- 1 Active substance / Generic: Indoxacarb-Permethrin
- 1.1 Activyl Tick Plus: Administrative particulars
- 1.2 Indoxacarb-Permethrin: Quality
- 1.3 Indoxacarb-Permethrin: Safety
- 1.4 Indoxacarb-Permethrin: Efficacy
- 1.5 Activyl Tick Plus: Benefit risk assessment
Active substance / Generic: Indoxacarb-Permethrin
This medicine is approved for use in the European Union
Activyl Tick Plus is an ectoparasiticide containing indoxacarb and permethrin as the active substances and is presented in cardboard boxes of 1, 4 or 6 pipettes. Activyl Tick Plus is indicated for flea and tick infestations in dogs and may be used as part of a treatment strategy for flea allergy dermatitis. Developing stages of fleas in the pet’s immediate surroundings are killed following contact with Activyl Tick Plus treated pets.
The route of administration is spot-on use. The target species is dogs.
Activyl Tick Plus: Administrative particulars
The bulk manufacture of the finished product is conducted in USA and the product is batch released in the EU from Intervet Productions SA at Igoville in France. The certificates of GMP compliance provided by the MAH were deemed satisfactory.
A Detailed Description of the Pharmacovigilance System that the applicant will have in place has been provided and is considered satisfactory. A statement has been provided by the applicant and the qualified pharmacovigilance person confirming their availability and the necessary means for the notification of adverse reactions.
The proposed veterinary medicinal product contains indoxacarb 150 mg/ml and permethrin 480 mg/ml in a non-aqueous solution of propylene glycol monomethylether with the antioxidant propyl gallate.
The product is packaged in single-dose spot-on applicators consisting of a polypropylene/cyclic-olefin-co-polymer/polypropylene blister and an aluminium foil/polypropylene co-extruded lid stock, secondary packed in aluminium sachets. There are five presentations, i.e. 0.5 ml, 1.0 ml, 2.0 ml, 4.0 ml, and 6.0 ml, each with a unique pipette size.
Indoxacarb, permethrin, propylene glycol monomethylether, and propyl gallate are all well-known pharmaceutical substances, already approved and used in veterinary spot-on solutions for dogs. The choice of the formulation is based on the solubility of indoxacarb and permethrin in several tested solvents and the evaluation of appearance and run-off of the applied solution on the animal in a standard repeatable process. Preservatives are not required in the formulation as the product is for single-use. Development studies have demonstrated that the addition of an antioxidant is required. A clear overview of the products that were used in the submitted clinical and non-clinical studies has been provided. All clinical studies have been done with the proposed commercial formulation. As preliminary data indicated an increase in water content upon exposure to higher relative humidity environments and photostability studies demonstrated that the product packed in the pipette is not stable in light, an aluminium sachet was added as additional packaging. The product is highly flammable. A warning is included in the SPC under section 4.5.
Method of manufacture
Propyl gallate, indoxacarb and permethrin are dissolved in propylene glycol monomethylether. As a flammability/safety precaution, the tank will be blanketed with nitrogen. The bulk solution is filtered in the filling process. The process is straightforward and considered as a standard process. The fill weight is based on the bulk product density and the previously determined residual volume that will remain in the containers after expression of the dose from the pipettes. Validation on three 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 hold times. Full scale validation data regarding the manufacturing process will be provided post-approval for this standard process.
Overall conclusions on quality
The dossier provides a detailed description of the active substances and the chosen formulations, and demonstrates that production of the active substances and the products leads to a stable product with consistent quality. In view of the standard production manufacturing process of the drug product and the provided validation data on pilot-scale, full scale validation may be performed post-approval. In general, the analytical methods are well described. Due to the introduction of new methods, a re-test period still needs to be established for permethrin. So far, active substance batches will be tested immediately prior to use. In view of the stability data provided, a shelf-life of 2 years is acceptable for the finished product. A clear overview on the formulations and products that were used in clinical studies has been provided. The administration in the clinical studies is acceptable in view of the method of administration indicated in the SPC. The packaging is as approved for the recently approved mono-component spot-on product from Intervet (Activyl).
The safety of indoxacarb was considered in the context of the recent application for a marketing authorisation for Activyl. 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 requires careful consideration of data.
Based on the no observed effect levels (NOAEL) generated with the racemic (50:50) mixture of enantiomers, the purified and the 75:25 ratio of enantiomers in rats (3 months studies), the toxicity of all three materials is quantitatively and qualitatively similar. Effects seen in subchronic 3-month 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 female rats.
Adverse events observed in the in vivo repeat dose 3-month toxicology studies in rats (at > 4 mg/kg bw per day with purified S-enantiomer) and dogs (at > 5 mg/kg bw per day with racemic (50:50) mixture of enantiomers) were mild haematological effects. 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-hydroxyaryllamine IN-MT713. 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.
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 dogs. No adverse reactions were observed.
Reproduction toxicity was studied in laboratory animals with indoxacarb and permethrin and has not shown any evidence of a foetotoxic or materno toxic effects at 1.5 mg/kg bw in rats with indoxacarb and at 170 mg/kg bw per day in rats with permethrin. In the developmental toxicity studies no evidence of a developmental or materno toxic effects were observed at 2 mg/kg bw per day in rats and at 500 mg/kg bw per day in rabbits with indoxacarb and at 225 mg/kg bw per day in rats and 1200 mg/kg bw per day in rabbits with permethrin. However, a reproductive toxicity study conducted in the dog at three times the recommended therapeutic dose did reveal a significant reduction in the live pup ratio. The clinical significance of this latter finding is unknown as no studies were carried out in dogs using the recommended therapeutic dose. Therefore, the product is not recommended for use in breeding, pregnant and lactating animals unless based on the benefit/risk assessment of a veterinarian.
The data provided adequately characterise the toxicological profile of indoxacarb.
In support of the pharmacology and toxicology of permethrin the applicant has submitted literature references. These references describe studies carried out over many years and using a variety of permethrin formulations, administered to various animal species.
Permethrin is a well known active substance with recognised efficacy and an acceptable level of safety as it has been used in agriculture and medicine for the control of arthropod infestations for decades.
Adverse effects are known, but the incidence is very low and the use of permethrin can be considered to have an acceptable level of safety. The safety of permethrin has been evaluated by CVMP resulting in the establishment of MRLs in cattle and sheep.
For the dog, permethrin has also been available for use as an ectoparasiticide.
Efficacy and safety are further supported by clinical study data, including tolerance, dose-confirmation and field studies. The applicant has also carried out studies to identify possible pharmacological interactions between indoxacarb and permethrin. No evidence for any interaction was detected.
Overall conclusions on the safety documentation
The toxicological profile of indoxacarb has been demonstrated by data submitted for the application made for Activyl.
Adequate safety has been demonstrated by tolerance studies carried out with indoxacarb as Activyl in the dog.
For permethrin literature and studies on the fixed combination have been submitted.
For further information on the safety of permethrin for the dog, the applicant refers to data on Exspot (Pulvex), an authorised spot on formulation that has been used on dogs for decades.
The number of reported adverse events is very low and the use of permethrin can be considered to have an acceptable level of safety. The use of permethrin is considered well established.
The absence of pharmaceutical/pharmacodynamic interaction of indoxacarb and permethrin has been demonstrated. It is concluded that the combination is unlikely to change the safety of both single substances.
The product is not expected to pose a risk for the user when used as recommended and appropriate warnings are included in the SPC.
The product is not expected to pose a risk for the environment when used as recommended and appropriate warnings are included in the SPC.
Indoxacarb is a synthetic insecticide that acts by blocking the sodium channel in neurons, a mode of action first identified in pyrazolines. Indoxacarb belongs to the oxadiazine class of insecticides (oxadiazine analogue of the pyrazoline ring system). Its original use was for the control of pest insects on a wide variety of plants, including vegetables, fruit trees, cotton, and row crops. Because of its use in agriculture, extensive information is available on the toxicity profile of this molecule, as well as its safety for mammals and the environment.
In order to be effective indoxacarb has to be metabolised. In the insect indoxacarb is converted to a more toxic substance IN-JT333. Indoxacarb and IN-JT333 possess different profiles in their potency in blocking sodium channels and the reversibility of the blocking effects in mammalian neurons, the metabolite being the most effective one.
Indoxacarb is a chiral molecule, the S-enantiomer (>99% S-isomer; DPX-KN128) is the insecticidal active substance; the R-enantiomer has no such activity. Both enantiomers are similar with respect to the toxic effects in the target animals.
The bioactivated metabolite of indoxacarb induces a hyperpolarisation of the membrane potential associated with an increase in input resistance and a reduction in action potential amplitude. It blocks the inward sodium current amplitude of the neurone without modification of either inactivation or activation kinetics, which is the case for pyrethoids.
The binding affinity of sodium channels, for indoxacarb and for its insecticidally active metabolite, is different in insects and mammals.
The voltage-dependent sodium channel blocking action of pyrazolines in mammals is known. This mechanism closely mirrors the action of therapeutic sodium chaimel blockers such as local anaesthetics.
Permethrin is a Type I synthetic pyrethoid. Type I pyrethroids can act as acaricides and insecticides, with repellent efficacy. The spectrum of activity includes flies, fleas, ticks, lice and mites.
Pyrethroids primarly affect voltage-gated sodium channels in vertebrates and non-vertebrates.
Insect sodium channels are up to 1000 times more sensitive to pyrethroids than mammalian sodium channels. Furthermore, mammalian sodium channels recover more rapidly and detoxification rate in mammals is higher.
Pyrethroids have a negative temperature effect, meaning that toxicity increases at lower temperatures.
Permethrin is a racemic mixture (R-cis/trans and S-cis/trans), with differences in effects and toxicity. The 1R cis isomer is the neurotoxic and most active one. The IS trans isomer is inactive and not toxic to mammals.
Permethrin has a widespread use in agriculture, industry, public health, veterinary medicine and domestic environment for decades.
Permethrin posesses repellent and lethal efficacy agianst ticks. Permethrin has been marketed as Exspot (also known as Pulvex spot) worldwide as a veterinary medicinal product for the dog, including in the EU for more than 10 years.
Permethrin is or has also been marketed by many other companies for the same purpose.
The topical use of permethrin for the control of tick infestations in dogs is considered well-established.
Overall conclusion on efficacy
It is concluded that the safety of the fixed combination product has been demonstrated for the dog, when used as recommended.
Data support a treatment and prevention claim for fleas and a persistent efficacy claim for ticks (Ixodes ricinus and Rhipicephalus sanguineus) for the fixed combination of indoxacarb and permethrin. The following indication was considered acceptable: “Treatment of flea infestations (Ctenocephalides felis); the product has persistent insecticidal efficacy for up to 4 weeks against Ctenocephalides felis.
The product has persistent acaricidal efficacy for up to 5 weeks against Ixodes ricinus and up to 3 weeks against Rhipicephalus sanguineus. If ticks of these species are present when the product is applied, all the ticks may not be killed within the first 48 hours but they may be killed within a week.
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 Tick Plus treated pets.”
Activyl Tick Plus: Benefit risk assessment
Activyl Tick Plus is a spot-on solution for the treatment and prevention of fleas and ticks in dogs and can be used as part of a treatment strategy for flea allergy dermatitis. The product contains two active substances, indoxacarb; an ectoparasiticide belonging to the oxadiazine chemical family, and has a history of use in plant protection and permethrin; a Type I synthetic pyrethoid which acts as an acaricide and insecticide, with repellent properties.
Direct therapeutic benefits
Permethrin has both insecticidal and acaricidal efficacy.
With respect to ectoparasites on dogs permethrin is active against fleas and ticks.
Indoxacarb is effective in controlling flea infestations and also preventing flea larval development in the surroundings of the treated animal.
The fixed combination of indoxacarb and permethrin is able to eliminate existing flea infestations. It has a persistent efficacy controlling and preventing flea and tick infestation for up to 3-4 weeks after administration. However, the product is not sufficiently effective against an existing tick burden.
Indirect or additional benefits
Indoxacarb is an active substance for the control of flea infestations.
The fixed combination reduces the need for using 2 different products against flea and tick infestations.
Five different presentations are supplied to facilitate flexibility in dosing for small to large dog sizes at the recommended treatment dose.
Both indoxacarb and permethrin are of low toxicity to mammals and data for this product have shown no systemic adverse reactions in target animals. Local reactions at the application site have been observed.
The product is not expected to pose a risk for the user or the environment when used as recommended and taking into account the risk mitigation SPC warnings include in sections 4.5 and 6.6.
To protect children from exposure to the content of a pipette, the applicant provided a child-resistant packaging.
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. The benefit risk balance is deemed positive.
The available data adequately support the claimed indication. No unacceptable risks are identified. Consequently, the benefit risk balance is 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.