ANIPRYL: Product Information

ANIPRYL- selegiline hydrochloride tablet
Zoetis Inc.

ANIPRYL®

(selegiline hydrochloride tablets)

For use in dogs only

CAUTION

Federal law restricts this drug to use by or on the order of a licensed veterinarian.

DESCRIPTION

Anipryl (selegiline hydrochloride tablets) are white, convex tablets containing 5, 10, 15, and 30 mg of selegiline HCl. It is commonly referred to in the clinical and pharmacological literature as L-deprenyl (the levorotatory form of deprenyl HCl).

Selegiline hydrochloride is (—)-(R)N ,α-Dimethyl-N -2-propynylphenethylamine hydrochloride.

Chemical Structure
(click image for full-size original)
Molecular Formula: C13 H17 N HClMolecular Weight: 223.75

PHARMACOLOGY

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO).1,2 MAOs are widely distributed throughout the body and are subclassified into 2 types, A and B, which differ in their substrate specificity and tissue distribution. Selegiline is believed to be a selective inhibitor of MAO-B at recommended dosages in the dog due to its greater affinity for type B enzyme active sites compared to type A sites.1 In CNS neurons, MAO plays a role in the catabolism of catecholamines, (dopamine, and, to a lesser extent, norepinephrine and epinephrine) and serotonin.1,2 Selegiline may have pharmacologic effects unrelated to MAO-B inhibition. There is some evidence that it may increase dopaminergic activity by other mechanisms, including increasing synthesis and release of dopamine into the synapse as well as interfering with dopamine re-uptake from the synapse.2–4 Effects resulting from selegiline administration may also be mediated through its metabolites. Two of its 3 principal metabolites, L-amphetamine and L-methamphetamine, have pharmacologic actions of their own. However, the extent to which these metabolites contribute to the effects of selegiline is unknown.

Therapeutic effects of selegiline are thought to result in part from enhanced catecholaminergic nerve function and increased dopamine levels in the CNS.5,6 The pathogenesis of the development of clinical signs associated with cognitive decline is considered to be partly a result of a decrease in the level of catecholamines in the CNS and deficiencies in neurotransmission.7 There is evidence which points to hypothalamic dopamine deficiency playing a role in the pathogenesis of pituitary dependent hyperadrenocorticism in the dog.8,9

Based upon IV administration of selegiline to 4 mixed breed female dogs, the plasma elimination half-life was estimated to be 60 ± 10 minutes (mean ± SD) and the volume of distribution at steady-state (Vss) was estimated to be 9.4 ± 1.6 L/kg (mean ± SD). The relatively large Vss suggests that the selegiline is extensively distributed to body tissues. The absolute bioavailability, F, of an oral solution was less than 10%.10

INDICATIONS

Anipryl tablets are indicated for the control of clinical signs associated with canine cognitive dysfunction syndrome (CDS) and control of clinical signs associated with uncomplicated canine pituitary dependent hyperadrenocorticism (PDH).

CONTRAINDICATIONS

Anipryl is contraindicated in patients with known hypersensitivity to this drug.
In humans, selegiline is contraindicated for use with meperidine and this contraindication is often extended to other opioids.

WARNINGS

Keep out of reach of children. Not for human use.
Anipryl should not be administered at doses exceeding those recommended (0.5–2.0 mg/kg once daily).
In humans, concurrent use of MAO inhibitors with alpha-2 agonists has resulted in extreme fluctuations of blood pressure; therefore, blood pressure monitoring is recommended with concurrent use in dogs. Also, in humans, severe CNS toxicity including death has been reported with the combination of selegiline and tricyclic antidepressants, and selegiline and selective serotonin reuptake inhibitors. Although no such adverse drug interactions were reported in the clinical trials in dogs, it seems prudent to avoid the combination of Anipryl and selective serotonin reuptake inhibitors (e.g., fluoxetine) as well as Anipryl and tricyclic (e.g., clomipramine, amitriptyline, imipramine) or other antidepressants.
At least 14 days should elapse between discontinuation of Anipryl and initiation of treatment with a tricyclic antidepressant or selective serotonin reuptake inhibitor. Because of the long half-life of fluoxetine and its active
metabolites, at least 5 weeks should elapse between discontinuation of fluoxetine and initiation of treatment with Anipryl.
Concurrent use of Anipryl with ephedrine or potential MAO inhibitors, such as amitraz, is not recommended.

PRECAUTIONS:

General

Anipryl is not recommended for other behavior problems such as aggression. In the clinical trials, 3 dogs showed an increase in aggression while on this drug. The safety and efficacy of Anipryl has not been evaluated in dogs with debilitating systemic diseases other than PDH.
The decision to prescribe Anipryl should take into consideration that the MAO system of enzymes is complex and incompletely understood and there is only a limited amount of carefully documented clinical experience with selegiline. Consequently, the full spectrum of possible responses to selegiline may not have been observed in pre-marketing evaluation of the drug. It is advisable, therefore, to observe patients carefully for atypical responses.
Endocrine function testing to confirm pituitary dependent hyperadrenocorticism should be performed prior to Anipryl administration for that condition. Anipryl is not recommended for treatment of patients with hyperadrenocorticism not of pituitary origin such as those due to an adrenal tumor or administration of glucocorticoids. If complications of PDH are evident at the time of diagnosis or emerge during Anipryl therapy, the patient should be evaluated and, if warranted, alternative therapy considered. Concurrent use of Anipryl in conjunction with other therapies of canine PDH has not been evaluated.

Laboratory Tests

No specific laboratory tests are deemed essential for the management of patients on Anipryl, as response to therapy should be based on the history and physical examinations for both PDH and CDS. In clinical trials for PDH, no correlation was found between an individual patient’s clinical response and results of the low dose dexamethasone suppression (LDDS) test. There was no evidence of adrenal insufficiency in these trials.In the 12 week clinical trial for CDS, a small number of dogs had a drop in hematocrit; some dropping within the normal range and some dropping below 37%. The clinical significance of this is unknown at this time. It is advisable to conduct a thorough physical examination and to consider appropriate laboratory tests to establish hematological and serum biochemical baseline data prior to administration of Anipryl.

Reproductive Safety

The safety of Anipryl in breeding, pregnant and lactating bitches, and breeding dogs has not been determined.

ADVERSE REACTIONS

In clinical trials, 404 dogs treated with Anipryl for as long as 18 months were monitored for the occurrence of adverse events. Many of the observations listed in the following table may be associated with the underlying disease (PDH or CDS), the advanced age of the patients or the development of unrelated concurrent disease. One index of relative importance, however, is whether or not a reaction caused treatment discontinuation. Eighteen dogs (4%) experienced one or more of the following adverse events that led either to discontinuation of therapy with Anipryl, dismissal from the study, or a reduction in dose: restlessness/agitation, vomiting, disorientation, diarrhea, diminished hearing, possible drug interaction (weakness, confusion, incoordination and “seizure-like” activity while being treated concurrently with metronidazole, prednisone, and trimethoprim sulfa), increase in destructive behavior in a dog with separation anxiety, anorexia, anemia, stiffness and polydipsia.

Percentage of Dogs with Adverse Events Reported in Clinical Field Trials
Adverse Event Anipryl (n=404) Placebo (n=67)
vomiting 26% 21%
diarrhea 18% 10%
hyperactive/restless* 12% 6%
anorexia 8% 1%
neurologic** 6% 1%
lethargy 6% 1%
salivation 5% 4%
urinary tract infection 4% 1%
pruritus/dermatologic 4% 1%
weakness 4% 0
pale gums 3% 1%
polyuria/polydipsia 3% 1%
weight loss 3% 0
diminished hearing 2% 0
panting 2% 1%
cardiovascular/respiratory*** 2% 0
licking 2% 1%

*This includes hyperactivity, irritability, abnormal repetitive movements, anxiousness, and restlessness.
**This includes ataxia, incoordination, staggering, disorientation, decreased proprioception, and seizure.
***This includes heart murmurs, tachycardia, collapse, dyspnea, pleural effusion, and sneezing.

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