Active substance / Generic: Spinosad
This medicine is approved for use in the European Union
Comfortis chewable tablets for dogs contain spinosad and are available in five different strengths, 270 mg, 425 mg, 665 mg, 1040 mg and 1620 mg. The route of administration is oral, and the target species is dogs. The (chewable) tablets are presented in packs of 6 or 36 tablets. The product is indicated for the treatment and prevention of flea infestations (Ctenocephalides felis) in dogs. Comfortis can also be used as part of a dermatological treatment strategy for the control of Flea Allergy Dermatitis (FAD).
Comfortis: Quality assessment
Spinosad is a fermentation product produced by a species of Actinomycetes, Saccharopolyspora spinosa and is a mixture of spinosyns A and D. The spinosyns represent a novel class of insecticides and were discovered in 1988. Structurally these compounds are macrolides (non-antibacterial) and contain a unique tetracyclic ring system to which two different sugars are attached.
Comfortis tablets are presented in five different strengths (270 mg, 425 mg, 665 mg, 1040 mg and 1620 mg spinosad) with an active substance content of 53.33%w/w. The active substance, spinosad (common name), is a mixture of spinosyn A and spinosyn D. Approximately 90% of spinosad is comprised of spinosyns A and D. Of that 90%, the ratio of spinosyn A to A+D is 0.85 when calculated as spinosyn A/(spinosyn A+D). The potency of spinosad is based on factors A and D and was justified.
The active substance is declared differently in the active substance and in the product, respectively. In the active substance, the specification distinguishes between spinosyn factors exhibiting greater than 90% activity excluding spinosyn A+D, and between spinosyn factors with less than 90% activity. In the product on the other hand, only spinosyn factors A and D are specified, and all other spinosyn factors are regarded as related substances. As a consequence, during manufacture of the product, the amount of spinosad added is adjusted based on the spinosyn A+D content only.
Well established excipients are used in the manufacture of Comfortis tablets, pharmaceutical grade microcrystalline cellulose and hydroxypropyl cellulose (serving as a diluent and as a binder), croscarmellose sodium (disintegrant), colloidal silicon dioxide (glidant) and magnesium stearate (lubricant). Artificial powdered beef flavour (gamma irradiated) is included to achieve palatability of the tablets. This flavouring agent has been used previously in several authorised veterinary medicinal products.
The finished product is presented in blister packs (six tablets per blister strip) inside a folding cardboard carton. The blister foil (clear PCTFE/PE/PVC laminate) is sealed with a PVC based heat seal coating (lacquered) aluminium foil (the product contact surface is PVC).
The choice of the excipients has been conclusively justified. It has been shown that the active substance is completely released within 30 minutes. This complies with the provisions of the European Pharmacopoeia (Ph. Eur.) 2.9.3 and Ph. Eur. 5.17.1 monographs (a single-point acceptance criterion is sufficient).
Method of manufacture
The manufacturing process is fully described and comprises wet granulation, followed by drying, then blending and compression of tablets. It is regarded as a standard manufacturing process. A comprehensive description of the manufacturing method and equipment utilised is provided in the documentation.
Overall conclusions on quality
The data provided on the active ingredient are satisfactory. Comprehensive information on the manufacture and characteristics of the active ingredient, spinosad, is provided, and routine tests and specifications are considered sufficient to assure the appropriate and consistent quality of the active substance. The proposed re-test period of 24 months is acceptable.
The excipients used are commonly employed in such tablet formulations and are acceptable, as are the packaging materials. All excipients contained in the tablets, except the Artificial Powdered Beef Flavour (containing pig liver powder), are of pharmacopoeial grade quality. The microbiological and virological safety of the Artificial Powdered Beef Flavour have been substantiated. There are no concerns in relation to TSE with any of the ingredients of the product.
The rationale for the choice of the formulation is acceptable.
An acceptable specification has been developed for release of the tablets. Control methods have been validated and the specification is considered to be relevant for a product of this type.
The stability data provided reflect the current VICH guidance. A shelf-life of 3 years was proposed, and the stability data on the finished product provided so far are acceptable as primary stability information. Data demonstrate stability of the product under both long term and accelerated storage conditions. The SPC and product information include the appropriate information.
Spinosad: Safety assessment
Following oral administration to rats, 14C-spinosyns are absorbed, extensively metabolised and rapidly eliminated in the faeces. There are no major differences in the ADME (ADME: Absorption, Distribution, Metabolism, Excretion) profiles of the two major factors of spinosad, spinosyns A and D. No differences in the pharmacokinetic behaviour in relation to gender could be identified. It can be concluded that the rats in the toxicity studies were exposed to significant systemic concentrations of spinosad.
Spinosad has a low acute toxicity following oral, intraperitoneal, and inhalational exposure. No systemic effects after dermal application were observed in rabbits up to a dose of 5000 mg/kg.
The most prominent effect of spinosad in repeat dose toxicity studies in mice and rats is dose dependent cytoplasmic vacuolation in numerous organs and tissues. This condition is diagnosed as phospholipidosis induced by intracellular accumulation of cationic amphiphilic/lipophilic drugs (CAD). A large variability has been shown among species or strains with respect to the tissue/organ specificity and severity of the condition induced by a particular CAD.
Spinosad induces phospholipidosis in the target species, dogs, at doses higher than the recommended dosing schedule.
No dermal effects and no systemic toxicity were observed in two dermal repeat dose toxicity studies in rabbits. It was concluded that spinosad was not irritating to the skin of rabbits.
The studies on reprotoxicity performed in rats and rabbits provided no evidence for adverse effects of spinosad on male or female reproductive functions at dose levels below parental toxic levels. At maternal toxic doses, decreased litter size, decreased neonatal survival and decreased pup body weights were observed in the multi-generation study in rats. No developmental effects occurred at maternal toxic levels. The NOAELs for parental and reproductive/developmental toxicity were 10 mg/kg bw/day. The lowest NOAEL for maternal toxicity determined in the developmental studies was 10 mg/kg bw/day in rabbits and the NOAEL for embryonal/foetal toxicity and teratogenicity was 50 mg/kg bw/day both in rats and rabbits. These NOELs are close to the therapeutic dose range which is recommended for dogs (although there are differences in dosing regimes, that is, single dosing in dogs once every four weeks, daily dosing in laboratory animals).
Reproductive toxicity in the target animal species is covered in the Target animal tolerance’ subsection of section 4 of this report.
Spinosad is not considered to be genotoxic, nor carcinogenic and did not show any acute, subchronic and chronic neurotoxic potential. Spinosad was not irritating to the skin of rabbits and not sensitising to the skin of guinea pigs. It caused reversible, slight to mild irritation in the eyes of rabbits.
In respect to spinosad, there is no health concern for the adult user, including pregnant and nursing women, when administering the product in accordance with the SPC and product information which include appropriate warnings and advice for users. The child-resistant nature of the packaging and the relevant warnings in the SPC and product information are considered satisfactorily to minimise the risks for children.
Spinosad is not expected to pose a risk to the environment when used in dogs at monthly intervals during the flea season.
Spinosad: Efficacy assessment
The proposed dosage regimen of Comfortis (spinosad) is 45-70 mg/kg bw. Treatment can be repeated at 4-weekly intervals, if needed. A number of EU dose determination/dose confirmation studies, performed according to current EU guidelines, confirmed the efficacy of spinosad at a dose of 45 mg/kg bw in the treatment and prevention of flea infestations (Ct. felis). Efficacy rates above the threshold of 95% were maintained for 3 weeks (98-99%) but were on average slightly below the threshold of 95% on day 30 post dose (arithmetic means: 85.6 to 91.6%) and 50% of dogs had zero fleas. The data justify a claim of residual insecticidal activity for up to four weeks after single oral treatment at a minimum dose of 45 mg spinosad/kg bw, which is supported by the field efficacy studies (statistically, spinosad proved to be non-inferior to the comparator product (selamectin). In fact, the spinosad efficacy values at each time point were significantly higher than the corresponding values for selamectin. Appropriate information is included in the SPC and other product information.
Comparative studies on fed/fasted dogs indicate that spinosad chewable tablets should be given with a meal to increase the systemic availability, and appropriate advice is included to this effect.
The therapeutic activity of spinosad against an existing flea infestation (treatment claim) is clearly demonstrated at 24 to 48 hours after treatment in several studies.
The knockdown and speed of kill effectiveness was investigated in a laboratory study on dogs. Effectiveness (100%) within 4 hours post-dose could be demonstrated
Data were provided from four Simulated Home Environmental (SHE) studies. Suitable advice regarding appropriate control measures, such as treatment of the home environment with suitable insecticides in case of heavy flea infestations, is included the SPC.
Two field studies conducted in Europe were run originally at a dose range of 30-90 mg/kg bw but were re-evaluated by rejecting all data from dogs that had received less or more than the claimed dose range of 45 -70 mg/kg bw.
In a one-month multi-centre field study conducted in Europe, spinosad proved to be non-inferior to the comparator product (selamectin). (The spinosad efficacy values at each time-point were significantly higher than the corresponding values for selamectin.) Palatability of the product was demonstrated.
The second European field study was performed over a treatment period of 3 months. Spinosad proved to be non-inferior to the comparator product (selamectin) again. (The spinosad efficacy values at each time were significantly higher than the corresponding values for selamectin.) Palatability was judged to be fair.
Meta-analysis of the pivotal clinical field studies showed that the flea infestation rate significantly decreased with increasing doses of spinosad, when dose was used as a continuous variable. Otherwise by using categorical dose groups, there was no significant difference between each of the fixed categories.
No relationship between the age or weight of a dog and the persistent efficacy could be established based on additional meta-analyses of the field data.
From the results of clinical field studies performed in the USA and in Australia, it can be concluded that spinosad can be used a part of a treatment strategy for the control of FAD. Advice is included in the SPC and product literature recommending additional control measures such as the use of suitable insecticides in the home environment and vacuum cleaning, and also the treatment of other pet animals living in the same household, in order to ensure efficacy. If fleas reappear in the fourth week, the treatment interval can be safely shortened by up to 3 days.
Comfortis: Benefit Risk Assessment
The application is for Comfortis flavoured chewable tablets for dogs. The active substance is spinosad, a compound not previously authorised in veterinary medicine in the European Community. The application is supported by a full dossier.
Direct therapeutic benefit
Comfortis chewable tablets are proposed for the treatment and prevention of flea infestations (Ctenocephalides felis) in dogs at a single oral dose of 45-70 mg/kg bw which may be repeated every month. Fleas do have a considerable nuisance value because of irritating bites causing distress in dogs. Hypersensitive animals may develop signs of flea allergy dermatitis. Fleas transmit a number of pathogens such as Dipylidium caninum and Bartonella henselae. Therefore, the treatment and prevention of flea infestations is considered beneficial to animal health.
Well conducted controlled clinical studies demonstrated that Comfortis is effective in the treatment of flea infestations in dogs with a persisting efficacy rate in the European laboratory studies of >95% for 3 weeks and 85.6 to 94% for 4 weeks after dosing. The data do justify a preventive effect of spinosad as a result of its residual insecticidal activity of up to 4 weeks.
Spinosad shows a rapid killing effect which provides fast relief for dogs harbouring fleas. Moreover, the rapid kill of fleas after a blood meal prevents the fleas subsequently laying eggs.
In the field studies, at the recommended dose, spinosad proved to be non-inferior to the reference product in the treatment and prevention of flea infestations in dogs.
There is clear evidence from the data that the frequency and severity of Flea Allergy Dermatitis (FAD) is significantly decreased in dogs treated with Comfortis. This is an indirect beneficial effect and therefore, the claimed use as part of a treatment strategy for the control of FAD is justified.
Comfortis tablets are flavoured, palatable, and are easily taken by most dogs.
The mode of action of spinosad is different from other chemical classes used for flea control in veterinary medicine such as neonicotinoides, fiproles, milbemycins, and avermectins and no cross-resistance is expected at present. The low egg drop after treatment prevents to a certain extent the spread of resistance genes into the next population of fleas.
The indirect benefits refer particularly to children living in close contact with treated dogs, since there is no or little opportunity to transfer spinosad to human skin. The active substance, in contrast to spot ons or insecticidal sprays, will not be washed off during rain, swimming or shampooing, and does not undergo UV degradation. There is also negligible opportunity for a direct transfer of spinosad to household items or (as possible after external treatment with marketed spot ons) to expose the environment via bathing or swimming.
Humans will also benefit from the successful treatment of their dogs (as fleas also bite humans).
Preclinical and clinical data reveal the most prominent adverse reaction to be emesis, which occurs within 0.5 to 2 hours post-dose, is dose-related, and is probably caused by a local effect on the small intestines. The incidence of emesis observed after the first and second treatments was higher in dogs dosed at the upper end of the dose band, and was shown to be a very common adverse event if the maximum recommended dose was exceeded. The incidence of emesis following treatment with spinosad at the label dose was judged to be acceptable from a clinical point of view as the data demonstrated that the emesis was usually mild and a single episode, and did not require veterinary intervention.
Other adverse events that are possibly treatment related include other gastrointestinal disorders (diarrhoea, soft faeces), and some cases of anorexia/loss of appetite, lethargy and seizures. These adverse events are all adequately addressed in the product literature.
Following overdosage, cell vacuolation/phospholipidosis was also found in dogs, in a dose dependant manner. Unlike the rat studies, the dog study design did not allow for demonstrating reversibility of the observed changes, however, it was demonstrated (using the bench mark approach) that phospholipidosis was unlikely to occur at the recommended dosing schedule. Cell vacuolation was considered to be a treatment related response that results in a change in morphology, but not in any known impairment of any body function, and the Committee concluded that there was no need for a margin of safety for this effect, and agreed that the SPC and package leaflet included adequate information to alert veterinarians to the possibility of phospholipidosis.
After overdosing, and/or dosing in short intervals over a prolonged period of time, other observed adverse events included slight alanine amino transferase elevations, or impaired growth (possibly secondary to emesis). Impaired growth was also reported in puppies <14 weeks old receiving 45-90 mg/kg bw spinosad, therefore the product should only be used in dogs over 14 weeks of age. This threshold was supported by data derived from the clinical field studies.
Spinosad was shown to be a substrate of P-glycoprotein, but was shown not to induce neurotoxicity in avermectin-sensitive Collies after its concurrent administration with milbemycin oxime. However, since adverse effects have been reported (from the US) after the use of spinosad in combination with high (off-label) doses of ivermectin, appropriate information is included in the product literature accordingly.
The study of spinosad on the reprotoxicity in dogs revealed a few early pregnancy losses in treated bitches. Although the relation to treatment remained unclear, a recommendation that Comfortis should be used with caution in pregnant and lactating bitches is included in the SPC and product literature. Spinosyns A and D, the main constituents of spinosad, are preferentially excreted in colostrum/ milk of treated nursing bitches, but the available data were not sufficient to confirm the safety of this for suckling puppies so appropriate information was included in the SPC and product literature accordingly.
The Committee concluded there is no health concern for adults, including pregnant and nursing women, administering this product (to dogs) in accordance with the SPC and product literature. The child-resistant packaging in conjunction with the warnings and advice in the SPC and product literature are considered satisfactorily to minimise risks for children.
When used as recommended spinosad is not expected to pose a risk to the environment.
Risk management or mitigation measures
In order to ensure the safe use in dogs and to minimise potential risks for the user appropriate instructions for the use of the product are included in the product literature. The child-resistant packaging is an additional risk mitigation measure.
Evaluation of the benefit risk balance
Overall, the benefit risk balance is considered positive for Comfortis 270 mg, 425 mg, 665 mg, 1040 mg, and 1620 mg chewable tablets for dogs.
Spinosad has been shown to be effective in the treatment and prevention of flea infestations (Ctenocephalides felis) in dogs for up to four weeks. The preventative effect against re-infestations is the result of the adulticidal activity and the reduction in egg production and persists for up to four weeks after a single administration of the product. Comfortis can be used as part of the treatment of flea allergic dermatitis. To ensure efficacy, adequate supplementary measures are included in the product literature.
The (initial) systemic exposure is considered very high in comparison to the concentrations needed for efficacy. However, the appropriateness of the proposed EU dosage regimen of 45-70 mg/kg bw has been adequately demonstrated with regard to efficacy and target animal safety. The treatment related risks are adequately described in the product literature.
Conclusion on benefit risk balance
The information provided in the dossier and in response to points raised was sufficient to confirm an overall positive benefit-risk balance for this veterinary medicinal product.
Based on the CVMP review of the data on quality, safety and efficacy, the CVMP considers that the application for Comfortis 270 mg, 425 mg, 665 mg, 1040 mg, and 1620 mg chewable tablets for dogs were considered to be in accordance with the requirements of Directive 2001/82/EC as amended and the benefit-risk balance was favourable.