Safety of an extended-release injectable moxidectin suspension formulation (ProHeart® 12) in dogs

Abstract

Background The safety of ProHeart® 12 (PH 12; extended-release injectable suspension; 10% moxidectin in glyceryl tristearate microspheres) was evaluated in four studies using Beagle dogs and one study using ivermectin-sensitive Collies. The recommended dose is 0.5 mg/kg subcutaneously once yearly. Methods Study 1: safety margin was evaluated as 3 treatments of PH 12 (0× (control); 1× (recommended dose); 3× (3 times recommended dose) and 5× (5 times recommended dose) in 12 months via clinical observations, body weights, food consumption, injection site observations, physical examinations, moxidectin tissue assay, pharmacokinetics, and clinical and anatomic pathology. Study 2: safety in breeding-age males was demonstrated by semen testing at 14-day intervals from Day 7 to Day 91 post-treatment (0× or 3×). Study 3: reproductive safety in females was demonstrated by monitoring dams and litters following treatments (0× or 3×) administered during breeding, gestation, or lactation. Study 4: safety in dogs surgically implanted with adult heartworms was evaluated by clinical and laboratory monitoring following treatment with 0× or 3× administered 61 days post-implantation. Study 5: safety in ivermectin-sensitive dogs (120 µg/kg SC) was by clinical monitoring for 1 week after administering 1×, 3× or 5×. Results Study 1: slight swelling clinically detectable at some 3× and 5× injection sites was characterized microscopically as granulomatous inflammation, like tissue responses to medical implants, interpreted as non-adverse. Pharmacokinetics were dose-proportional and there was little or no systemic accumulation. Residual moxidectin mean (range) at 1× injection sites after 1 year was 16.0% (0.045–37.6%) of the administered mass. Studies 2 and 3: no effects were identified in reproductive indices (females) or semen quality characteristics (males). Study 4: PH 12 produced marked reductions in circulating microfilariae and lower numbers of adult heartworms, but no adverse clinical signs were identified. Study 5: there were no abnormal clinical signs at 1×, 3× or 5× overdoses of PH 12 in ivermectin-sensitive dogs. Conclusions PH 12 has a > 5× safety margin in both normal and ivermectin-sensitive dogs, has no effects on canine reproduction, and is well tolerated in heartworm-positive dogs. The only treatment-related finding was non-adverse, granulomatous inflammation at the injection site.

Efficacy of semi-annual therapy of an extended-release injectable moxidectin suspension and oral doxycycline in Dirofilaria immitis naturally infected dogs

“…Treatment-related adverse effects were not reported by dog owners or treating veterinarians, and hematologic and biochemical parameters were maintained within reference ranges throughout the treatment. Results of previous studies have shown that administration of up to 5× the label dose of 0.5 mg/ kg of extended-release injectable moxidectin suspension, administered every six months for three consecutive treatments, was well tolerated [22]. Additional studies should be conducted to establish safety of the combined protocol with moxidectin plus doxycycline; however, from a clinical perspective, the treatment protocol followed in this study was shown to be effective and well tolerated in these pet dogs with naturally occurring heartworm infections.…”

“…In a previous study of the same extended-release moxidectin suspension in dogs experimentally infected with D. immitis , microfilaremia decreased rapidly, with an average reduction of 20.9% one day after treatment and 96.9% on day 84, although this study used a ML-resistant strain [ 17 ]. In a study conducted as part of the pivotal safety evaluation of ProHeart ® 12, a 3× dose (1.5 mg/kg) demonstrated a > 99% reduction in geometric mean microfilaria counts on day 15 post-treatment against a susceptible strain of heartworm [ 22 ].…”

“…ProHeart ® 12 and ProHeart ® SR-12 are brand names of the same extended-release microsphere formulation of moxidectin, the former being marketed in the USA and the later in Australia, Japan, southeast Asia and Brazil. Recently published studies report the efficacy of a single administration of injectable moxidectin at 0.5 mg/kg (1 ml/20 kg) by subcutaneous (SC) injection as a heartworm preventative and safety of 1×, 3× and 5× the dose every six months for three treatments in normal beagles beginning at six months of age and as high as 5× the use rate in reproducing animals, ivermectin-sensitive dogs, and heartworm-positive dogs [16,22].…”

An Accessible Alternative to Melarsomine: “Moxi-Doxy” for Treatment of Adult Heartworm Infection in Dogs

“…An extensive pharmacovigilance monitoring program and post-marketing surveillance showed allergic reactions of 1.26 per 10,000, with a similar rate (1.19) for non-allergic reactions ( 75 ). Recent studies of 12-month SR moxidectin demonstrated safety and efficacy as a preventive ( 64 , 76 ). Reports of adverse events over an extended period were comparable to those reported for ivermectin/pyrantel (Heartgard® Plus, Boehringer Ingelheim) ( 64 ).…”

Use of Slow-Release Injectable Moxidectin for Treatment of Dirofilaria immitis Infection During Pregnancy

“…This long-term treatment is also called "alternative treatment, " "slow kill, " "soft kill, " "doxy-moxi, " or "moxi-doxy" and is recommended to be used when the arsenical drug is unavailable or when fast kill is contraindicated (2, 7). The injectable moxidectin is an extended-release injectable formulation that can be used in breeding animals and a 5X safety margin has been shown (16).…”