Comfortis Chewable Flea Tablets

Comfortis chewable tablets for Dogs and Cats

Qualitative and quantitative composition

Each tablet contains:

Active substance:

Comfortis 90 mg spinosad 90 mg

Comfortis 140 mg spinosad 140 mg

Comfortis 180 mg spinosad 180 mg

Comfortis 270 mg spinosad 270 mg

Comfortis 425 mg spinosad 425 mg

Comfortis 665 mg spinosad 665 mg

Comfortis 1040 mg spinosad 1040 mg

Comfortis 1620 mg spinosad 1620 mg

For the full list of excipients, see Pharmaceutical particulars section

Pharmaceutical form

Chewable tablets

Tan to brown, or speckled, round, flat, bevelled edge tablets, plain on one side and debossed with a

number as listed below on the other:

140 mg: 4222

425 mg: 4229

1040 mg: 4231

1620 mg: 4227

Tan to brown, or speckled, round, flat, bevelled edge tablets, plain on one side and debossed with a

number underlined as listed below on the other:

90 mg: 4221

270 mg: 4223

665 mg: 4230

Tan to brown, or speckled with embedded darker particles, round, flat, bevelled edge tablets plain on

one side and debossed with a number and a line above on the other side:

180 mg: 4228

Clinical particulars

Target species

Dogs and cats.

Indications for use, specifying the target species

Treatment and prevention of flea infestations (Ctenocephalides felis).

The preventive effect against re-infestations is a result of the adulticidal activity and the reduction in

egg production and persists for up to 4 weeks after a single administration of the product.

The veterinary medicinal product can be used as part of a treatment strategy for the control of flea

allergy dermatitis (FAD).

Contraindications

Do not use in dogs or cats under 14 weeks of age.

Do not use in case of known hypersensitivity to the active substance or to any of the excipients.

Special warnings for each target species

The veterinary medicinal product should be administered with food or immediately after feeding. The

duration of efficacy may be reduced if the dose is administered on an empty stomach.

All dogs and cats within the household should be treated.

Fleas from pets often infest the animal’s basket, bedding and regular resting areas such as carpets and

soft furnishings, which should be treated in case of massive infestation and at the beginning of the

treatment with a suitable insecticide and vacuumed regularly.

Fleas may persist for a period of time after administration of the product due to the emergence of adult

fleas from pupae already in the environment. Regular monthly treatments with Comfortis break the

fleas’ life cycle and may be needed to control the flea population in contaminated households.

Special precautions for use

Special precautions for use in animals

Use with caution in dogs and cats with pre-existing epilepsy.

Accurate dosing is not possible in dogs weighing less than 1.3 kg and in cats weighing less than

1.2 kg. The use of the product in smaller dogs and smaller cats is therefore not recommended.

The recommended dosage regimen should be followed (see overdose section).

Special precautions to be taken by the person administering the veterinary medicinal product to animals

Accidental ingestion may cause adverse reactions.

Children should not come into contact with the veterinary medicinal product.

In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the

label to the physician.

Wash hands after use.

Adverse reactions (frequency and seriousness)

Dogs

In dogs, a commonly observed adverse reaction is vomiting, which occurs in the first 48 hours after

dosing and is most likely caused by a local effect on the small intestines. On the day of, or the day

following administration of spinosad at a dose of 45–70 mg/kg bodyweight, the observed incidence of

vomiting in the field trial was 5.6%, 4.2% and 3.6% after the first, second and third monthly

treatments respectively. The incidence of vomiting observed after the first and second treatments was

higher (8%) in dogs dosed at the upper end of the dose band. In the majority of cases, vomiting was

transient, mild and did not require symptomatic treatment.

In dogs lethargy, anorexia and diarrhoea were uncommon and muscle tremor, ataxia and seizures

were rare. In very rare cases, blindness, impaired vision and other eye disorders were observed.

Cats

In cats, a commonly observed adverse reaction is vomiting, which occurs in the first 48 hours after

dosing and is most likely caused by a local effect on the small intestines. On the day of, or the day

following administration of spinosad at a dose of 50–75 mg/kg bodyweight, the observed incidence of

vomiting in the global field trial was between 6% and 11% in the first three months of treatment. In

the majority of cases, vomiting was transient, mild and did not require symptomatic treatment.

Other commonly observed adverse reactions in cats were diarrhoea and anorexia. Lethargy, loss of

condition and salivation were uncommon. Seizures were rare adverse reactions.

The frequency of adverse reactions is defined using the following convention:

- very common (more than 1 in 10 animals displaying adverse reactions during the course of one

treatment)

- common (more than 1 but less than 10 animals in 100 animals)

- uncommon (more than 1 but less than 10 animals in 1,000 animals)

- rare (more than 1 but less than 10 animals in 10,000 animals)

- very rare (less than 1 animal in 10,000 animals, including isolated reports).

Use during pregnancy, lactation or lay

Pregnancy:

Laboratory studies in rats and rabbits have not produced any evidence of teratogenic, foetotoxic or

maternotoxic effects.

In pregnant dogs (bitches), the safety of spinosad has not been sufficiently established. The safety of

spinosad in pregnant cats (queens) has not been evaluated.

Lactation:

In dogs, spinosad is excreted in the colostrum and milk of lactating bitches and it is therefore assumed

that spinosad is excreted in the colostrum and milk of lactating queens. As the safety of this for

suckling puppies and kittens has not been established, the product should only be used during

pregnancy and lactation according to the benefit-risk assessment by the responsible veterinarian.

Fertility:

Laboratory studies in rats and rabbits have not produced any evidence of any effect on the

reproductive capacity in males and females.

The safety of the product in male dogs and male cats used for breeding has not been determined.

Interaction with other medicinal products and other forms of interaction

Spinosad has been shown to be a substrate for P-glycoprotein (PgP). Spinosad could therefore interact

with other PgP-substrates (for example, digoxin, doxorubicin) and possibly enhance adverse reactions

from such molecules or compromise efficacy.

Post marketing reports, following the concomitant use of Comfortis with ‘off label’ high dose

ivermectin indicate that dogs have experienced trembling/twitching, salivation/drooling, seizures,

ataxia, mydriasis, blindness and disorientation.

Amounts to be administered and administration route

For oral use.

The veterinary medicinal product should be administered with food or immediately after feeding.

Dogs:

The veterinary medicinal product should be administered in accordance with the following table to

ensure a dose of 45–70 mg/kg bodyweight for dogs:

Dog bodyweight (kg) Number of tablets and strength (mg spinosad)

1.3–2 1 x 90 mg tablet

2.1–3 1 x 140 mg tablet

3.1–3.8 1 x 180 mg tablet

3.9–6 1 x 270 mg tablet

6.1–9.4 1 x 425 mg tablet

9.5–14.7 1 x 665 mg tablet

14.8–23.1 1 x 1040 mg tablet

23.2–36 1 x 1620 mg tablet

36.1–50.7 1 x 1620 mg tablet + 1 x 665 mg tablet

50.8–72 2 x 1620 mg tablets

Cats:

The veterinary medicinal product should be administered in accordance with the following table to

ensure a dose of 50–75 mg/kg bodyweight for cats:

Cat bodyweight (kg) Number of tablets and strength (mg spinosad)

1.2–1.8 1 x 90 mg tablet

1.9–2.8 1 x 140 mg tablet

2.9–3.6 1 x 180 mg tablet

3.7–5.4 1 x 270 mg tablet

5.5–8.5 † 1 x 425 mg tablet

†Cats over 8.5 kg: give the appropriate combination of tablets.

Comfortis tablets are chewable and palatable for dogs. If the dog or cat does not accept the tablets

directly they may be administered with food, or directly by opening the animal’s mouth and placing

the tablet onto the back of the tongue.

If vomiting occurs within an hour of administration and the tablet is visible, re-dose the animal with

another full dose to ensure maximum effectiveness of the product.

If a dose is missed, administer the veterinary medicinal product with the next offering of food and

resume a monthly dosing schedule.

The veterinary medicinal product may safely be given at monthly intervals at the recommended dose.

The residual insecticidal properties of the product persist for up to 4 weeks after a single

administration. If fleas reappear in the fourth week, the treatment interval can be shortened by up to

3 days in dogs. In cats, the full 4 week gap between treatments should be maintained, even if fleas

reappear before the end of the 4 weeks.

Seek veterinary advice regarding information on the optimal time to start treatment with this product.

Overdose (symptoms, emergency procedures, antidotes), if necessary

There is no antidote available. In case of adverse clinical signs, the animal should be treated

symptomatically.

Dogs:

The incidence of vomiting on the day of, or the day after, dosing has been observed to increase as a

function of dose. Vomiting is most likely caused by a local effect on the small intestines. At doses in

excess of the recommended dose vomiting becomes a very common event. At doses of approximately

2.5 times the recommended dose, spinosad caused vomiting in the vast majority of dogs.

At doses up to 100 mg/kg bodyweight per day for 10 days, the only clinical symptom of overdose was

vomiting, which occurred usually within 2.5 hours of dosing. Mild elevations of ALT (alanine

aminotransferase) occurred in all dogs treated with Comfortis, although values returned to their

baseline by day 24. Phospholipidosis (vacuolation of lymphoid tissues) also occurred; although this

was not related to clinical signs in dogs treated up to 6 months.

Cats:

After a single acute overdose corresponding to 1.6 times the maximum label dose, spinosad caused

vomiting in approximately half of the cats, and depression, pacing/panting and severe diarrhoea on

rare occasions.

At doses of 75 to 100 mg/kg bodyweight per day for 5 days, given at monthly intervals for a period of

six months, the most commonly observed clinical sign was vomiting. Furthermore, a reduction of food

intake was observed in females, however a significant reduction in their bodyweight was not observed.

Phospholipidosis (vacuolation of the cells of the liver, adrenal gland and lung) also occurred. Also

noted were diffuse hepatocellular hypertrophy in males and females, and this finding correlated with

higher pooled mean liver weights. However there was no evidence in the clinical observations and

clinical chemistry parameters that indicated any loss in organ function.

Withdrawal period

Not applicable.

Pharmacological particulars

Pharmacotherapeutic group: other ectoparasiticides for systemic use.

ATCvet code: QP53BX03.

Pharmacodynamic properties

Spinosad comprises spinosyn A and spinosyn D. The insecticidal activity of spinosad is characterised

by nervous excitation leading to muscle contractions and tremors, prostration, paralysis and rapid

death of the flea. These effects are caused primarily by activation of nicotinic acetylcholine receptors

(nAChRs). Spinosad therefore has a different mode of action to other flea control or insect control

products. It does not interact with known binding sites of other nicotinic or GABAergic insecticides

such as neonicotinides (imidacloprid or nitenpyram), fiproles (fipronil), milbemycins, avermectins

(e.g. selamectin) or cyclodienes, but through a novel insecticidal mechanism.

The product starts killing fleas 30 minutes after administration; 100% of fleas are dead/moribund

within 4 hours post-treatment in dogs, and in cats within 24 hours.

Insecticidal activity against new infestations persists for up to 4 weeks.

Pharmacokinetic particulars

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 consistency of this

figure in pharmacokinetic and other studies indicates comparability in the absorption, metabolism and

elimination of the two major spinosyns.

In dogs, spinosyns A and D are rapidly absorbed and extensively distributed after oral administration.

Bioavailability was shown to be approximately 70%. The mean Tmax for spinosyns A and D ranged

from 2–4 hours and the mean elimination half-life ranged from 127.5 to 162.6 hours and 101.3 to

131.9 hours respectively. AUC and Cmax values were higher in fed than fasted dogs and increased

approximately linearly with increasing dose-rates over the intended therapeutic dose range. Therefore,

it is recommended to treat dogs with food as this maximises the opportunity for fleas to ingest lethal

amounts of spinosad. The primary biliary, faecal and urinary metabolites in both the rat and the dog

were identified as the demethylated spinosyns, glutathione conjugates of the parent compounds and Ndemethylated

spinosyns A and D. Excretion is primarily via the bile and faeces, and also to a lesser

extent in the urine. Faecal excretion accounted for the vast majority of metabolites in dogs. In lactating

bitches, spinosad is excreted in the colostrum/milk.

In cats, spinosyns A and D are equally rapidly absorbed and extensively distributed after oral

administration. Plasma protein binding is high (~99%). Bioavailability was shown to be approximately

100%, with maximum plasma concentrations attained approximately 4–12 hours post treatment, and

with half-lives of spinosyn A and spinosyn D ranging between 5 days and 20 days in cats dosed at

50-100 mg spinosad/kg bodyweight. AUC and Cmax values were higher in fed than fasted cats.

Therefore, it is recommended to treat cats with food as this maximises the opportunity for fleas to

ingest lethal amounts of spinosad. In adult cats, the AUC increased over 3 consecutive months of

dosing with 75 mg spinosad/kg bodyweight, after which steady state was achieved; however, no

clinical impact occurred as a result of this.

The primary faecal and urinary metabolites in both the rat and the cat were identified as the

glutathione conjugates of the parent compounds and N-demethylated spinosyns A and D. Excretion is

primarily via the faeces, and also to a lesser extent in the urine. Faecal excretion accounted for the vast

majority of metabolites in cats.

Pharmaceutical particulars

List of excipients

Microcrystalline cellulose

Artificial beef flavour

Hydroxypropylcellulose

Colloidal silicon, anhydrous

Croscarmellose sodium

Magnesium stearate

Incompatibilities

Not applicable.

Shelf life

Shelf life of the veterinary medicinal product as packaged for sale: 3 years.

Special precautions for storage

Keep the blister in the outer carton to protect from light.

Nature and composition of immediate packaging

Clear PCTFE/PE/PVC blister sealed with aluminium foil containing 3 or 6 chewable tablets in

cardboard box.

Not all pack sizes may be marketed.

Special precautions for the disposal of unused veterinary medicinal product or waste

materials derived from the use of such products

Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal

products should be disposed of in accordance with local requirements.

Marketing Authorisation Holder (if different from distributor)

NA

Marketing Authorisation Number

EU/2/10/115/016 (90 mg, 3 tablets)

EU/2/10/115/017 (90 mg, 6 tablets)

EU/2/10/115/018 (140 mg, 3 tablets)

EU/2/10/115/019 (140 mg, 6 tablets)

EU/2/10/115/020 (180 mg, 3 tablets)

EU/2/10/115/021 (180 mg, 6 tablets)

EU/2/10/115/011 (270 mg, 3 tablets)

EU/2/10/115/001 (270 mg, 6 tablets)

EU/2/10/115/012 (425 mg, 3 tablets)

EU/2/10/115/003 (425 mg, 6 tablets)

EU/2/10/115/013 (665 mg, 3 tablets)

EU/2/10/115/005 (665 mg, 6 tablets)

EU/2/10/115/014 (1040 mg, 3 tablets)

EU/2/10/115/007 (1040 mg, 6 tablets)

EU/2/10/115/015 (1620 mg, 3 tablets)

EU/2/10/115/009 (1620 mg, 6 tablets)

Date of the first authorisation or date of renewal

11/02/2011.

Date of revision of the text

Any other information

Legal category