Insistor 10 mg/ml Solution for Injection for Dogs and Cats

Composition

Each ml contains:

Active substance:

Methadone hydrochloride 10 mg

(equivalent to 8.9 mg Methadone)

Excipients:

Clear colourless to slightly yellow solution.

3

Pharmacological properties

4.1 ATCvet code: QN02AC90

4.2 Pharmacodynamics

Methadone is structurally unrelated to other opium-derived analgesics and exists as a racemic mixture. Each enantiomer has a separate mode of action; the d-isomer noncompetitively antagonises the NMDA receptor and inhibits norepinephrine reuptake; the l-isomer is a µ-opioid receptor agonist.

There are two subtypes µ1 and µ2. The analgesic effects of methadone are believed to be mediated by both the µ1 and µ2 subtypes, whereas the µ2 subtype appears to mediate respiratory depression and inhibition of gastrointestinal motility. The µ1 subtype produces supraspinal analgesia and the µ2 receptors produce spinal analgesia. Methadone has the ability to produce profound analgesia. It can also be used for premedication and it can assist in the production of sedation in combination with tranquilisers or sedatives. The duration of effects may vary from 1.5 to 6.5 hours. Opioids produce a dose-dependent respiratory depression. Very high doses may result in convulsions.

4.3 Pharmacokinetics

In dogs, methadone is absorbed very rapidly (Tmax 5-15 min) following intramuscular injection of 0.3 to 0.5 mg/kg. Tmax tends to be later at the higher dose levels indicating that an increase in dose tends to prolong the absorption phase. The rate and extent of systemic exposure of dogs to methadone appears to be characterised by dose- independent (linear) kinetics following intramuscular administration. The bioavailability is high and ranges between 65.4 and 100 %, with a mean estimate of 90 %. Following subcutaneous administration of 0.4 mg/kg methadone is absorbed slower (Tmax 15 – 140 min) and bioavailability is 79 ± 22 %.

In dogs, volume of distribution at steady state (Vss) was 4.84 and 6.11 l/kg in males and females respectively. The terminal half-life is in the range 0.9 to 2.2 hours following intramuscular administration, and is independent of dose and sex. The terminal half-life may be slightly longer following intravenous administration. The terminal half-life ranges from 6.4 to 15 hours following subcutaneous administration. Total plasma clearance (CL) of methadone following intravenous administration is high 2.92 to 3.56 l/h/kg or ca 70 % to 85 % of the cardiac plasma output in dogs (4.18 l/h/kg).

In cats, methadone is also rapidly absorbed following intramuscular injection (peak values occur at 20 minutes), however, when the veterinary medicinal product is administered inadvertently subcutaneously (or in another poorly vascularised area) absorption will be slower. The terminal half-life is in the range of 6 to 15 hours. Clearance is medium to low with a mean (sd) value of 9.06 (3.3) ml/kg/min.

Methadone is extensively protein bound (60 % to 90 %). Opioids are lipophilic and weak bases. These physiochemical properties favour intracellular accumulation.

Consequently, opioids have a large volume of distribution, which greatly exceeds total body water. A small amount (3 % to 4 % in the dog) of the administered dose is excreted unchanged in the urine; the remainder is metabolised in the liver and subsequently excreted.

3

Target species

Dogs and cats

3

Indications

• Analgesia.

• Premedication for general anaesthesia or neuroleptanalgesia in combination with a neuroleptic drug.

3

Dosage

Dogs: Intravenous, intramuscular or subcutaneous use.

Cats: Intramuscular use.

To ensure a correct dosage, body weight should be determined as accurately as possible.

Analgesia

Dogs: 0.5 to 1 mg Methadone HCl per kg bodyweight, s.c., i.m. or i.v. (corresponding to 0.05 to 0.1 ml/kg)

Cats: 0.3 to 0.6 mg Methadone HCl per kg bodyweight, i.m. (corresponding to 0.03 to 0.06 ml/kg)

To ensure accuracy of dosing in cats, an appropriately calibrated syringe should be used to administer the veterinary medicinal product.

As the individual response to methadone is variable, and depends partly on the dosage, the age of the patient, individual differences in pain sensitivity and general condition the optimal dosing regimen should be individually based.

In dogs, onset of action is 1 hour following subcutaneous administration, approximately 15 minutes following intramuscular injection and within 10 minutes following intravenous injection. Duration of effect is approximately 4 hours following intramuscular or intravenous administration.

In cats, following intramuscular administration, onset of action is 15 minutes and the duration of effect is 4 hours on average.

The animal should be examined regularly to assess if additional analgesia is subsequently required.

Premedication and/or neuroleptanalgesia

Dogs:

Methadone HCl 0.5-1 mg/kg bodyweight, i.v., s.c. or i.m. (corresponding to 0.05 to 0.1 ml/kg)

Combinations e.g.:

• Methadone HCl 0.5 mg/kg bodyweight, i.v. (corresponding to 0.05 ml/kg) + e.g. midazolam or diazepam.

Induction with propofol, maintenance with isoflurane in oxygen.

• Methadone HCl 0.5 mg/kg bodyweight, i.v. (corresponding to 0.05 ml/kg), + e.g acepromazine Induction with thiopentone or propofol to effect, maintenance with isoflurane in oxygen or induction with diazepam and ketamine.

• Methadone HCl 0.5 -1.0 mg/kg bodyweight, i.v. or i.m. (corresponding to 0.05 to 0.1 ml/kg), + α2-agonist (e.g. xylazine or medetomidine).

Induction with propofol, maintenance with isoflurane in oxygen in combination with fentanyl or total intravenous anaesthesia (TIVA) protocol: maintenance with propofol in combination with fentanyl.

TIVA protocol: induction propofol, to effect. Maintenance with propofol and remifentanil. Chemical-physical compatibility has only been demonstrated for dilutions 1:5 with the following solutions for infusion: sodium chloride 0.9 %, Ringer’s solution, Ringer’s lactate solution and glucose 5 %.

Cats:

• Methadone HCl 0.3 to 0.6 mg/kg bodyweight, i.m. (corresponding to 0.03 to 0.06 ml/kg)

- Induction with benzodiazepine (e.g. midazolam) and dissociative (e.g. ketamine).

- With a tranquiliser (e.g. acepromazine) and NSAID (meloxicam) or sedative (e.g. α2-agonist).

- Induction with propofol, maintenance with isoflurane in oxygen.

Doses are dependent on the desired degree of analgesia and sedation, desired duration of effect and the concurrent use of other analgesics and anaesthetics.

When used in combination with other veterinary medicinal products, lower dosages can be used.

For safe use with other veterinary medicinal products, reference must be made to the relevant product literature.

The stopper should not be punctured more than 20 times.

3

Contraindications

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

Do not use in animals with advanced respiratory failure.

Do not use in animals with severe liver and renal dysfunction.

3

Adverse reactions

Cats:

Very common (>1 animal / 10 animals treated):

Respiratory depression

Lip licking1, Involuntary defecation1, Diarrhoea1

Excitation1, Vocalisation1

Urination1

Mydriasis1, Hypersensitivity to pain

Hyperthermia1

All reactions were transient.

1Mild

Dogs:

Very common (>1 animal / 10 animals treated):

Respiratory depression, Panting, Irregular breathing;

Bradycardia;

Lip licking, Hypersalivation;

Vocalisation;

Hypothermia;

Urination;2

Involuntary defecation;,2

Tremor, Staring.

All reactions were transient.

1Mild

2Occasional within the first hour post dose.

Reporting adverse events is important. It allows continuous safety monitoring of a veterinary medicinal product. Reports should be sent, preferably via a veterinarian, to either the marketing authorisation holder or its local representative or the national competent authority via the national reporting system. See the package leaflet for respective contact details.

3

Warnings

Special precautions for safe use in the target species:

Methadone may occasionally cause respiratory depression and, as with other opioid drugs, care should be taken when treating animals with impaired respiratory function, or animals that are receiving drugs that can cause respiratory depression. To ensure safe use of the veterinary medicinal product, treated animals should be monitored regularly, including examination of heart rate and respiratory rate.

As methadone is metabolised by the liver, its intensity and duration of action may be affected in animals with impaired liver function.

In case of renal, cardiac or hepatic dysfunction, or shock, there may be greater risk associated with the use of the veterinary medicinal product.

The safety of methadone has not been demonstrated in dogs less than 8 weeks and cats less than 5 months of age.

The effect of an opioid on head injury is dependent on the type and severity of the injury and the respiratory support supplied.

Safety has not been fully evaluated in clinically compromised cats. Due to the risk of excitation, repeated administration in cats should be used with care.

The benefit/risk ratio for using the veterinary medicinal product should be made by the attending veterinarian.

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

Methadone can cause respiratory depression following spillage on the skin or accidental self-injection. Avoid skin, eyes and mouth contact, and wear impermeable gloves when handling the veterinary medicinal product. In cases of spillage onto the skin, or splashing into the eyes, wash immediately with large amounts of water. Remove contaminated clothes.

People with known hypersensitivity to methadone should avoid contact with the veterinary medicinal product. Methadone has the potential to cause stillbirths. Pregnant women are advised not to handle the veterinary medicinal product.

In the case of accidental self-injection, seek medical advice immediately and show the package leaflet or the label to the physician but DO NOT DRIVE as sedation may occur. To the physician: Methadone is an opioid whose toxicity may cause clinical effects including respiratory depression or apnoea, sedation, hypotension and coma. When respiratory depression occurs controlled ventilation should be initiated. Administration of the opioid antagonist naloxone to reverse the symptoms is recommended.

Special precautions for the protection of the environment:

Not applicable.

3.11 Special restrictions for use and special conditions for use, including restrictions on the use of antimicrobial and antiparasitic veterinary medicinal products in order to limit the risk of development of resistance

(to be completed in accordance with national requirements)

3

Use during pregnancy, lactation or lay

Pregnancy and lactation:

The safety of the veterinary medicinal product has not been established during pregnancy and lactation. Methadone diffuses across the placenta.

Studies in laboratory animals have shown evicence of adverse effects on reproduction. The use of the veterinary medicinal product is not recommended during pregnancy or lactation.

3

Interactions

For concurrent use with neuroleptics refer to section 3.9.

Methadone can potentiate the effects of analgesics, central nervous system inhibiters and substances that cause respiratory depression. Concomitant or subsequent use of the veterinary medicinal product with buprenorphine may lead to lack of efficacy.

3

Overdose

A 1.5 fold overdose resulted in the effects described in section 3.6.

Cats: In case of overdoses (> 2 mg/kg) the following signs can be observed: increased salivation, excitation, hind leg paralysis and loss of righting reflex. Seizures, convulsion and hypoxia were also recorded in some cats. A dose of 4 mg/kg could be fatal in cats. Respiratory depression has been described.

Dogs: Respiratory depression has been described.

Methadone can be antagonized by naloxone. Naloxone should be given to effect. A starting dose of 0.1 mg/kg intravenously is recommended.

3

Special warnings

Due to the variable individual response to methadone, animals should be monitored regularly to ensure sufficient efficacy for the desired duration of effect. Use of the veterinary medicinal product must be preceded by a thorough clinical examination.

In cats, pupil dilation is seen long after the analgesic effect has disappeared. It is therefore not an adequate parameter to assess clinical efficacy of the administered dose.

Greyhounds may require higher doses than other breeds to achieve efficacious plasma levels.

3

Withdrawal period

Not applicable.

3

Incompatibilities

Do not mix with any other veterinary medicinal product except for the infusion solutions indicated in section 3.9.

The veterinary medicinal product is incompatible with injection fluids containing meloxicam or any other nonaqueous solution.

3

Immediate packaging

Clear glass vial with grey, coated chlorobutyl rubber stopper and aluminium pull off cap or aluminium/plastic flip off cap.

Package size: 1 x 5 ml, 5 x 5 ml, 1 x 10 ml, 5 x 10 ml.

Not all pack sizes may be marketed.

3

Storage

This veterinary medicinal product does not require any special temperature storage conditions.

Keep the vial in the outer carton in order to protect from light.

3

Shelf life

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

Shelf life after first opening the immediate packaging: 28 days

Shelf life after dilution according to directions: Chemical and physical stability of the dilutions has been demonstrated for 24 hours at 25 °C, protected from light. From a microbiological point of view, the dilutions should be used immediately.

3

Disposal of unused product

Medicines should not be disposed of via wastewater.

Use take-back schemes for the disposal of any unused veterinary medicinal product or waste materials derived thereof in accordance with local requirements and with any national collection systems applicable to the veterinary medicinal product concerned.

3

Additional information

Vm 57446/4011

8 DATE OF FIRST AUTHORISATION

19 July 2018

9 DATE OF THE LAST REVISION OF THE SUMMARY OF THE PRODUCT CHARACTERISTICS

April 2025

10 CLASSIFICATION OF VETERINARY MEDICINAL PRODUCT

Veterinary medicinal product subject to prescription.

Find more product information by searching for the ‘Product Information Database’ on www.gov.uk.

3

Registration holder

VetViva Richter GmbH

3