Epiphen 30 mg (Canada)

Phenobarbital Tablets

VETERINARY USE ONLY

Epiphen 30 mg Indication

For the control of seizures in canine idiopathic epilepsy. Epilepsy is a non-progressive intracranial disease that produces recurring seizures, including idiopathic epilepsy.

Epiphen 30 mg Dosage And Administration

For oral administration in dogs.

The required dosage will differ to some extent between individuals, and even within individuals, and with the nature and the severity of the disorder. Dogs should be started with an oral dose of 2 mg per kg bodyweight twice daily (Ref. 1). Steady state serum concentrations are not reached for 2-3 weeks after treatment is initiated. The full effect of the medication does not appear for two weeks and doses should not be increased during this time. The serum Phenobarbital level should be measured two weeks after initiation of treatment.

If seizures are not controlled the dosage may be increased with associated monitoring of serum Phenobarbital levels after steady state has been achieved. Serum Phenobarbital concentrations should be measured 2 weeks after every dosage change and every 6 to 12 months thereafter.

Optimal Phenobarbital serum concentrations are between 100 and 130 µmol/L (23-30 µg/mL) (Ref. 2). Serum Phenobarbital levels above 170 µmol/L (39.5 µg/mL) have been associated with an increased risk of hepatotoxicity (Ref. 3).

Most dogs affected by epilepsy will require life long anticonvulsant treatment.

Contraindications

Do not administer to animals with impaired hepatic function or animals that have demonstrated previous hypersensitivity reactions to barbiturates.

Epiphen 30 mg Cautions

The safe use of this drug has not been established in breeding, pregnant or lactating dogs; the potential benefits vs. the potential risks must be considered in each case. The safe use of this drug has not been established in animals under 6 months of age.

Serum Phenobarbital concentrations should be measured after every dosage change. There is an increased risk for hepatic toxicity developing at serum Phenobarbital levels above 170 µmol/L (39.5 µg/mL). Hepatic function should be evaluated before initiating therapy and on a regular basis (every 6 to 12 months). Blood levels of hepatic enzymes alanine aminotransferase (ALT) and alkaline phosphatase (ALP) are usually increased with Phenobarbital treatment without necessarily indicating liver damage.

Phenobarbital has been associated with a rare but serious bone marrow dyscrasia in dogs. A complete blood count should be evaluated in the month following initiation of therapy and on a regular basis thereafter (every 6 to 12 months) to monitor for any potential leukopenia, anemia, or thrombocytopenia.

Phenobarbital treatment should never be stopped abruptly as signs of physical dependence (i.e. tremors, incoordination, restlessness, and seizures) may develop. There is also a danger of status epilepticus during withdrawal. The dosage should therefore be gradually reduced in small steps over a prolonged period.

Use with caution when administered concurrently with any other depressant of the central nervous system.

Warnings

Keep out of reach of children. Keep locked up.

Adverse Effects

Common side effects include sedation, polyphagia, polyuria and polydipsia. These effects are usually transient and disappear after the first two weeks of treatment. Although less common, Phenobarbital administration can cause hepatotoxicity and serious bone marrow dyscrasias in dogs.

Pharmacology

Phenobarbital is reported to increase the seizure threshold required for seizure discharge and decrease the spread of discharge to surrounding neurons. It works primarily by enhancing responsiveness of the inhibitory postsynaptic effects of the gamma-aminobutyric acid (GABA). The bioavailability of Phenobarbital is high and it is rapidly absorbed after oral administration, with maximal serum concentrations achieved 4 to 6 hours after administration. Phenobarbital is widely distributed into tissues (reported volume of distribution: 0.6 L/kg). It is primarily metabolized by the liver, with the remaining up to 25% excreted unchanged by the kidneys. The reported elimination half-life of Phenobarbital ranges from 30 to 90 hours. Steady state concentrations are achieved within 2 to 3 weeks of initiation of therapy. Phenobarbital causes enzymatic induction in the liver which can lead to drug interactions and increases in its own metabolism.

Efficacy

Two blinded clinical trials were conducted in Canada with Epiphen.

The first study included 37 dogs previously diagnosed with idiopathic epilepsy and for which the seizures where currently controlled with Phenobarbital tablets for human use. Of this number, 22 where switched to Epiphen for three months. The study concluded that seizure control was similar in the two treatment groups. Furthermore, the serum Phenobarbital concentrations were maintained at the same extent for both products.

In the second study, 22 dogs recently diagnosed with idiopathic epilepsy and not receiving any

anticonvulsant drug where enrolled to receive Epiphen for at least three months. Serum Phenobarbital concentrations were monitored and doses were adjusted to obtain approximately 25 µg/mL (107.5 µmol/L), but no higher than 35 µg/mL (150.5 µmol/L). Adequate seizure control was observed in the 13 dogs that completed the study.

Drug Interactions

Phenobarbital therapy may enhance the biotransformation of several drugs, including digoxin, digitoxin, glucocorticoids, phenylbutazone, metronidazole, doxycycline and certain anesthetic drugs (i.e. thiopental, xylazine). Chloramphenicol, cimetidine, valproic acid and ketoconazole could inhibit Phenobarbital metabolism and therefore increase its toxicity. Phenobarbital may impair the absorption of griseofulvin and also influence the results of ACTH response tests and dexamethasone suppression tests.

Storage Conditions

Store in a dry place, between 15°C and 25°C.

PRESENTATION: Circular biconvex white tablets for oral administration.

Vetoquinol N.-A. Inc., 2000, ch. Georges, Lavaltrie, QC, Canada J5T 3S5

References

1- Boothe DM. Anticonvulsants and Other Neurologic Therapies in Small Animals. In: Boothe DM, Small Animal Clinical Pharmacology and Therapeutics, W.B. Saunders Company, Philadelphia, 2001, p. 431-456.

2- Quesnel A. Antiepileptic Drug Therapy in Dogs and Cats - An update. World Small Animal Veterinary Association Congress, Vancouver, August 8-11 2001

3- Dayrell-Hart B. et al. Hepatotoxicity of Phenobarbital in dogs: 18 cases (1985-1989). JAVMA, 199(8): 1060-1066. 1991.

1218A

CPN: 1234388.1