Withdrawal of Phenylpropanolamine (PPA) for Human Use by the FDA and Implications for the Use of PPA in Dogs
From an editorial at VetMedCenter.com (www.VetMedCenter.com)
Author Mark Papich, DVM, MS, DACVCP
Introduction
November 15, 2000: Phenylpropanolamine, often abbreviated as PPA, is used in animals for its action as an adrenergic agonist. Specifically, it has been used frequently in dogs for the treatment of urinary incontinence. The Federal Food and Drug Administration (FDA) announced on November 6, 2000 that it is taking steps to remove phenylpropanolamine from all drug products and has requested that all drug companies discontinue marketing products containing phenylpropanolamine. This action already has affected veterinarians that have tried to obtain phenylpropanolamine for their patients.
Discussion
Phenylpropanolamine was first approved in 1959 and has been widely available as a nonprescription, over-the-counter (OTC) drug for humans for many years. Familiar brand names are Dexatrim and Acutrim (appetite suppressants) and Propagest and Rhindecon (decongestants). It has never been registered for treatment of dogs in the United States but has been legally prescribed by veterinarians as an off-label drug.
A report from the Yale University School of Medicine earlier this year indicated that phenylpropanolamine increases the risk of hemorrhagic strokes in women. Men also may be at risk. With concerns regarding risk of stroke, the FDA issued their public safety advisory. This advisory and the report can be found at http://www.fda.gov/cder/drug/infopage/ppa/default.htm.
In addition to the dose forms listed in the first paragraph of this editorial, phenylpropanolamine is usually found in many combination products used to treat coughs, colds, and allergies. Many OTC combinations that contain a cough suppressant, an antihistamine, or both also contain phenylpropanolamine if the product makes a claim as a decongestant. The decongestant effect of phenylpropanolamine is derived from its effects as an alpha-receptor agonist. Alpha-receptor effects constrict blood vessels in the mucous membranes of the sinus cavities to produce a decongestant effect. Phenylpropanolamine is a nonselective, adrenergic agonist and also has beta-receptor effects. It may act as a weak bronchodilator, but this is debated. Its central nervous system (CNS) effects result in its use as an OTC appetite suppressant. Phenylpropanolamine is used to treat urinary incontinence because of its effect on alpha receptors of increasing the tone of the urinary sphincter as well as its beta-receptor effects of relaxing the detrusor muscle of the bladder wall and allowing more urine filling.
No well-documented evidence indicates that the use of phenylpropanolamine in animals has produced serious adverse effects. It is possible that hypertension, cardiac arrhythmias, and congestive heart failure could be worsened by phenylpropanolamine because of its action as an alpha- and beta-receptor agonist. These side effects also could develop with the use of other adrenergic agonists. Adrenergic agonists should be used cautiously, if at all, in patients with these problems. Monoamine oxidase inhibitors (MOA inhibitors) and beta-blockers interfere with the action of phenylpropanolamine, and phenylpropanolamine may decrease the effectiveness of vasodilator drugs.
Without the availability of phenylpropanolamine, what are veterinarians to do? Some veterinarians have purchased an inventory of phenylpropanolamine for their clinics to meet their patients' needs for the coming weeks. A registered formulation (ie, Propalin syrup) of phenylpropanolamine is available in the United Kingdom for treatment of urinary incontinence in dogs, marketed by Vetoquinol (http://www.vetoquinoluk.co.uk/), but this product has not been registered in the United States. Some compounding pharmacies in the United States are selling compounded forms of phenylpropanolamine to veterinarians or are in the process of obtaining bulk drugs to provide phenylpropanolamine to veterinarians. A 1996 law requires the reporting of large bulk sales of phenylpropanolamine to the Drug Enforcement Administration (DEA) because it has the potential to be diverted to the illegal manufacture of amphetamine and methamphetamine.
Many veterinarians consider estrogen replacement with diethylstilbesterol (DES) to be the first drug of choice for treating urinary incontinence in dogs. This drug has been removed from the human market, but it is still available from some pharmacies for veterinary use. If estrogen replacement is not effective, adrenergic agonists such as phenylpropanolamine have been used. Other adrenergic agonists besides phenylpropanolamine also may be effective. Some veterinarians have used a similar drug, pseudoephedrine, because of anecdotal accounts of its efficacy in treating urinary incontinence. Pharmacologically, pseudoephedrine (eg, Sudafed, Pseudocot, Novafed, and generic forms) is similar to phenylpropanolamine but has not caused as much change in blood pressure. Pseudoephedrine does not have the adverse effects on blood pressure, heart rate, and the CNS as its stereoisomer ephedrine. Pseudoephedrine has been supplied as 30- and 60-mg tablets and administered empirically to dogs as either a 30- or 60-mg dose. Among the side effects to monitor are CNS excitement.
Other drugs with antimuscarinic effects have been used in humans to treat urinary incontinence. An example of such a drug is oxybutynin (Ditropam), which has antimuscarinic action and causes an increase in urine retention. Side effects that are typical for antimuscarinic drugs are dry mouth, increased heart rate, and cycloplegia. Oxybutynin has been used in dogs at a dosage of 5 mg/dog (supplied as 5-mg tablets), but its efficacy or safety in dogs has not been evaluated. Tricyclic antidepressant drugs (eg, amitriptyline, imipramine) also cause urine retention in some patients but have not been evaluated for treating urinary incontinence in dogs.
Summary
The Federal Drug Administration has recommended the withdrawal of phenylpropanolamine from over-the-counter human medications. Without its availability, veterinarians will have to investigate other sources of phenylpropanolamine or consider replacements (eg, pseudoephedrine) for treating dogs with urinary incontinence.
References
http://www.fda.gov/cder/drug/infopage/ppa/default.htm