VetInfo Digest                                                                                                                  January 2007

 


Table of Contents:

Generic Drug Information

Ordering Foreign Medications for Compassionate Use

Using NSAIDs in Cancer Patients

 


This Month's Note:

February is the month in veterinary medicine that dental care is usually emphasized. This is almost certainly one of the most neglected areas of care for pets. There are many reasons for this but the bottom line is that pet's teeth are just easy to ignore. Truly diseased teeth don't grab your attention as much as eyes or ears with similar degrees of infection or pathology. People often don't like to have their own teeth cleaned or to have dental work done and it is easy to transfer these feelings to pets. There are very few things that we do in practice that improve the quality of life for pets more than dealing with persistent dental problems, though. It is sometimes amazing how much difference it makes to remove diseased teeth and to clean the remaining teeth in an older dog or cat. There is some risk involved in cleaning pet's teeth and attending to dental problems due to the need for anesthetic but it really does make pets feel much better. It is a tough reality that anesthetic complications sometimes result in the death of a pet but this risk seems worth taking to me. Quality of life is as important a consideration as quantity of life -- and it is possible to truly increase the quality of a pet's life by dealing with chronic dental problems.


Generic Drug Use in Veterinary Medicine

After last monthís issue I got some questions about the use of generic medications in pets. This is a topic that has a lot of different aspects. The use of generic drugs in pets is not quite the same as it is in people. For veterinary drugs in which a generic exists you can assume that the generic is bioequivalent and that the major difference is cost. Most of the generic drugs used in veterinary medicine are not generics of drugs approved for dogs and cats, though. They are generics of drugs intended for human use that are being used by veterinarians because they are available for use. This raises some significant concerns that have to be considered when choosing to use a generic drug.

Overall, generic drugs have a very good track record. There are a few isolated incidences in which generic drugs that appeared to be bioequivalent prior to widespread use turned out to have differences from the brand name drugs in a way that mattered for patient care. These problems generally surface pretty quickly after the use of the generic drugs becomes widespread. At the present time I am not aware of a significant known difference between a generic drug and brand name drug among the medications available in both forms. However, this information applies only to drugs that are being used for the species they are approved for use in.

Whether or not a drug has equivalent biologic activity in a dog when it appears to have equivalent activity in a human is a slight uncertainty. Most of the time there isnít a significant difference between a medication approved for people and one approved for pets. There are exceptions to this rule, though. Dogs do not always digest the enteric coating on some medications in the same way that humans do, making this aspect of medication delivery a variable, for instance. This is most important when considering the use of a generic drug that is available for humans but where a generic doesnít exist in a veterinary formulation. Two examples of this are meloxicam (Mobic Rx for humans, Metacam Rx for pets) and selegiline ( Anipryl Rx for pets, l-deprenyl for humans), both of which are available in generic formulations for humans but not for pets. The human generics are likely to work as well, but there is a small chance that bioequivalence for human use might not translate into bioequivalence for canine or feline use. Over time it usually becomes clear if a problem exists so if you can afford to use brand name drugs for a few months after the advent of equivalent human generic drugs you might want to do this. Other people will try the drugs due to cost differences. Switching later when it is clear that the medications do work well, without problems, is then a little safer.

The other situation that we deal with in pets is the use of generic drugs with human approved uses that are not approved at all for use in pets. Perhaps the most commonly used drug in this class is the antibiotic cephalexin. As far as I know there has never been a pet approved form of cephalexin, yet it is one of the most widely used antibiotics in veterinary medicine. Veterinarians started using the medication because its spectrum of activity is very good for the bacterial skin infections that occur in dogs and cats. Small studies were done to establish dose guidelines but the overall safety of cephalexin and other concerns that are addressed in the original approval process by the FDA were not done specifically for dogs and cats. Over the years cephalexin has proven to be a fairly safe medication but when your veterinarian chooses to use a human generic medication because a veterinary drug is not available that use is experimental to some degree.

Fortunately for veterinarians and pet owners, there are at least small studies that support the use of most of the human generic medications that make it into widespread use in veterinary medicine. Unfortunately, some drugs are used by veterinarians before any study results are available. It is always reasonable to ask your veterinarian if a drug prescribed for your pet is an approved drug for the species and if not, what studies support its use.

It would be nearly impossible to practice veterinary medicine with great success without using some medications that have never been officially approved for use in pets by the FDA. This is particularly true for cats due the dearth of approved drugs for a number of serious cat diseases, including the retroviral infections, hyperthyroidism and chronic kidney disease. For this reason, veterinarians are very accustomed to using medications in an off-label manner and it may not even occur to your vet to explain this to you because the use seems so routine to the vet. Despite this widespread feeling among vets, it is better if you are informed when a drug is being used in an experimental or non-approved manner.

Veterinarians can generally acquire almost any human medication that comes in a generic form. In any case, veterinarians can write prescriptions for human brand name or generic medications so most of the spectrum of human approved medications as well as medications specifically approved for use in pets is available in some way to pet owners. For the most part this is a good thing since pharmaceutical companies rarely develop drugs they donít expect to be profitable and it is harder to make profits on medications that only have veterinary applications. Without the availability of the human products the practice of veterinary medicine would be severely limited. I think that I might even consider retiring if it became unlawful to use human medications in pets as it would be too disheartening to know that a beneficial medication was available but to be unable to use it. This sometimes happens now due to cost concerns or availability problems and it is hard enough to deal with on an occasional basis.

For those of you who do not know how drug regulation works, a drug company has 15 years of exclusive use of a newly patented drug before companies that make generic versions are allowed to do so. A brand name drug comes on the market and is expected to pay for itself and produce the majority of the profits it will produce for the drug company during this time. There is variation in how long it actually takes generics to appear for brand name drugs because the clock starts ticking on the fifteen years before the drugs actually make it to the market in most cases. For some drugs there is very little time left when the drug actually makes it to market and for others there is most of the fifteen year time period. This is part of the reason that you hear about drug companies ďrushing a drug to marketĒ. The sooner they get it out for actual sale the longer they have to enjoy exclusive rights to the patent. There is a financial incentive to get a medicine to market.

This legal situation causes some interesting problems for veterinarians at times. Some drugs approved for use in humans eventually also are approved for use in pets. One example of this is the anti-depressant clomipramine (Anafranil Rx for humans). It was approved for people long before it was FDA approved for use in pets as the brand name drug Clomicalm (Rx). This led to a situation in which the human generic clomipramine was available to veterinarians within a few months of the availability of Clomicalm. This made for a real dilemma in how to best serve veterinary clients. Clomicalm is the approved drug. Technically, a veterinarian should use an approved drug when one is available. However, as is usually the case, the generic human drug is significantly less costly than the brand name veterinary drug. Veterinarians are caught between wanting to do what is best from a regulatory standpoint (i.e. their licenses are important to them), how to best treat the pet ( is the human generic truly bioequivalent?) and how to best serve their clients (who usually would prefer the less expensive medication). How this choice is made boils down to the individual vetís concerns over all of these issues.

Generic versus brand name drugs is one of the things that makes me wonder if it would be better for pets and pet owners in the long run if veterinarians did not serve as the pharmacists for pets. To some extent there is a clear conflict of interest for the veterinarian who makes the diagnosis and then chooses the medication for the pet. Does the veterinarian provide the least expensive among equivalent medications or does the veterinarian choose the most expensive medication because the profit is higher? This conflict is at the root of a much dissatisfaction among pet owners when comparing prices between ďtheirĒ veterinarian and other vets. It is entirely possible to reduce office visit fees, surgical fees, etc. simply by upping pharmaceutical fees and/or using the most expensive of pharmaceuticals when a choice has to be made. If you consider vaccines to be among the pharmaceuticals it is clear that this is exactly the model that many veterinary practices were founded on. It is a way of obscuring what the client is actually paying for. I donít understand the logic entirely, but I know that most of my clients are happier paying $45 for Frontline Topspot and having something to take home with them than $45 for an office visit in which I provide the best answers I can for their petís problems based on years of training and experience. This leads many veterinarians to conclude that it is better to keep office visit prices down but to always provide medications (or shampoos, or vitamins, or something), no matter what. This is not in the best interest of the pet when the medications are not necessary. It is made a little worse when there is a generic drug that is very inexpensive that isnít dispensed because there is more profit in a brand name medication.

Veterinary clients like the fact that generic drugs usually cost less than brand name drugs. In some cases the difference can be quite dramatic. To use Baytril (Rx) to treat a 20 lbs. dog for cystitis in our practice would run just about $90. To use ciprofloxacin, which is a roughly equivalent medication available generically, costs less than $10. Obviously, the cost comparison runs strongly in favor of ciprofloxacin. Veterinarians like the fact that stocking generic medications is less expensive than stocking brand name drugs. A large veterinary practice can have a drug inventory of a hundred thousand dollars or more fairly easily. Cutting down on the cost of this inventory is a great advantage for cash flow. On the other hand, most veterinary practices roughly double the cost of a medication when pricing it for sale to clients. The markups vary from practice to practice and even from one medication to another but on the average, drugs cost clients roughly twice what they cost the veterinarian. So a veterinarian who sells you ciprofloxacin might make a $5.00 profit while a vet who sells you Baytril might make a $45 profit. Even though the percent markup is the same, there is an economic incentive for some vets to sell the brand name medication even though their inventory costs are significantly higher.

This situation is slightly more complex than simply worrying about the profit. Technically, according to FDA guidelines, a veterinarian should use the approved drug first and then go to alternatives only if the approved drug doesnít work. If there is no veterinary generic product the approved drug would be the only choice if guidelines were followed exactly. It would be hard to practice restricting oneself to this guideline but it does serve as one justification for using the brand name drugs in initial treatment. For a veterinarian who has had a run in with the FDA or the state pharmaceutical board, this can be a very powerful incentive to stick to approved drugs first under almost all circumstances. It can also be difficult to make some treatment decisions when using generic drugs.

Baytril (Rx) would be enrofloxacin if sold generically. At the present time enrofloxacin is not available as a generic medication, to the best of my knowledge. Ciprofloxacin is the human pharmaceutical Cipro (Rx), which is also a fluoroquinolone class antibiotic. It is available generically. It is a good equivalent drug for enrofloxacin for an interesting reason that helps to point out one of the major problems with using generic drugs. Ciprofloxacin is processed, at least in dogs, into enrofloxacin in the body. Approximately 75% of ciprofloxacin becomes enrofloxacin once it has been processed by the liver in the first pass through the circulation. So when ciprofloxacin is used in dogs, should the dose be increased 25% in order to compensate for the difference? As far as I know, no one really knows the answer to that question with certainty. We assume that might be the case based on our knowledge of how the drug is processed but there isnít a lot of money to do studies of generic drugs since there isnít much incentive for the drug company to study a medication that anyone can produce. So when we use ciprofloxacin, it is with some uncertainty about how well it really will work. As you can imagine, if the cost difference for a 20 lb. dog is $80 there is huge incentive to use ciprofloxacin when the dog weighs 120 lbs. and a fluoroquinolone antibiotic seems necessary and the cost difference may be $200, or more. So far, ciprofloxacin has worked as well as enrofloxacin in our practice and we are reasonably confident that itís use is warranted but I think you can see where a very cautious veterinarian might feel very uncomfortable making the switch.

The possibility for differences in processing of medications between dogs and cats and humans is very real and there are some good examples of major differences that have been discovered over the years. Perhaps the one that most people are familiar with is acetaminophen (Tylenol Rx) use in humans and pets. Acetaminophen seems reasonably safe for use in people. This is also true in most instances for dogs. Cats, on the other hand, will often die if they are given one extra-strength acetaminophen capsule or even if lower dosages are given over the course of several days. Cats canít process acetaminophen properly and toxic doses build up quickly in their system.

Toxicity is not the only problem with using medications studied in humans and hoping they have equivalent uses in pets. Celecoxib (Celebrex Rx) would be a good medication to consider for dogs with severe degenerative joint disease because it is in the same class as deracoxib (Deramaxx Rx) or firocoxib (Previcox Rx), except for one problem. About half the dogs who are given celebrex can process it completely in about an hour. So these dogs get very little benefit from the medication. Where humans can take celecoxib once a day and expect the benefits to last all day, a dog who is in the ďfast processingĒ half of dogs would have to take the medication once an hour to keep similar daily blood levels. This is not something that you would intuitively expect to occur with a medication, but it does.

Dosage differences between humans and pets also occur and can impact on the use of medications. One example of this is the use of generic thyroxine made for human use. The drug is the same as the one used for dogs but the human dose range is so low that most of our patients would need to take 4 to 8 tablets per day of the available human generic sizes of thyroxine, negating any cost savings. Fortunately there are generic thyroxine preparations for us in dogs. Thyroxine is one of two drugs I am aware of in which there was some question about whether the generic preparations worked as well as the brand name drugs but as far as I know there is currently no reason to believe it does not.

One aspect of the use of generics that is difficult to assess is the difference in owner compliance when using an inexpensive drug versus an expensive one. Sometimes this works to the advantage of the pet. It is more likely that a pet with severe pyoderma will get antibiotics long enough if I dispense an inexpensive generic. It is difficult enough to get clients to give antibiotics faithfully for 6 to 8 weeks without having to convince them to buy $500 worth of medication. On the other hand, there are several studies that seem to show that people are more likely to actually give medications if they cost more. This is not a sure effect but it does seem like some clients are more likely to use an expensive medication as directed.

Another important aspect of generic drugs for many of my clients is that I can write prescriptions for them and they can be obtained from pharmacies. This makes refilling prescriptions much more convenient for veterinary clients who donít want to take time off from work to come to our office or who work far enough from home that they couldnít get to our office without taking most of the day off from work. It is also helpful when clients spend part of the time in our area and the rest of the time somewhere else, such as Florida or Arizona in the winter. I can usually call a pharmacy anywhere in the country and have prescriptions filled.

Generic drugs can be a source of confusion for our clients. There are multiple manufacturers of generic drugs and it is not uncommon for them to make the medications in different shapes, different colors, different sizes or even in different forms such as a capsule instead of a tablet. When we refill ongoing prescriptions with a medication that is suddenly a different color and shape, it can be disconcerting for the client. We try to explain this to every client when a change occurs but inevitably we forget sometimes or distracted people donít get the message. This results in frantic phone calls at times. It is best to check with your vet when you are unsure that a medication dispensed is the one you were expecting but donít be too concerned if the veterinarian is sure it is the right medication despite changes in appearance.

There is a good chance that there is a generic medication for most of the conditions that affect your pets. If the cost of medications is a burden it is always worthwhile to ask your vet if a generically available drug might work as well. Just to give you one example, meloxicam (Mobic Rx, Metacam Rx) works as well for many pets as deracoxib (Deramaxx Rx) or firocoxib (Previcox Rx) but costs much less. At the present time a monthís supply of meloxicam generic tablets for a large dog runs around $10 on the average, while Deramaxx is closer to $60 month. Even though meloxicam is not a direct generic for Dermaxx it may work as well with a substantial reduction in the cost of therapy.

Veterinary clients shouldnít be afraid of the use of generic drugs even though it is important to understand some aspects of their use. Your veterinarian can help in deciding when a generic drug is appropriate. If there are good reasons to use a generic drug, even if isnít approved specifically for dogs or cats it is generally safe to do so as long as the use has been shown to be generally safe and effective in at least one well controlled study. If you are worried about the use of a particular drug go ahead and ask for a reference that outlines its use. If it turns out your vet heard about the drug from a distributorís representative or other questionable source it may be best to take the time to find a good quality reference for its use. In an emergency situation it is probably best to trust your vetís judgment on the need and safety of medications used.


Obtaining Foreign Medications Legally

There are times when it seems important to use a medication that is approved in another country but not in the U.S.A. There is a procedure for doing this. It is fairly detailed and this may make your vet reluctant to help you obtain the medication but I want to provide the procedure to you in case there is a need in the future for using a foreign medication. At the current time I think that this procedure is probably used most often to obtain a small number of medications, including trilostane for hypoadrenocorticism (Cushingís disease), pimobendan to treat cardiomyopathy and other forms of heart failure and enilconazole, an antifungal drug used to treat aspergillosis and malazzesia yeast infections topically.

The procedure for obtaining medications is termed ďImporting Drugs for Compassionate UseĒ. It is necessary to obtain FDA approval prior to importing these medications to meet the legal importation requirements. This applies to pets. It is not usually possible to obtain medications legally for animals that might be used for food. Your veterinarian must make this request. A letter must be sent to the FDA that contains all of the following information:

1) Veterinarianís name, address and telephone number.

2) Clinic name and address.

3) Client name and address.

4) Patient name and species

5) Name of drug, both generic and brand names if possible.

6) Class of the drug, such as antibiotic or steroid analog (as for trilostane)

7) Name and address of drug supplier, must include the country in the address

8) Legal status of the drug in the country it is ordered from, such as ďapproved for use for cardiomyopathyĒ

9) Amount of drug to be imported ( generally not more than 90 day supply)

10) The disease condition being treated in the patient

11) Reasons why this drug must be used instead of a domestically approved drug

12) A statement (from the vet) that says: A) The vet will notify the animal owner that the drug is not approved for use in the U.S. B) The drug will not be used in any food animal C) That the vet agrees to notify the FDA if there is any adverse reaction

13) How the veterinarian learned of the existence of the drug

The letter should be sent to Toni Wooten, Division of Compliance HFA-230, Center for Veterinary Medicine FDA, Metro Park North, 7500 Standish Place, Rockville MD 20855. The letter may be faxed to 301-827-1498. If there are problems with approval that require telephone contact the telephone number for contact is 301-827-0796.

It seems likely that the contact person for this note may change over time but I suspect that the address will stay the same.


NSAIDs for Cancer

For some time it has been recognized that piroxicam, a non-steroidal anti-inflammatory agent, worked well to reduce tumor size and slow metastasis of some tumors. It now appears that this effect may be more generalized. The non-steroidal anti-inflammatory medications that block Cox-2, such as deracoxib (Deramaxx Rx) and firocoxib ( Previcox Rx) appear to work about as well as piroxicam in a small number of studies. This is not a way to cure cancer but it does slow the progress of some cancers and has the added benefit of providing some pain relief, often an important thing to control when cancers are present. The major benefit of this information is that the newer Cox-2 inhibitors are less likely than piroxicam to cause gastrointestinal problems such as gastric ulcers.

 


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