- 1 Active substance / Generic: Indoxacarb
- 1.1 Activyl: Quality assessment
- 1.2 Indoxacarb: Safety assessment
- 1.3 Indoxacarb: Efficacy assessment
- 1.4 Activyl: Benefit risk assessment
Active substance / Generic: Indoxacarb
This medicine is approved for use in the European Union
Activyl, a spot-on solution contains indoxacarb as the active substance and is presented in containers of one or four pipettes for single-use. It is indicated for the treatment and prevention of flea infestation. The target species are dogs and cats. The applicant for this veterinary medicinal product is Intervet International B.V., The Netherlands.
The active substance of Activyl is indoxacarb an ectoparasiticide for topical use, ATCvet QP53AX27, which after bioactivation by insects’ enzymes interferes with the nervous system of the parasites and causes paralysis and death.
The benefits of Activyl are its effectiveness in the treatment and prevention of flea infestations in dogs and cats. The most common side effect is hypersalivation if the animal licks the application site.
The approved indication is: For dogs and cats:
Treatment and prevention of flea infestation (Ctenocephalides felis)
The veterinary medicinal product can be used as part of a treatment strategy for flea allergy dermatitis (FAD).
Developing stages of fleas in the pet’s immediate surroundings are killed following contact with Activyl treated pets.
The GMP status of the dosage form manufacturing, assembly and release sites is satisfactory.
The pharmacovigilance system in place complies with the requirements in the guideline on monitoring of compliance with pharmacovigilance regulatory obligations and pharmacovigilance inspections for veterinary medicinal products in Volume 9 of the Rules governing medicinal products in the EU.
Activyl: Quality assessment
Activyl contains indoxacarb 195 mg / ml in a non-aqueous solution of triacetin, ethyl acetoacetate and isopropyl alcohol and is packed in single-dose spot-on applicators of different sizes for both dogs and cats.
Activyl is packed in single-dose spot-on pipettes composed of a polypropylene / cyclic-olefin-co-polymer / polypropylene blister foil and an aluminium / polypropylene co-extruded lidstock which are then secondary packed in aluminium sachets. The unit dose pipettes are presented as 0.51 ml, 0.77 ml, 1.54 ml, 3.08 ml, and 4.62 ml for very small dogs, small dogs, medium dogs, large dogs and very large dogs respectively. Two sizes of pipettes 0.51 ml and 1.03 ml are authorised for small cats and large cats respectively.
The choice of the formulation is based on the solubility of indoxacarb in several tested solvents and evaluation of appearance on the animal in an iterative process of appearance evaluations. Preservatives are not required as the product is for single-use. An early formulation has been replaced by the final formulation to achieve less ‘run-off’ of the product from the skin of the animals. Clinical and non-clinical studies have been performed with both formulations. A clear overview of the products that were used in the submitted clinical and non-clinical studies has been provided. As preliminary data indicated an increase in water content upon exposure to higher relative humidity environments, an aluminium sachet was added as additional packaging.
Method of manufacture
Indoxacarb is dissolved in the mixture of ethyl acetoacetate, triacetin and isopropyl alcohol. As a flammability / safety precaution, the tank is blanketed with nitrogen. The bulk solution is filtered in-line in the filling process. The process is straightforward and considered as a standard process. The fill weight is based on the assay and the previously determined residual volume that will remain in the containers after expression of the dose. Validation of pilot-scale batches indicates that the manufacturing process yields a robust reproducible product, yet the fill weight will be confirmed in the validation with production scale batches, together with mixing speeds and times, purge volumes, filling speed, and hold times.
Overall Conclusion On Quality
The dossier provides an appropriately detailed description of the active substance and the chosen formulation, and demonstrates that production of the active substance and the product leads to a consistent quality. The analytical methods are well described, and data of their validation confirm their suitability. Stability studies have been performed according to relevant VICH guidelines. The primary stability studies are on-going. The stability studies done on the active substance allow a re-test period of 2 years, if not stored above 30°C for the active substance indoxacarb and a shelf-life of 2 years, stored in the original packaging in order to protect from moisture for the drug product.
Overall the documentation on quality relating to both indoxacarb, the active substance and the final product is satisfactory and provides reassurance that product of consistent quality will be produced.
Indoxacarb: Safety assessment
Pharmacokinetics in dogs and cats
The pharmacokinetics of indoxacarb was studied in the dog and the cat, both after oral and topical administration, in a total of 3 studies. As for the rat, less than 10% of an orally administered dose is transformed into IN-JT333.
Topical application of radiolabelled indoxacarb to dogs and cats revealed concentrations in hair and skin at the treatment site higher than on the rest of the body areas at one week after application, while the concentration in hair was always much higher than in skin. In general, the concentrations in hair and skin in the regions outside the treatment site were fairly similar for each animal indicating the material had spread evenly. Although the dose level for cats was 1.7-fold that of dogs, the respective mean concentrations in hair and skin outside of the treatment site for dogs and cats were comparable. This observation, along with the accompanying observation that a higher percentage of dosed radioactivity was excreted in cats, might be explained by oral ingestión of the product via grooming behaviour in cats. However, oral absorption in cats by grooming cannot easily be distinguished from higher dermal absorption with the presented data.
Dermal absorption of indoxacarb from the final formulation during 28 days was at least 19% and 34% in dogs and cats, respectively.
Oral absorption of indoxacarb administered in a polyethylene glycol formulation in dogs and cats after 0.32 mg / kg BW treatment was approximately 85% and 82%, respectively.
The absorbed indoxacarb was extensively metabolised by the liver to a variety of small metabolites eliminated in urine and faeces. Indoxacarb metabolism in cats and dogs was similar.
Overall conclusions on safety
Due to its use for agricultural purposes, the safety of indoxacarb has been studied thoroughly. However, these studies served another purpose, i.e. user and consumer safety rather than safety in the target species. Consequently, differences in study design, implementation and reporting as well as formulations used were observed. Although the information is valid as such, extrapolation to safety-aspects of indoxacarb in target animal species required careful consideration of data.
Based on the no observed effect levels (NOAEL) generated with the racemic (50:50) mixture of enantiomers, the purified S-enantiomer and the 75:25 ratio of enantiomers in rats (3 months studies), the toxicity of all three materials is quantitatively and qualitatively similar. Adverse effects seen in subchronic feeding studies in mice and dogs with the racemic (50:50) mixture of enantiomers are qualitatively very similar to those seen in rats, moreover mice appeared less sensitive than rats.
Adverse events observed in the in vivo repeat dose toxicology studies in rats and dogs were mild haematological effects and effects on the body weight. This toxicological effect of indoxacarb is mild regenerative red cell haemolysis, which is thought to be the result of oxidative damage to red cells mediated by the putative metabolite N-hydroxyarylamine. This metabolite contains the structure of the hydroxylated metabolites of aniline, a known substance causing haemolysis (or methaemoglobinaemia). Slight increases in methaemoglobin as well could be seen in rats in subchronic oral toxicity studies with the purified S-enantiomer. Methaemoglobin results from oxidation of haemoglobin iron from the ferrous to the ferric state.
Reproduction toxicity was only studied in laboratory animals and not in the target species.
In view of the data on reproduction toxicity in rats, it is concluded that effects on reproduction in the target species are unlikely to occur. However, given the observations made in the cat (increased number early pregnancy terminations; decreased litter size) when treated prior to mating, then through mating, gestation and lactation, the product is not recommended for use in breeding, pregnant and lactating animals.
Possible risks for the user are mitigated by appropriate warnings and precautions which are included in the product information.
Indoxacarb: Efficacy assessment
Indoxacarb is a novel substance in the EU and intended for the control of flea infestations in the dog and the cat. After being converted into its toxic metabolite IN-JT333 by the insect, it has a high and specific receptor affinity, rapidly leading to inactivation of the insect and death.
In the insect, the rate of metabolic conversion of indoxacarb to the active metabolite IN-JT333 is high (at least 90%) and formation of IN-JT333 (i.e., “bioactivation”) is the major metabolic pathway of indoxacarb in insects.
Mammals are much less efficient in their ability to convert indoxacarb to IN-JT333. In mammals, the metabolic pathway of indoxacarb differs from that of in insect leading to conversion of indoxacarb to mainly nontoxic metabolites (e.g., IN-KG433).
After topical administration indoxacarb becomes systemically available, but levels remain far below those needed for toxic effects. A specific haemolytic effect has been demonstrated, but levels needed to elicit this effect are not reached in the target animal when the product is used as recommended.
Tolerance studies were carried out in the target species as a spot on treatment at the recommended dose as well as 3x and 5x overdoses. The minimum age was 8 weeks for both species. No adverse reactions were observed.
Applied as a spot-on formulation, adequate levels of flea control are achieved for a dose of 15 mg/kg BW in the dog and of 25 mg/kg BW in the cat. Optimal efficacy is achieved after 48 hours and maintained for up to 4 weeks in the dog and the cat.
Treatment results in a parricidal effect for up to 5 weeks in both animal species.
Adequate efficacy was demonstrated under EU-field conditions.
Activyl: Benefit risk assessment
Activyl is a spot-on solution for the treatment and prevention of fleas in dogs and cats, and can be used as part of a treatment strategy for flea allergy dermatitis. The product contains one active substance, indoxacarb, which has not been previously authorised as a veterinary medicine in the EU. Indoxacarb is an ectoparasiticide belonging to the oxadiazine chemical family, and has a history of use in plant protection.
Direct therapeutic benefit
Clinical studies have demonstrated adequate efficacy of Activyl under EU-field conditions. The mode of action is characterised by the bioactivation of indoxacarb into a metabolite that subsequently blocks the sodium channels in the fleas. This toxic metabolite is produced in high amounts in insects but in low amounts in mammals.
Indoxacarb exerts its effects by blocking the sodium channels in the fleas, but shows no overt neurotoxic signs in mammals because the responsible metabolite is formed in quite low amounts in mammals. However, other metabolites of indoxacarb are capable to cause some adverse effects at high doses. In particular an N-hydroxylarylamine metabolite is considered to be responsible for red blood cell haemolysis.
Nevertheless, indoxacarb in its final formulation is well tolerated in dogs and cats, even at dermal doses ten times the recommended dose.
The safety for the user has been adequately addressed. Although all margins of exposure were greater than one, some were too low to exclude any toxic effects.
Risk management or mitigation measures
No specific risk management or mitigation measures seem to be needed for the safety of the target animals.
To protect children from exposure to the content of a pipette, the applicant provided a child-resistant packaging. Other proposed warnings were considered adequate to mitigate any other possible risks arising from user exposure to the product.
Evaluation of the benefit risk balance
It can be concluded that the product appears to be effective and safe for target animals and for the users. Some outstanding issues need to be addressed by the applicant post-authorisation; however these are related to the quality part and will not impact on the benefit risk balance.
Conclusion on benefit risk balance
The benefit risk balance is considered to be positive.
Based on the original and complementary data presented, the Committee for Medicinal Products for Veterinary Use concluded that the quality, safety and efficacy of the product were considered to be in accordance with the requirements of Directive 2001 / 82 / EC as amended.