Comfortan 10 mg/mL (Canada)

Company: Dechra

Methadone Hydrochloride Injection

Veterinary Use Only

DIN 02496658

Sterile 10 mg/mL

In Clinic Use Only

Description

Comfortan is clear colourless to pale yellow sterile aqueous solution for injection in cats containing the opioid analgesic methadone. It is a racemic mixture of two isomers: L-methadone and D-methadone.

Active Ingredient

Preservatives

Comfortan 10 mg/mL Indication

As a part of a pre-medication regimen, for the control of post-operative pain associated with ovariohysterectomy and castration in cats.

Comfortan 10 mg/mL Dosage And Administration

Administer 0.5 mg/kg (0.05 mL/kg) intramuscularly.

Due to the variable individual response to methadone, cats should be monitored regularly to ensure sufficient efficacy for the desired duration of effect. 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.

Contraindications

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

Do not use in animals with respiratory or cardiac failure.

Do not use in animals with liver and renal dysfunction.

Comfortan 10 mg/mL Cautions

Safety has not been established in cats less than 5 months of age.

Efficacy was demonstrated when methadone was used as a pre-medication as part of a complete anesthetic protocol in healthy cats.

The cat should be examined regularly to assess if additional analgesia is required. If pain control is not adequate, additional non-opioid analgesia should be considered.

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 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 product.

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

Methadone diffuses across the placenta. Studies in laboratory animals have shown adverse effects on reproduction. The safety of the product during pregnancy and lactation has not been assessed in cats.

The use of the product is not recommended during pregnancy or lactation.

Methadone can potentiate the effects of analgesics, central nervous system inhibitors and substances that cause respiratory depression. Concomitant or subsequent use of methadone with other opioids may lead to lack of efficacy.

Warnings

Keep out of reach of children.

Methadone can cause respiratory depression. Avoid skin, eye and mouth contact, when handling the product. In cases of spillage onto the skin, or splashing into the eyes, wash immediately with large amounts of water.

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

In the case of accidental self-injection, seek medical advice immediately but DO NOT DRIVE as sedation may occur.

Overdose

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, and hypoxia were also recorded in some cats.

A dose of 4 mg/kg is fatal in some cats. Respiratory depression has been described.

Methadone can be antagonised by a pure opioid antagonist.

Adverse Reactions

Although all adverse reactions are not reported, the following information is based on voluntary post-approval drug experience reporting. It is generally recognized that this results in significant under-reporting. The adverse events listed here reflect reporting and not necessarily causality. The following adverse events are listed in decreasing order of frequency: apnea, dyspnea, tachypnea, hyperactivity, lip licking, vocalization, mydriasis and hyperthermia.

Clinical Pharmacology

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 non-competitively antagonises the NMDA receptor and inhibits norepinephrine reuptake; the l-isomer is a μ-opioid receptor agonist.

In cats, methadone is absorbed following intramuscular injection with peak values occurring at 65 (± 108.83) minutes. However, when the product is administered inadvertently subcutaneously (or in another poorly vascularised area) absorption will be slower. The mean terminal half-life is 10.5 (± 3.5) hours. Clearance is medium to low with a mean (sd) value of 9.06 (3.3) mL/kg/min. Methadone hydrochloride plasma concentrations do not directly correlate with effectiveness since the drug is distributed to the site of action.

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 of the administered dose is excreted unchanged in the urine; the remainder is metabolised in the liver and subsequently excreted.

Efficacy Studies

Efficacy was demonstrated in a blinded, positive controlled, single site study conducted in the United Kingdom using client or agent owned adult cats. In this study, 90 cats presenting for ovariohysterectomy or castration were randomly assigned to a treatment group. The study design had two arms, acepromazine (ACP) and medetomidine (MED), each of which enrolled 45 cats. In each arm of the study, 15 cats (7 males and 8 females) were assigned to one of the three opioid groups given with premedication agent ACP or MED. A total of 30 cats were assigned to the methadone (Comfortan, 0.5 mg/kg IM) group, whereas 30 cats were assigned to a second opioid group and another 30 cats were assigned to a third opioid group. The opioids were administered as premedication along with either ACP or MED. After the surgery, if pain was not controlled, cats would receive methadone (0.5 mg/kg IM) and a NSAID as rescue analgesia. Six hours after the premedication, all cats that did not receive rescue analgesia were administered methadone (0.5 mg/kg IM) and an NSAID 8 hours after the premedication. As a result, all 90 cats in this study were exposed to at least one dose of methadone and 30 cats received two doses of methadone. In the ACP arm, anesthesia was induced with alfaxalone IV whereas in the MED arm it was with propofol IV. Isoflurane was used to maintain anesthesia during surgery.

Assessment of pain was made before premedication, at time of IV catheterization, and post-operatively 90 min, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h and 20-24 h after premedication. Pain was assessed using a behavioural pain score recorded on a 100 Visual Analog Scale (VAS) with ends anchored at 0 = no pain and 100 = worst pain possible. Rescue analgesia was administered if pain scores ≥ 50. Mechanical nociceptive thresholds were measured at the wound site (scrotum in male cats and left flank in female cats) using a Pressure Rate Onset Device.

In the ACP arm, pain scores were lower in males than females; pain scores were generally low throughout the study.

There was no significant differences between treatment groups at any time point. Of the seven cats, six females and one male, that needed rescue analgesia, 3 female cats were in the methadone group.

In the MED arm of the study, pain scores were lower in males than females. There was a significant difference between the 2 other opioid groups at 3 hours for females. Otherwise, there was no significant differences between groups at any other time point. Seven female and no male cats required rescue analgesia: 2 of the female cats were in the methadone group.

Storage

Store between 5°C and 25°C in the original package to protect from light. Do not freeze. Contents should be used within 28 days after first use.

PRESENTATIONS

Multidose vials of 5 mL available.

Eurovet Animal Health B.V., Handelsweg 25, 5531 AE Bladel, The Netherlands

Imported and distributed by:

Dechra Veterinary Products Inc., 1 Holiday Avenue, Tower East, Suite 345, Pointe-Claire, Québec, H9R 5N3, Canada

617690

CPN: 1786059.0