Hemophyt (Canada)

its epimer at C* and their enantiomers

Hemophyt Indications

1) For the maintenance treatment of anticoagulant poisoning in dogs following emergency vitamin K₁ parenteral treatment in the presence of clinical coagulopathy; or

2) As a sole agent for the treatment of subclinical coagulopathy caused by anticoagulant poisoning.

Clinical coagulopathy is defined as the presence of haemorrhage that may occur on a single or on multiple locations, combined with a prolonged one-stage Prothrombin Time (PT) value.

Subclinical coagulopathy is defined as a mild coagulopathy (≥ 20% increase from the upper end of normal Prothrombin Time reference range) occurring in the early phase of anticoagulant poisoning, when dogs do not show any clinical signs.

DOSAGE AND ADMINISTRATION

Oral treatment should be undertaken within 12 hours after the end of emergency Vitamin K₁ treatment by the intravenous route, or during the first 36-72 hours (early phase) after the time of confirmed/suspected anticoagulant rodenticide ingestion.

Administer 5 mg of phytomenadione/kg body weight/day, orally once daily for a minimum of 21 days, according to the dosing table provided below. Tablets are scored for easy division into halves and quarters.

Dosing Table

It is recommended to administer Hemophyt™ tablets 30-60 minutes after a meal.

As the anticoagulant effects of rodenticides are known to be long lasting, it is recommended to administer Hemophyt™ until the clotting time is normal (i.e., that the PT values are no longer elevated). Regular monitoring of the coagulation status is thus needed. PT should be evaluated 48 hours after the last administration of Hemophyt™.

-If it is normal, a second PT test should be performed 48 hours later, to avoid relapse. If still normal, treatment with Hemophyt™ can be stopped.

-If it is prolonged, the treatment needs to be continued for another 7 days.

PT should then be re-evaluated 48 hours after the last administration of Hemophyt™, as instructed above.

The duration of Hemophyt™ treatment can be safely extended up to 6 weeks.

Contraindications

During the treatment with Hemophyt™, do not administer the following drugs:

- Non-steroidal anti-inflammatory drugs (NSAID), including salicylates

- Cimetidine

- Some antibiotics, including chloramphenicol, sulfonamides-trimethoprim, metronidazole, dimetridazole, and cephalosporin antibiotics presenting the N-methyl-thiotetrazole (NMTT) moiety. These cephalosporins can reduce the effect of vitamin K₁, by inhibition of the vitamin K₁ recycling.¹

CAUTIONS

The formation of prothrombin may be inadequate when dealing with patients with severe liver dysfunction. Therefore, in these animals, careful monitoring of coagulation parameters after administration of the product is required.

The safety of this product has not been established in bitches during pregnancy and lactation and in breeding males. Phytomenadione (vitamin K₁) crosses the placental barrier. Studies conducted in rats have shown no teratogenic or foetotoxic effects. Use in reproduction dogs only when the benefit/risk assessment is positive.

WARNINGS

People with known hypersensitivity to phytomenadione should avoid contact with this product. Wash hands after use. To avoid accidental ingestion, particularly by a child, unused part-tablets should be returned to the open blister space and inserted back into the carton.

KEEP OUT OF REACH OF CHILDREN.

ADVERSE REACTIONS

Very rarely, erythema, pruritus, dermatitis, vomiting, diarrhea, anorexia, and allergic edema have been reported.

The frequency of adverse reactions is defined using the following convention:-very common (more than 1 in 10 animals treated displaying adverse reaction(s))-common (more than 1 but less than 10 animals in 100 animals treated)-uncommon (more than 1 but less than 10 animals in 1,000 animals treated)-rare (more than 1 but less than 10 animals in 10,000 animals treated)-very rare (less than 1 animal in 10,000 animals treated, including isolated reports).

CLINICAL PHARMACOLOGY

Mode of action: Phytomenadione (vitamin K₁) is a co-factor necessary for the synthesis of vitamin K-dependent coagulation factors (factors II, VII, IX and X). During this synthesis, vitamin K₁ is converted into vitamin K₁ hydroquinone (active form) and then into vitamin K₁ epoxide. It is then recycled back into vitamin K₁. Antivitamin K rodenticides inhibit the recycling of vitamin K₁ epoxide, causing a risk of uncontrolled bleeding through the absence of functional factors II, VII, IX and X. The supply of vitamin K₁ must be sufficiently large to activate the alternative hydrogenase enzyme pathway that converts it to its active (hydroquinone) form.

Pharmacokinetics: In healthy dogs, phytomenadione (vitamin K₁) is rapidly absorbed after oral administration. Some of it is eliminated with the bile in the intestinal tract after metabolism in the liver, and some is eliminated in urine (in the form of glucurono-conjugated metabolites).

In anticoagulant-poisoned dogs, serum vitamin K₁ concentrations rapidly increased to peak levels 1 to 4 hours after an oral dose (T_max) and ranged from 726.3 to 4,545.3 ng/mL (C_max). The elimination half-life was 5.20 ± 1.14 hours (4.3 to 6.9 hours). The pharmacokinetics of vitamin K₁ in brodifacoum-dosed dogs were not significantly different from healthy dogs given vitamin K₁ at the same dosage.²

ANIMAL SAFETY

A placebo-controlled margin of study was conducted to determine the local and general tolerance of vitamin K₁ tablets in dogs. Hemophyt™ was administered orally once daily at 15 mg/kg body weight (2-3 times the recommended daily therapeutic dose of 5 mg/kg body weight) to twelve (12) healthy dogs, 7-10 months of age and weighing 7.2-10.3 kg, during 21 consecutive days. No hematological or biochemical abnormalities were observed in relation with the product administration. There were no significant statistical differences between the treated group and the control group for commonly used exploratory coagulation tests. No adverse events were attributed to the activity of the drug.

Although the youngest/lower-weight dogs will be exposed to doses up to 12.5 mg/kg bw of vitamin K₁ when administered Hemophyt™, no particular toxicity is expected in these sub-groups. The very low toxicity of oral vitamin K₁ and the safety of a long-term treatment (up to 6 weeks) have been well documented through literature data.

EFFICACY

A controlled study was conducted with 12 young adult dogs showing a significantly prolonged PT after experimentally-induced oral anticoagulant rodenticide poisoning. Each dog was allocated to either a placebo group or a treated group (Hemophyt™ tablets at 5 mg/kg/day for a minimum of 21 days).

All dogs in the placebo group had to receive an immediate emergency rescue treatment based on two IV injections of Vitamin K₁ injectable at 5 mg/kg body weight, 12 hours apart. This was followed, 12 hours later, by daily oral administration of 5 mg/kg/day Hemophyt™ for an additional 21 consecutive days. None of these dogs were considered a Treatment Success (0%). None of the dogs in the treated group needed an emergency rescue treatment and were all considered Treatment Successes (100%). This difference was statistically significant (p< 0.05). Statistical analysis also showed a significant difference between the placebo and the treated groups in PT values as early as 10 h after the first oral vitamin K₁ treatment or placebo tablets. No serious adverse events were reported for any of the dogs administered Hemophyt™ tablets.

STORAGE

Store between 15 and 30°C in the original packaging, away from light. Any unused divided tablet should be discarded after 3 days. After opening the blister pocket, replace the remaining portion(s) of tablet in the blister pocket and return the blister strip to the carton. The remaining tablet portion should be given at the next administration.

PRESENTATION

Available in thermosealed PVC/aluminum blister strips of 7 tablets in cartons of 1, 2, 3, 4, 5, 10 or 12 blister strips. Not all formats may be marketed.

REFERENCES

1. Shearer MJ et al., “Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status”
J Clin Pharmacol. 1988 Jan;28(1):88-95

2. Chalermchaikit T. et al., “The pharmacokinetics of brodifacoum and vitamin K₁ (phylloquinone) in dogs”
WVA, WSAVA (eds) XXV congress of the World Veterinary Association, XX congress of the World Small Animal Veterinary Association, Yokohama, 3-9 September 1995, 168

Manufactured by: Dômes Pharma, 3 rue André Citroën, 63430 Pont-du-Château, France

Imported and Distributed by: Modern Veterinary Therapeutics Inc., 261065 Wagon Wheel Way, Bay 3 - Balzac, AB T4A 0T5

Date: February 24, 2023

102603NT23-1 - 504582

CPN: 1354037.0