wheezing, alopecia, hair color and coat character change, miscella-
neous skin problem, ataxia, disorientation, fatigue/tires easily, miscellaneous eye problem, weight
loss, convul- sion/seizure, leukocytosis, polydipsia, and restlessness.

Mortality

Death is a possible sequelae of heartworm disease in dogs with or without treatment, especially in the Class 3 dogs. The following table shows the percentage of dogs that died in clinical trials with melarsomine dihydrochloride and the causes of death, if known.

In one small (n=15), uncontrolled field study in severely ill (Class 3) dogs, 5 dogs died following treatment. Pulmonary thromboembolism was the cause of one death. The remaining dogs were not necropsied. All 5 dogs were in right heart failure at the time of treatment. Clinical signs seen in this study which were not seen in the larger studies include atrial fibrillation, collapse, hypothermia, and weakness.

Post Approval Experience

In addition to the aforementioned adverse reactions reported in pre-approval clinical studies, there have also been rare
reports of paresis and paralysis in dogs following administration of melarsomine dihydrochloride.
To report a suspected adverse reaction, contact Zoetis Inc. at 1-888-963-8471.

Overdosage

Three dogs were inadvertently overdosed with melarsomine dihydrochloride in the clinical field trials when the dose was calculated on a
mg/lb basis rather than a mg/kg basis (2X overdosage). Within 30 minutes of injection, one dog  showed excessive
salivation, panting, restlessness, and fever with all signs resolving within 4 hours. Vomiting and
diarrhea were seen in the second dog within 24 hours of injection. The dog vomited once and the diarrhea resolved within 24 hours. The third dog showed no systemic  reaction to the overdosage. Clinical observations in healthy beagle dogs after receiving up to 3X
the recommended dose included tremors, lethargy, unsteadiness/ataxia, restlessness, panting,  shallow and labored respiration, rales, severe salivation, and vomiting which progressed to respiratory distress, collapse, cyanosis, stupor, and death (see SAFETY).

BAL in Oil Ampules (Dimercaprol Injection, USP) [Akorn, San Clemente, California, at 1-800-223-9851] is reported in the literature to be an antidote for arsenic toxicity and was shown in one study to reduce the signs of toxicity associated with overdosage of melarsomine  dihydrochloride. The efficacy of melarsomine dihydrochloride may be reduced with co-administration of BAL.

Laboratory Studies

Placebo-controlled  laboratory studies, melarsomine dihydrochloride, administered at
2.5 mg/kg twice, 24 hours apart, was 90.7% effective against transplanted adult heartworms and
90.8% effective against induced infections of 4 month old (L5) immature heartworms. To evaluate the
effectiveness of the alternate dosing regimen, dogs with transplanted heartworms were treated with
either 2.5 mg/kg once or 2.5 mg/kg once followed 1 month later with 2.5 mg/kg administered twice 24 hours apart. A single
injection of melarsomine dihydrochloride at 2.5 mg/kg reduced male worms 87.7% and female worms
16.9% (total 51.7%). When the full regime was used 100% of male worms and 98% of female worms were
killed (total 99%). Dogs with natural D. immitis infections were treated with melarsomine
dihydrochloride at 2.5 mg/kg twice, 24 hours apart. This dose was repeated 4 months later. Antigen
tests performed at month 4 showed a 90% conversion from antigen positive to negative status. Worm
counts at month 9 showed a 98.7% reduction in worm numbers as compared to placebo controls.

Clinical Field Studies

In two well-controlled field studies, 169 client-owned dogs, 1 to 12 years old and weighing 3.0 to 59.0 kg, with Class 1 or
stabilized Class 2 heartworm disease were treated with the recommended dose of melarsomine
dihydrochloride. In-office blood antigen tests were used pretreatment to diagnose the D. immitis infection and 4
months after drug administration to assess treatment response. At month 4, 76.2 to 81% of the dogs
had converted from antigen positive to antigen negative status. The conver- sion rate ranged from
89.7 to 98.2% after two treatment series. In an open-label study in 102 dogs, 1 to 18 years old and
weighing 4.4 to 40.8 kg, with Class 1 or stabilized Class 2 heartworm disease, the conversion
rate was 84% 4 months after one series of treatments. When a second series was given at month 4,
the conversion rate was 94%.

An open-label clinical field study was conducted in 44 dogs, 1.5 to 14 years old and weighing 3.2 to 50.0 kg, with stabilized, Class 3 heartworm  disease. Dogs received the alternate dosing regime (2.5 mg/kg once followed 1 month later by 2.5
mg/kg twice 24 hours apart). The conversion rate was 89.2% 4 months after the final treatment. In a small, uncontrolled field trial (n=10) in Class 3 dogs the conversion rate was 100% 4 months after treatment.

Disease Classification

It is vital to classify the severity of heartworm disease to apply the appropriate dosage regime for DIROBAN (see INDICATIONS).

Dosing Table

Care must be taken to administer the proper dose. Accurately weigh the dog and calculate the volume to be injected based on the dose of 2.5 mg/kg (1.1 mg/lb). This is equivalent to 0.1 mL/kg (0.045 mL/lb). The following table should be used as a guide to ensure that the proper volume has been calculated.

*Limited data were collected on the administration >5.0 mL at a single injection site

Preparation

DIROBAN should be aseptically reconstituted only with 2.0 mL of sterile water for injection (provided as 2.0 mL sterile water for
injection USP). This provides 2.5 mg melarsomine dihydrochloride per 0.1 mL of injectable solution. Two 50 mg vials will be required for dogs weighing > 20 kg and 40 kg  and 3 vials will be required for dogs > 40 kg and 60 kg. Use immediately. Reconstituted solution may be used within 36 hours if refrigerated and kept from light.

Treatment Response

A baseline can be established pre-treatment by using commercially available in-office heartworm antigen test kits prior to
treatment. Treatment response can be assessed best by heartworm antigen testing applied 4 months after
treatment. A successful treatment is determined to be conversion from an antigen positive to an
antigen negative status. In dogs with signs of heartworm disease, gradual improvement should be
observed as the long-term effects of the heartworm infection resolve. Some dogs may have chronic effects that will not totally resolve.

Routine Prophylaxis

If the dog is not currently receiving commercially available heartworm preventatives, they may be administered consistent with label recommendations and re-exposure risk.