IMMITICIDE® (melarsomine dihydrochloride) Sterile Powder: Approved by the FDA as a canine heartworm treatment

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Dirofilaria immitis, also known as canine heartworm, is arguably the most notable parasite that affects dogs in North America. Canine heartworm is a potentially deadly disease that results in 100,000 new canine cases a year.¹ While this disease is preventable, levels of compliance for administration remain less than optimal. Animals not on prevention can become infected with heartworm, which then needs to be treated. Currently, there is only one compound for heartworm treatment that is approved by the FDA, and that is melarsomine dihydrochloride, the active ingredient in IMMITICIDE® (melarsomine dihydrochloride) Sterile Powder. Unfortunately, there is no approved treatment for cats, as killing heartworms in cats would be contraindicated.

Life cycle

There are several important stages of D. immitis in relation to the life cycle. Adult female worms can grow to a length of 10 to 12 in, whereas males can grow to a length of 4 to 6 in. Adults can live up to 5 to 7 years in dogs; during this time, the adults will mate and release microfilariae into the blood, with each adult female producing over 11,000 microfilariae per day. The microfilariae can then be ingested by a mosquito intermediate host. Once inside the mosquito, the microfilariae migrate within the insect for an average period of approximately 10 to 14 days, during which the microfilariae develop to first-stage larvae (L1). Afterward, the L1 molt twice to become infectious third-stage larvae (L3), which migrate to the mouthparts of the mosquito. Upon landing on a host, the mosquito will then take a bloodmeal and the L3 will “bust out” of the labium (the fleshy lip of the mouthparts). The L3 will then surround the stylet (the piercing portion of the mouthparts) in a pool of mosquito hemolymph. When the stylet is removed, the larvae then enter the host through the hole made by the stylet.²

Once inside the definitive host, the L3 follow a complicated migration pathway. The L3 remain at the site of entrance for approximately 3 to 4 days. During this time, L3 molt to fourth-stage larvae (L4). It is generally agreed that the molt to the last stage, known as the juvenile adult, occurs by day 58.³ By days 67 to 70, worms arrive at their final location, the pulmonary arteries.^3,4 Most worms have reached this location by day 120 postinfection. By day 180, worms are sexually mature and have begun to produce microfilariae, thus completing the life cycle.³

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Pathology of heartworm disease

Adult worms cause the pathologic changes associated with heartworm disease. The severity of disease and extent of pathology can result from a myriad of factors, such as the number of adult worms, duration of infection, individual host immune response, and presence of dead worms. The presence of dead worms is the most crucial factor, as when worms die, they are pushed deeper into the pulmonary vessels, resulting in pulmonary thromboembolism.⁵

Living heartworms are constantly moved back and forth by blood flow, which results in inflammation and thickening of the vessel wall. These vessels appear roughened and stippled, which is pathognomonic for heartworm disease.^6,7

Furthermore, many of these lesions will remain long after heartworms
have been removed. Resulting vessel inelasticity increases pressure on the main pulmonary artery, right heart, and vena cava, which can ultimately lead to pulmonary hypertension, chronic passive congestion of the liver, and ascites.⁵ The longer worms are present in the vessels, the more damage can occur.

Clinical signs of heartworms and classification

Clinical signs are a result of the pathology of the disease, which is dependent on the number of worms and the duration of infection. There are 4 recognized classes of heartworm disease as defined by the American Heartworm Society (AHS). These classes are a continuum, so patients may not fall discreetly into one category. Each of the heartworm disease classes should be treated with IMMITICIDE antiparasitic with one exception: caval syndrome. Dogs with caval syndrome should have worms surgically removed.⁵ The classes are as follows:

Class 1 (mild): Dogs are normally asymptomatic or have a mild cough.

Class 2 (moderate): Dogs will have a more moderate cough, potential dyspnea, and be somewhat exercise intolerant.

Class 3 (severe): These animals are severely dyspneic and exercise intolerant. They will have signs of right-sided conges- tive heart failure, such as ascites. Syncope and hemoptysis may also be present.

Class 4 (caval syndrome): This life-threatening syndrome is associated with acute presentation of signs, which, if not treated, will result in death within 12 to 72 hours. Caval syndrome is normally associated with the presence of a large number of worms obstructing blood flow through the tricuspid valve. Hemoglobinemia and hemoglobinuria are components of this syndrome.⁵

Treatment

When IMMITICIDE antiparasitic first came to market in 1995, it was an immense improvement compared with the efficacy of the previous heartworm adulticide drug, thiacetarsamide sodium, which was injected intravenously. While fairly effective, thiacetarsamide sodium could cause particularly nasty adverse effects, such as skin sloughing.⁸ While not free of adverse effects, IMMITICIDE® (melarsomine dihydrochloride) Sterile Powder was developed to be injected intramuscularly in the epaxial muscles (2.5 mg/kg) as 2 injections that are administered 24 hours apart. This treatment protocol is straightforward and used for dogs with class 1 and 2 heartworm disease.⁹ For class 3 heartworm disease, an alternate protocol is recommended, which consists of 1 injection (2.5 mg/kg), followed 30 days later by 2 injections that are administered 24 hours apart. It is crucial for drug efficacy that the 2 doses be administered no more than 24 hours apart, whether the 2-dose or alternate protocol is used.

The treatment protocol

IMMITICIDE antiparasitic is labeled to kill 4-month and older worms. While both the 2-dose and alternate dosing protocol (3-dose) kill adult worms, the percentage of worms killed and number of dogs cleared of worms differ between dosage regimens. In one study, 90.7% of the total worms were killed; however, out of the 6 treated dogs, 3 were still positive. While the overall clearance rate was above 90%, the clearance rate of worms from dogs was only 50%. This contrasts with the 3-dose protocol, in which the first dose killed 51.7% of worms, the majority of which were males. After 2 more doses were administered 24 hours apart, the efficacy was 99.0% and most dogs were cleared of adult heartworms.¹⁰ The difference in effectiveness between the 2 regimens, both regarding the number of worms and number of dogs cleared of infection, led the AHS to recommend the alternate dosing or 3-dose protocol for all animals.⁵

The 3-dose regimen is also recommended because fewer worms were killed at once (51.7%) with the first dose vs the greater percentage of worms killed with the 2-dose protocol (90.7%).¹⁰ The concept of a staged kill is especially important in cases of class 3 heartworm disease, in which there could be a greater number of worms. When worms die, regardless of whether it is from natural or pharmaceutical means, pulmonary thromboemboli (PTE) will result. PTEs are an inevitable consequence of heartworm treatment and are, by definition, potentially harmful to the patient. Therefore, the goal is to minimize the number of PTEs that happen at once while balancing the need to clear the animal of worms that will cause further damage the longer they remain. Additional components of the heartworm treatment, such as doxycycline and steroids, help mitigate the clinical signs that result from PTEs.⁵

Exercise restriction

As stated above, PTEs and pulmonary damage are inevitable consequences of successful adulticide therapy. No known tests are predictive for PTE; therefore, it is imperative that the dog is exercise restricted post IMMITICIDE® (melarsomine dihydrochloride) Sterile Powder treatment. Worms usually die within 7 to 10 days after IMMITICIDE injection, but their death may take up to 4 weeks. This time corresponds to the occurrence of the clinical signs of embolism, which can include fever, cough, and hemoptysis. For this reason, it is essential to restrict exercise from the time of the first injection to 6 to 8 weeks after the last injection (for a total of 10 to 12 weeks) during heartworm treatment.⁵

Cage rest and leash walking only are strongly recommended. In order to facilitate exercise restriction, however, some alterations to the exercise restriction protocol may be necessary. Assessing the owner’s ability to restrict the animal will aid in tailoring the exercise restriction recommendations to the individual patient. Questions may be asked such as, “How easy, on a scale of 1 to 10, would it be for you to crate rest your pet for 10 to 12 weeks?” Depending on how the owner answers, the recommendation can be altered to fit the owner’s lifestyle while also facilitating the patient’s safety during this crucial time of recovery after IMMITICIDE injection. A good example of amending the protocol would be if the dog is anxious in a crate but calmer in a small room.

Administration of IMMITICIDE antiparasitic

IMMITICIDE antiparasitic is a safe drug when used as per label; however, as with all pharmaceuticals, particularly parenterally administered ones, proper technique must be used. This proper technique begins with weighing the animal. The exact weight is essential to ensure that the proper dosage is administered. The 2.5% solution is prepared by adding 2 ml of sterile diluent (supplied with the package) to the 50 mg of IMMITICIDE antiparasitic in the vial. After reconstitution, use should be avoided after a 24-hour period, as the efficacy of the drug will be reduced. The vial should also be refrigerated and exposure to light minimized.¹¹

Prior to injection, proper volume for administration should be determined, as well as the proper needle size for injection (< 10 kg dogs 23-gauge, 1 in; > 10 kg dogs 22-gauge, 1-0.5 in). The appropriate volume of the drug should be drawn into a syringe and the needle changed, as a fresh needle should always be used for administration.¹¹

IMMITICIDE® (melarsomine dihydrochloride) Sterile Powder should be administered only in the epaxial muscles by deep intramuscular injection in the third through fifth lumbar region, targeting the belly of the epaxial musculature. To locate this region, one should palpate the dorsal process of the seventh lumbar vertebrae, located between the ileal crests. As one palpates cranially, the fifth through third lumbar vertebrae may be located. The injection sites will be located in the epaxial muscles 1 to 2 in lateral to the dorsal processes. Fingers should not be put on the plunger until the needle is fully inserted to minimize accidental administration of the drug into the subcutaneous tissue, which can result in inflammation. After administration, it is crucial to apply pressure to the injection site to minimize leakage of the drug. Finally, when administering 2 injections within a 24-hour period, alternating sides of the lumbar region should be used. By following these guidelines, IMMITICIDE (melarsomine dihydrochloride) Sterile Powder can be safely administered and the animal appropriately treated.¹¹

Conclusion

Melarsomine dihydrochloride (IMMITICIDE) is the only adulticide approved for use for adult heartworms by the FDA. When used appropriately, the drug can treat heartworm disease and allow infected animals to resume a normal lifestyle.

Andy Moorhead, DVM, MS, PhD, DACVIM (Parasitology), is a parasitologist and associate professor at the University of Georgia, College of Veterinary Medicine. He received a DVM degree from North Carolina State University, followed by an MS in veterinary parasitology from Purdue University. He then received his PhD from Cornell University. Moorhead’s main research interests are the role of host-specific cues in development of filarial worms and heartworm treatment. He became a Diplomate of ACVM (Parasitology) in 2015. He has also been an at-large member of the executive board of the American Heartworm Society since 2016. He is currently the Symposium Chair for the 2025 symposium. He is also vice president of the American Association of Parasitologists.

References

1. Self SW, Pulaski CN, McMahan CS, Brown DA, Yabsley MJ, Gettings JR. Regional and local temporal trends in the prevalence of canine heartworm infection in the contiguous United States: 2012-2018. Parasit Vectors. 2019;12(1):380. doi:10.1186/s13071-019-3633-2
2. Anderson RC. Nematode parasites of vertebrates: their development and transmission. 2nd ed. CABI Publishing; 2000.
3. Kotani T, Powers KG. Developmental stages of Dirofilaria immitis in the dog. Am J Vet Res. 1982;43(12):2199-2206.
4. Orihel TC. Morphology of the larval stages of Dirofilaria immitis in the dog. J Parasitol. 1961;47:251-262.
5. American Heartworm Society. Current canine guidelines for the prevention, diagnosis, and management of heartworm (Dirofilaria immitis) infection in dogs. Updated 2020. www.heartwormsociety.org/veterinary-resources/ american-heartworm-society-guidelines
6. Keith JC Jr, Schaub RG, Rawlings C. Early arterial injury-induced myointimal proliferation in canine pulmonary arteries. Am J Vet Res. 1983;44(2):181-186.
7. Falcón-Cordón Y, Montoya-Alonso JA, Caro-Vadillo A, Matos-Rivero JI, Carretón E. Persistence of pulmonary endarteritis in canine heartworm infection 10 months after the eradication of adult parasites of Dirofilaria immitis. Vet Parasitol. 2019;273:1-4. doi:10.1016/j.vetpar.2019.07.008
8. Hoskins JD, Hribernik TN, Kearney MT. Complications following thiacetarsamide sodium therapy in Louisiana dogs with naturally-occurring heartworm disease. Cornell Vet. 1985;75(4):531-539.
9. Raynaud JP. Thiacetarsamide (adulticide) versus melarsomine (RM 340) developed as macrofilaricide (adulticide and larvicide) to cure canine heartworm infection in dogs. Ann Rech Vet 1992;23(1):1-25.
10. Keister DM, Dzimianski MT, McTier TL, et al. Dose selection and confirmation of RM 340, a new filaricide for the treatment of dogs with immature and mature Dirofilaria immitis. In: Soll MD, ed. Proceedings of the Heartworm Symposium ’92: Austin, Texas, March 27-29, 1992. American Heartworm Society; 1992:225-229.
11. Rhone Merieux, Inc. IMMITICIDE (melarsomine dihydrochloride): A safer, more effective and convenient treatment for canine heartworm disease: technical information bulletin. 1995:1-18.

IMMITICIDE Sterile Powder should not be used in dogs with very severe (Class 4) heartworm disease. IMMITICIDE Sterile Powder should be administered by deep intramuscular injection in the lumbar (epaxial) muscles (L3–L5) only. Do not use in any other muscle group. Do not use intravenously. Care should be taken to avoid superficial injection or leakage. Serious adverse reactions may occur in any dog with heartworm disease due to the killing of heartworms in the pulmonary arteries. Reactions may include thromboembolism, dyspnea, coughing, depression, right side heart failure, and death. Dogs should be cage rested following treatment due to possible thromboembolic disease. Post-injection site reactions (eg, pain, swelling) were the most commonly reported adverse events. See full prescribing information for dosing and administration directions prior to each use of IMMITICIDE Sterile Powder.

For full prescribing information visit IMMITICIDEClinic.com