Before you institute a facility-wide switch, however, you should be aware of the safety issues that may be involved with using generics. You may be called upon to defend this decision to the surgeons and anesthesia staff, who may be concerned that a switch will compromise patient care. This article will look at the issues involved with generic drugs in general, examine some of the most common generic IV anesthetics, and tell you the dos and don'ts of how to proceed in switching from brand-names to generics.
What is a generic drug?
In a recent stopover in the Atlanta airport, I happened to stop in a shop selling "designer-style" sunglasses. While at first glance they looked similar to brand-names, even casual inspection of the glasses revealed that there were clear differences in quality. Fortunately, this is not the case for generic drugs-while these drugs may be slightly different from their brand-name counterparts, the differences are usually not significant enough to be of concern. To understand how they differ, let's first look at how a generic drug is developed.
New drugs are typically developed under patent protection. Before they go on the market, they must pass a rigorous gamut of FDA tests. The patent runs 17 years from the time it is issued, regardless of when the FDA actually approves the drug for use with patients. Thus, manufacturers race to get patent protection early enough so that no one else copies their drug (the data from the testing may be part of the public record) but not so early that the patent runs out before they can get it to market and recoup their investment. During the time that the drug is the only one of its kind on the market, the innovator company tries to recoup the research and development costs. The FDA may issue exclusivity for a particular use of the drug for a period of three to 3.5 years, depending on circumstances. New formulations/routes of administrations may also be protected by exclusivity.
When the drugs go off-patent, other companies may try to develop generic varieties. To gain FDA approval, however, a company must prove that a generic is both pharmaceutically equivalent and therapeutically equivalent to the name brand.
Pharmaceutical equivalence means that the drug contains the same amount of active ingredient in the same dosage form and meets the same or other applicable standards (as far as strength, quality, purity, and identity) as the brand-name product. It must also be able to be administered in the same manner as the brand-name drug. It may, however, differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, expiration time, labeling (within certain limits), and excipients. Excipients are inactive ingredients that may include coloring agents, flavors, and preservatives (which is the main concern in the case of IV drugs). These inactive ingredients must be "generally recognized as safe" (GRAS list), or undergo studies to establish safety. The reason why it is important to establish the safety of even the inactive ingredients is that components such as preservatives, colors, and flavors may have a clinically important effect in patients, especially patients with certain allergies (more on this later).
Therapeutic equivalence is somewhat more difficult to achieve than phamaceutical equivalence. The term refers to the effect the drug has in the human body, including the overall effect in potency variations and the effects of the excipients. According to the FDA, a therapeutically-equivalent drug must meet the following general criteria:
- It must be approved as safe and effective.
- It must be manufactured in compliance with Current Good Manufacturing Practice regulations.
- It must have no known or suspected bioequivalence problems. Bioequivalence refers to the fundamental structure of the two drugs. An example of this would be a drug administered by mouth that has a different binder to make the pill (the binder would be an excipient). The manufacturer would have to show that the pill dissolves in the right amount of time. The manufacturer must address any suspected bioequivalence problems with appropriate testing.
- It must be adequately labeled. The label has to clearly identify the active ingredients and any other components (such as preservatives), and comply with all FDA labeling regulations.
Potential Problems with Generics
Because all generics have the same active ingredient as the brand-name equivalent, only two things can cause potential problems: the drug formulation and the excipients.
The drug formulation can cause problems if it does not deliver the active ingredient effectively. According to the FDA, a therapeutically equivalent preparation must deliver between 80 to 125 percent of the active ingredient that the innovator drug does. All generic variations of a drug are compared to the original reference formulation to minimize straying from the standard.
Some drugs have what is called a narrow therapeutic index, which means that the difference between the toxic dose and the therapeutic dose is so small that the 80 to 125 percent range allowed may be a problem. This is seen in such drugs as Coumadin, certain anticonvulsants, and thyroid medications (levothyroxine). In these cases, even small differences in generic and brand-name formulations can lead to major clinical effects. Typically, a clinician would order these drugs with a "dispense as written" or "do not substitute" designation.
Fortunately, most anesthesia drugs have a wide therapeutic index, and varying drug formulations rarely affect outcomes. In most cases, the clinician will simply continue administering the drug until the desired effect is reached. One prominent example is morphine. Generic formulations of morphine may differ widely, but it doesn't really matter if the patient gets 10 mg of Brand X morphine but would have gotten 12 mg of Brand Y had that been used. Many narcotics have generic formulations and are treated as commodities (meaning that they are completely interchangeable). We recently saw this with the shortage of fentanyl. Our pharmacy obtained both brand-name and generic fentanyl from any supplier that had either. We used whatever we could get without even thinking about the manufacturer. However, for some drugs, this kind of full-scale substitution is not possible.
Excipients are the more serious concern. They can cause the following three problems: some patients may be allergic to them, they may affect the stability of the preparation (a problem that may not be detected in the development stages), and they may affect the active ingredient depending on how the patient receives the medication. For example, one generic formulation of cyclosporine (used to reduce transplant rejection) appeared to be therapeutically equivalent during testing, but then it was found that when patients would take it with certain foods, the excipients in the formulation would reduce the effectiveness of the drug.
Because of the excipient-related concerns, the FDA labels drugs that have been determined to be therapeutically equivalent using the following designations:
- There are no known or suspected bioequivalence problems. These are designated AA (no suspected problems), AN (for aerosol administration), AO (for injectable oil preparations), AP (injectable aqueous or in some instances, non-aqueous), or AT (topically -administered products).
- There are actual or potential bioequivalence problems (including different excipients, pill formulations, and the vehicle of delivery) that have been resolved with adequate in vivo and/or in vitro evidence that supports a designation of bioequivalence. These drugs are designated AB.
For example, the generic version of Forane is AN rated because the active ingredient is the only thing in the bottle. The generic version of propofol is AB rated because there was a question about bioequivalence that has since been resolved. Even though the generic version is proven to be safe, the FDA still requires the AB designation.
To ensure patient safety, it is widely recommended that you only consider substituting brand-name drugs with generic drugs that have been labeled as AA, AB, or other A-rated equivalent s such as AN, AO, AP, etc. B-rated drugs can't be freely interchanged because they may not have the same bioequivalence. For example, different extended-release pills may release the active ingredient at different rates, so they can't simply be swapped. With appropriate monitoring, they can be switched in an individual patient. However, these types of drugs are rarely used in outpatient surgery.
If a generic drug is proven to have therapeutic and pharmaceutical equivalence, it may provide an excellent opportunity for cost savings. The main reason why generics are so much cheaper than name brands is that the companies manufacturing the generic formulation are not burdened by the research and development costs that the innovator manufacturer had. Generic drug manufacturers merely have to show that their products are equivalent-the efficacy of the original formula is already established. Furthermore, they typically do not have the marketing expense that the innovator does, because there is already a built-in marketplace. However, some generic manufacturers do try to establish brand identity, to gain a name-recognition advantage over competitors.
The biggest impact of the entry of generic formulations may actually be downward pricing pressure on brand-name drugs as they try to maintain their market share. This has certainly been the case in our market with the entry of propofol and midazolam. Likewise, the cost of Versed is now 20 percent of what it was before its patent ran out. Not all innovator formulas follow this pattern after the patent expires, however. For example, generic vecuronium is 22 percent cheaper than brand-name Norcuron vecuronium.
However, the drug prices you pay at your facility are very dependent on your drug-supply contract. In some cases, the generic may actually be more expensive than the brand-name. Our facility is in a consortium that gets volume pricing. As a result, a 20-ml vial of generic propofol actually is priced 35 percent higher than brand-name Diprivan! Conversely, our contract price for generic midazolam is about half the price for the brand-name (Versed).
Small ASCs, however, may not have the benefit of getting in on volume pricing. In that case the generic is usually the cheaper option, although the difference may not be all that significant. It should be noted, too, that some of the Total IV Anesthesia (TIVA) agents such as remifentanil are still protected by patent (for remifentanil, approval was 1996 and the patent runs through 2009) and buying a generic version of certain anesthetic is not always possible.
IV Generic Drugs
These are some of the more common generic IV anesthetics that you may consider switching over to at your facility.
Propofol: This drug (Diprivan, manufactured by AstraZeneca, is the brand-name drug) was first marketed as a sedative-hypnotic for the induction of anesthesia. It has become very popular in the outpatient setting because of fast recovery and antiemetic effects; a generic version became available in 1999.
The generic drug has generated some controversy. I am personally convinced that generic propofol is fine to use with almost all patients (our facility's decision to continue using Diprivan instead of generic propofol was strictly economic). However, the generic has come under scrutiny because some clinicians feel that the drug vehicle (lipid emulsion) and the preservative used in the formulation may have unintended clinical effects.
One question concerned the stability of the lipid emulsion; a few studies suggested that under extreme temperature or pressure conditions, the emulsion could separate, or "crack," which would be difficult to detect on casual inspection. The separated lipid could trap lipid droplets in the lungs and lead to fat embolism syndrome; it could also accumulate in the circulatory system and cause pulmonary problems such as bronchospasm and elevated pulmonary artery pressures.
While this was a hot topic when the generic was first released, post-marketing surveillance has not picked up this as a clinically-significant problem. A 2000 study published in Anesthesia and Analgesia showed the generic version to be safe and effective. There is some indirect evidence that there is a difference in stability in the laboratory when the formulations are subjected to extreme conditions, but there is no data looking at clinical outcomes. There isn't any anecdotal evidence that I'm aware of that suggests that the stability differences are clinically significant.
A potentially more important issue concerns the preservative. Diprivan contains EDTA as a preservative; the generic formulation contains an FDA-approved bisulfite preservative. It's thought that bisulfites can cause allergic reactions, including bronchospasm, in sensitive patients (you may remember that sulfites were banned from salad bars, where they were used to maintain freshness, because of the incidence of allergic response). It is my opinion, however, that the bisulfite issue is not a major problem. Sulfite allergy is uncommon (five to 10 percent of chronic asthmatics have it, and it occurs in a fraction of a percent of the general population). While there are a few case reports that suggest a relationship between the incidence of allergic reactions and the presence of the sulfites, the evidence is far from conclusive that the sulfites caused the response.
Of course, if you have a patient who is definitely allergic to sulfites, the bisulfites in propofol would certainly be an issue. You should be able to screen out these patients by taking a thorough pre-op history and asking about sulfite allergies. Even if patients don't know if they have a sulfite allergy, you may be able to extrapolate this from other clues; for example, sensitivity to chardonnay or white wines, which often contain sulfites, warrants caution. You may want to avoid administering generic propofol to any asthmatic patient. In most cases, however, you should be able to administer generic propofol without any problems.
Midazolam: This is another recent entry in the generic market. Originally produced by Roche under the Versed brand, midazolam has become tremendously popular both in the OR and other procedure areas such as endoscopy. Midazolam is a water soluble benzodiazepine that is used to produce sedation and anxiolysis and is used as an adjuvant to general anesthetics. Given orally, it is very useful as a premedicant for pediatric cases. Because of its water solubility, it is less painful to inject than diazepam (a once-common drug used for anesthesia, relief of nervousness, and sedation) and its shorter duration of action lends itself to outpatient procedures. Interestingly, Roche still has exclusive rights to market midazolam in a premixed oral form specifically for pediatric sedation. For the IV formulation, there is little difference in clinical efficacy between the brand-name and generic formulations. In fact, at my institution, because of the similar size and shape of the vials, no one in the OR could tell the difference between the two.
Etomidate (Amidate): This is used for the induction of anesthesia. It is shorter acting than the barbiturate anesthetics (such as thiopental). It has a steroid-based structure and has been associated with adrenal suppression. The excipient is propylene glycol and large doses of this have been associated with seizures. The main reason etomidate is used is because there is less myocardial depression than with thiopental, and it does not release histamine. A generic formulation became available in 1996. I have used both the original and generic formulations without noticing a difference.
Fentanyl (Sublimaze): This first became available as a generic in 1985 (some formulations came out in the early 1990s). Fentanyl is a short-acting narcotic and is very popular for many anesthetic regimens. I don't know anyone who cares which brand they use- so much so that clinicians who still refer to fentanyl as "Sublimaze" run the risk of sounding dated!
Atracurium (Tracrium): This drug is a short-acting non-depolarizing muscle reactant that undergoes Hofmann degradation (it spontaneously breaks down in the blood without the need for enzymes, so its metabolism and duration of effect is independent of the medical status of the patient). A generic became available in 1997. There was little resistance to this as the innovator company was pushing its newer agent, cisatracurium, which was approved by the FDA in 1995.
Ketorolac: This drug (Toradol was released in 1989, the generics in 1997,1999, and 2000, depending on manufacturer) is an injectable non-steroidal anti-inflammatory drug (NSAID) that is frequently used in the management of post-op acute pain in patients unable to take medications by mouth. The major benefit is that it blocks prostaglandin synthesis at the site of pain. The importance of this in ambulatory surgery is that it reduces the amount of narcotic needed to control pain. This can minimize undesired side effects such as nausea, sedation, and reduced respiration. I think that drugs of this class are an excellent adjuvant to narcotics for the treatment of acute pain. The down side is that there are some undesired effects such as inhibition of platelets which can lead to bleeding problems and also effects on the stomach lining that can increase the incidence of ulcers.
You may find that there is not much resistance to changing to many generics. Many of the adjuvant drugs used in the operating room such as atropine, epinephrine, neostigmine, and ephedrine are "generic"; i.e. they are AA rated or pre-date this system, and are frequently obtained from a best price source. Some drugs such as succinylcholine have a brand-name following, but are actually branded generics (Anectine, Quelicin) for which there are also no-name generics available. Apparent differences in effect may be due to observer bias (the doctor can read the label) or possibly issues in handling and storage of the drug. For example, at one previous practice, I encountered a situation where we had problems with certain local anesthetics for spinal anesthesia every autumn and we speculated that the drugs had sat in the sun in this southern town while on the loading dock. Given the turnover, the overheated supplies from the summer wound up in the OR a couple of months later.
How to implement a switchover to generics at your facility
Switching to generic drugs may be a great cost-cutting move, but it's important to do this only after getting buy-in from your physicians and anesthesia staff. If they don't understand the economic benefits and are suspicious of generics (especially controversial ones such as propofol), you risk alienating them and giving the impression that you are taking cost-cutting measures at the risk of patient safety. Here's a plan for making the switch.
- Identify generic possibilities: Determine which drugs you use in high volume, and which ones cost the most. If the volume is small, the cost savings may not be enough to offset the cost of analysis and switching.
- Involve your physicians: Solicit the opinions of all the medical staff who would be using the generic drugs; this would certainly include your anesthesia staff who would be administering the drugs, but you should also survey your other physicians (such as endoscopists who may use propofol). You may also want to survey other facilities to see if and how they use generics and what their results are. Since there has to be a mechanism for obtaining "non-formulary" drugs, if your doctors don't agree to the change, they will continue to specify the brand name in a "dispense as written" manner. For ASCs that are part of an integrated delivery system or a hospital, there may be a Pharmacy and Therapeutics Committee that already establishes a formulary and should have a process in place.
- Endeavor to understand physician concerns: This process works well with the majority of physicians. But how do you deal with the physician that is reluctant to change? First try to identify the fundamental concern of the physician. The concern may not be directly related to the generic formulation at all. Some of these concerns include a resistance to change ("I've always used Drug X and I'm comfortable with it"), bias toward the products sold by friendly sales reps, misinformation on what generics are, or concern that the clinical aspects of patient care are being overrun by financial concerns.
As we saw in the case of propofol, there may be legitimate concerns about the true therapeutic equivalence of the formulations, and input from the end-users is key. Managers and administrators may not have the expertise to individually evaluate these clinical issues, but if they are convinced based on the outside information and recommendations they've obtained and the clinicians are still not in agreement, there are ways to persuade them.
One possibility would be to identify an opinion leader in the same or similar specialty who can approach the physician and assuage his or her concerns. You may also consider involving a mediator, such as surgeon or anesthesiologist who is not involved with your facility. It may be prudent to stay with brand-names if your physicians have strong feelings about them. In the end, the opportunity for cost savings, the potential for adverse reactions, and the importance of keeping your physicians happy all play a part in this decision.
The switchover from brand-names to generics need not be a painful process. With some willingness to research drugs and their generic equivalents and by maintaining open communication with your doctors, it is possible to keep your physicians happy and your patient outcomes high, while improving your bottom line.