CE Online: Pharmacist's Letter

Pharmacist's Letter
Online Continuing Education

Pharmacist's Letter / Prescriber's Letter on
Generic Drugs: A Law CE

Volume 2006, Course No. 36

Self-Study Course #06036

Many patients and healthcare professionals eagerly await the expiration of patents on expensive, brand-name drugs. This allows cheaper, generic versions to come onto the market, resulting in substantial savings for pharmacies, healthcare organizations, and patients.

It's estimated that in 2006, drug companies making brand-name drugs will lose $12 to $23 billion in sales due to new generics coming on the market.^1,2 This includes many big drugs in the near future...Altace, Ambien, Lamisil, Norvasc, Pravachol, Proscar, Zocor, and Zoloft. And many more expected in the next couple of years...Coreg, Imitrex, Provigil, Tequin, and Zyrtec.

Currently about 50 percent of all prescriptions dispensed are generic.³ On average, generic prescriptions cost about $50 to $60 less than their brand name counterparts.^3,4 The potential savings from the use of generics is estimated to be in excess of $20 billion a year.^4,5 Both brand-name and generic manufacturers have millions of dollars at stake when a drug patent expires. Often there are complex legal battles between companies for the right to market the drug.

Predicting when a generic drug will be available is tricky. It's not as straight forward as looking at the patent expiration date for its brand name counterpart. Lawyers for both brand and generic companies are maneuvering behind the scenes. Brand-name drugs often have multiple patents...a patent on the drug molecule, a patent on the indication, another patent on the dosage form or manufacturing process, etc.

In response, generic companies often challenge a patent BEFORE it expires. In many cases, these challenges are successful and generic companies can market a generic drug before the brand-name drug's patent expires. On the other hand, generic availability can be delayed due to litigation or exclusivity issues.

Question #1
Which of the following is TRUE regarding generic drugs?
	a. Nearly 50% of all prescription drugs are dispensed as generics.
	b. Generic prescriptions cost patients about $60 less than brand name prescriptions.
	c. A patent expiration on a drug isn't always a good indication of when a generic drug may become available.
	d. All of the above

Background on the Generic Drug Approval Process

Patent and Exclusivity

Patent protection provides exclusive rights to the brand-name (innovator) company for a limited period of time in exchange for disclosure of the invention details. This serves the dual purpose of protecting the inventor and promoting the advancement of scientific knowledge.

Drug patents have a life of 20 years from the date of filing the application.⁶ The life of a patent after a drug is approved is usually much less than 20 years because patents are filed very early in the development of a drug, and the drug approval process usually takes several years. The patent life of a drug after FDA approval is limited to 14 years. New drugs lose almost half the time of their patent protection before they ever reach the market.⁶

The Drug Price Competition and Patent Term Restoration Act of 1984 (also known as the Hatch-Waxman Act) created a compromise in the drug industry by giving generic companies greater access to the prescription drug market, and restoring some of the patent life lost on brand-name drugs during the approval process.^6,7 The Act also included patent extensions as incentives for brand-name companies to develop new products.

There are several types of exclusivities available to add to the patent life of a brand-name drug.^8,9

Pediatric exclusivity (6 months)
New Clinical Investigation exclusivity (3 years)
New Chemical Entity (NCE) exclusivity (5 years)
Orphan Drug exclusivity (7 years)

Drug companies are not required to apply for exclusivities. FDA grants exclusivities with or without a company's request.

Pediatric exclusivity is granted to drugs with pediatric clinical studies. This is an incentive to drug companies to perform pediatric studies. Clinical Investigation exclusivity is granted to drugs with additional clinical testing to develop new dosage forms, new indications, or to switch from prescription to over-the-counter use. NCE exclusivity is granted to innovative drugs containing an "active moiety" that has not been previously approved by FDA. Orphan Drug exclusivity is granted to drugs that treat rare diseases affecting less than 200,000 Americans.^8,9

Orphan Drug status provides tax incentives that enable sponsors to study drugs that would otherwise be too costly to move through the regulatory hurdles required to bring a new drug to market.¹⁰

Brand-name companies benefit financially from these extensions because they restore some of the patent life lost during the drug approval process. For example, the patents for Zocor and Zoloft were set to expire December of 2005, but were extended to June of 2006 due to the addition of Pediatric Exclusivity.

Patent Challenges

Once patents and periods of exclusivity expire, generic manufacturers can submit Abbreviated New Drug Applications (ANDAs) for approval to market a generic version of a drug. One of the following four certifications (commonly referred to as paragraphs I, II, III, and IV) must be made upon filing of ANDAs:^9,11-13

that the drug had not already been patented
that the patent has expired
that the generic drug would not go on the market until the patent is expired
that the patent is invalid or will not be infringed

Under the Hatch-Waxman Act, a generic company can seek approval to market a generic drug before the expiration of the brand-name drug's patent. Generic companies often challenge a patent under paragraph IV certification.

The first generic company to successfully challenge a patent has the right to be the only company marketing the generic version for 180 days.^8,9,11,12 This is why the first generic available often costs more than you'd expect. It's not until after the 180-day period that the price really comes down, once multiple manufacturers start selling generic versions and competition drives the price down.

A brand-name company can also sue a generic company for patent infringement. This automatically postpones FDA approval of the generic version for 30 months if the infringement lawsuit is filed within 45 days of the brand-name company receiving notice of patent challenge.^6,11,13 This 30-month "stay of approval" allows the patent holder time to assert its patent rights in court before generic competition enters the market. Generics for Fosamax, Sonata, and Wellbutrin XL are stuck in this legal limbo right now.

Prior to 2003, ANDAs were subject to multiple 30-month stays due to legal loopholes of the Hatch-Waxman Act. The Medicare Modernization Act of 2003 closed the loopholes by limiting ANDAs to a single 30-month stay in most cases.¹⁴

The approval of generic Altace (ramipril) illustrates how paragraph IV certification, 180-day generic exclusivity, and 30-month stay affect the marketing of generic products.¹⁴ Altace patents are scheduled to expire in 2008 and 2012. However, Cobalt Pharmaceuticals submitted an ANDA for ramipril with paragraph IV certification stating that Altace patents will not be infringed by their product. King Pharmaceutics, the owner of Altace patents, then filed a patent infringement suit against Cobalt Pharmaceuticals. This resulted in a 30-month stay on Cobalt's ramipril ANDA. Cobalt won the lawsuit and gained final approval of ramipril in October 2005. Since Cobalt was the first to submit ANDA for ramipril with paragraph IV certification, they were granted 180-day generic drug exclusivity.¹⁵

Question #2
Which of the following is TRUE regarding market exclusivity of brand name drugs?
	a. Zocor (simvastatin) received an Orphan Drug exclusivity because of clinical research in children.
	b. Manufacturers are interested in patent extensions because they allow generic drugs to be marketed earlier than normal.
	c. Pediatric exclusivity encourages companies to study drugs in children, normally an understudied patient population.
	d. Patent protection prevents any generic version of a drug 20 years after a new drug is approved.

Impact of Generics

Besides the sales revenue brand-name drug companies lose to generic drugs, new generic drugs also affect prescribers and pharmacists. New generics trigger formulary changes and therapeutic switches. For example, some insurance plans may require trying generic simvastatin or pravastatin before Lipitor...or generic zolpidem before Sonata or Lunesta. These formulary changes can be difficult to keep track of for prescribers, pharmacists, and especially patients.

The benefit of new generic drugs, of course, is cost savings. Patients are able to save money on the cost of prescription drugs by using generics. Pharmacies can also benefit, as they can earn more money on generics than on brand-name medications.²

Upcoming Generics

Here are our best estimates for some soon to be generic medications. For updated estimates of availability, see Detail-Document #220101.

Table 1: Anticipated Availability of First-Time Generics
Brand^a (Manufacturer)	Generic Name	Generic Manu- facturer(s)^b	Anticipated Availability^c
Norvasc (Pfizer)	Amlodipine	Apotex, Mylan, Roxane, Teva, Watson	October 2005
Amaryl (Sanofi-Aventis)	Glimepiride	Andrx, Corepharma, Dr. Reddy's Labs, Invagen, Mylan, Ranbaxy, Teva	October 2005
Altace (King Pharma- ceuticals)	Ramipril	Cobalt	October 2005
Metaglip (Bristol-Myers Squibb)	Glipizide/ Metformin	Corepharma, Teva	October 2005
Floxin Otic Solution (Daiichi)	Ofloxacin Otic Solution	Bausch & Lomb, HiTech, Novex	November 2005
Copegus (Roche)	Ribavirin Tablet	Teva, Three Rivers, Zydus	December 2005
Dostinex (Pfizer)	Cabergoline	Par	December 2005
Pravachol (Bristol-Myers Squibb)	Pravastatin	Teva, Ranbaxy, Lek, Ivax, Geneva	April 2006
Zoloft (Pfizer)	Sertraline	Andrx, Aurobindo, Genpharm, Ivax, Mylan, Roxane	June 2006
Proscar/ Propecia (Merck)	Finasteride	Dr. Reddy's Labs, Teva, Ivax	June 2006
Zocor (Merck)	Simvastatin	Ranbaxy	June 2006
Ambien (Sanofi-Aventis)	Zolpidem	Mylan, Par	October 2006
Lamisil (Novartis)	Terbinafine	Dr. Reddy's Labs, Gedeon Richter USA, Genpharm, Mylan, Ranbaxy, Roxane, Teva	December 2006
Zofran ODT (Glaxo- SmithKline)	Ondansetron Orally Disintegrating Tablet	Kali	December 2006
Cerebyx (Parke-Davis)	Fosphenytoin	Sicor	August 2007
Coreg (Glaxo- SmithKline)	Carvedilol	Teva, Ranbaxy, Dr. Reddy's Labs	March 2007
Zyrtec (Pfizer)	Cetirizine Tablets	Teva, Par	December 2007
Kytril (Roche)	Granisetron	Baxter, Sicor	December 2007
Sonata (King Pharma- ceuticals)	Zaleplon	Roxane, Teva	June 2008 (December 2007)^d
Zerit (Bristol-Myers Squibb)	Stavudine	Aurobindo	December 2008
Tequin (Bristol-Myers Squibb)	Gatifloxacin	Teva, Zydus	December 2009 (June 2007)^d
Imitrex (Glaxo- SmithKline)	Sumatriptan	Cobalt	February 2009 (June 2007)^d
Actos (Takeda)	Pioglitazone	Alphapharm, Mylan, Watson	Uncertain^e
Avandia (Glaxo- SmithKline)	Rosiglitazone	Dr. Reddy's Labs, Teva	Uncertain^e
Exelon (Novartis)	Rivastigmine	Watson	Uncertain^e
Depakote (Abbott)	Divalproex Delayed Release Tablet	Zydus	Uncertain^e
Depakote ER (Abbott)	Divalproex Extended Release Tablet	Ranbaxy	Uncertain^e
Fosamax (Merck)	Alendronate	Barr, Ivax, Mylan, Teva, Watson	Uncertain^e
Provigil (Cephalon)	Modafinil	Barr, Carlsbad, Mylan, Ranbaxy, Teva	Uncertain^e
Risperdal (Janssen)	Risperidone Tablet and Solution	Mylan (tablet), Roxane (solution)	Uncertain^e
Ditropan XL (Ortho-McNeil)	Oxybutynin Extended Release Tablet	Impax, Mylan	Uncertain^e
Topamax (Ortho-McNeil)	Topiramate	Barr, Ivax, Mylan, Par, Ranbaxy, Roxane, Teva	Uncertain^e
Wellbutrin XL (Glaxo- SmithKline)	Bupropion Extended Release Tablet	Anchen	Uncertain^e

^a This list is not all-inclusive.
^b Current as of December 2005. These are manufacturers with either approval or tentative approval to market the generic version of the drug.
^c Generic availability is subject to change as a result of litigations and patent exclusivities. Products with anticipated availability in 2005 have received final approval, but may not be marketed, yet. All others are tentatively approved and waiting for patents to expire or resolution of litigation to gain final approval.
^d Ongoing litigation, availability may be sooner than patent expiration date.
^e Generic product(s) also tentatively approved. Availability uncertain due to ongoing litigation. Because there are multiple patent expiration dates and little information concerning which patents are being challenged, it is difficult to estimate an availability date.

This chart is also available as a handy print out, click here to get it.

Generic Substitution

Each state has its own generic substitution laws. These laws allow a pharmacist to dispense a generic equivalent rather than a brand-name drug. The FDA's Approved Drug Products with Therapeutic Equivalence Evaluations, more commonly known as the "Orange Book," is the bioequivalency standard by which many states allow generic substitution. As its formal title implies, the Orange Book contains ratings for therapeutic equivalence between medications. The Orange Book designates AB ratings for products that are therapeutically equivalent. BX ratings are assigned to drug products for which FDA has insufficient information to determine therapeutic equivalence. For states that rely on the Orange Book for generic substitution decisions, only AB-rated products can be substituted.

Generic substitution rules apply when a prescription is written for a specific drug, usually indicated by the specific brand name for a drug. Alternatively, when a prescriber writes a prescription using the generic name of a medication, a pharmacist may dispense either a brand or generic.¹⁶ In these cases, cost or insurance co-pay will likely influence what the patient receives. Pharmacists may NOT substitute when prescribers specifically indicate that substitution is not allowed.

When substitution is allowed, pharmacists should only substitute a medication which is therapeutically equivalent.¹⁷ Generic substitution is legal in many states, but without prescriber authorization, therapeutic substitution is illegal. To clarify, generic substitution is the substitution of therapeutically EQUIVALENT medications. Therapeutic SUBSTITUTION is the substitution of medications in the same therapeutic class, as examples, one proton pump inhibitor (PPI) for another, or one prescription antihistamine for another.¹⁸

These practices make perfect sense today, but these laws are a result of a history of unregulated substitution and unreliable generic drugs. Fortunately, this is not the current state of things.

For help with substitution, get our chart showing your state's requirements...and another chart showing which generics are A-rated to drugs with multiple brand names. Detail-Document #220901.

One area that still causes concerns for many prescribers, pharmacists, and patients are drugs with a Narrow Therapeutic Index (NTI). It's true that some drugs have a narrow range between doses that are subpotent...and doses that are toxic, or in other words, a drug where the "effective" dose is not too different from a "toxic" dose. These drugs can require a careful titration to the correct dose for each individual patient followed by regular monitoring for efficacy and side effects. Warfarin is a classic example of a drug with a narrow therapeutic index where slight differences in drug concentration in the blood can result in either inefficacy or toxicity.^19-21

Examples of NTI Drugs

carbamazepine
digoxin
levothyroxine
phenytoin
theophylline
warfarin

We'll now cover some examples and the controversy surrounding generic substitution.

Question #3
Which is appropriate considering generic substitution?
	a. A pharmacist substituting Allegra for Zyrtec at a patient's request because of cost.
	b. A prescription written for fluoxetine dispensed with brand name Prozac at a patient's request.
	c. A prescriber writing "Do not substitute" or other required wording on a prescription.
	d. Both B and C

Question #4
Narrow Therapeutic Index drugs:
	a. Are frequently substituted with medications from the same therapeutic class.
	b. Can require dose titration and follow-up monitoring for efficacy and toxicity.
	c. Are identified by an FDA rating of BX.
	d. Should never be substituted with a generic version.

Warfarin

Warfarin is an effective anticoagulant. It's used for the treatment and/or prevention of thromboembolism in a wide variety of conditions including deep venous thrombosis, atrial fibrillation, valvular heart disease, and in patients with mechanical or biological prosthetic heart valves.^22,23 In addition to being a drug with an NTI, warfarin is associated with many drug-drug interactions and drug-food interactions, further necessitating careful titration and monitoring.^22,23

Traditionally, brand-name crystalline warfarin sodium (Coumadin) has been used. The introduction of amorphous warfarin sodium in the 1980s was associated with increased cost of patient care and an increased risk of bleeding.²¹ Subsequently, amorphous warfarin was removed from the market, leaving Coumadin as the only available warfarin product until 1997. At that time, Barr Laboratories became the first company to receive FDA approval to manufacture and market a generic version of crystalline warfarin sodium.

Historically, debate over the use of generic warfarin developed partly because of residual "fear" over the problems associated with amorphous warfarin sodium. In addition, the question of bioequivalence and comparable clinical efficacy between the innovator brand and generic products raised concern.^19,21,22

FDA approval of generic warfarin products caused a considerable amount of controversy and concern in the medical community.^19,21,22 And just as with any new generic, there were economic implications with the availability of lower cost generics. But clinically, the question was whether patients could be safely switched from Coumadin to a generic version of warfarin.

Bioequivalence of Generic vs. Brand Warfarin

The approved generic versions of warfarin are AB rated and listed in the FDA Orange Book.²⁴ FDA defines AB-rated products to be therapeutically equivalent to the innovator brand based on in vivo and/or in vitro evidence supporting bioequivalence.²⁴

For a generic drug to be considered bioequivalent, mean bioavailability parameters (e.g., extent and rate of absorption) of the generic product may differ from that of the innovator brand by -20% to +25%.^19,20,24 While at first this range may seem large, the 90% confidence interval (CI) for the ratio of the generic products mean area under the concentration-time curve (AUC) and maximum serum/blood concentration (Cmax) to that of the innovator must lie entirely within this range (80% to 125%).^19,20,24,25 To meet the CI requirement, it would be difficult for the generic product to differ from the innovator brand by more than 10%.¹⁹ In the case of Barr brand warfarin, the bioavailability parameters fall well within the 80% to 125% limits. The 90% CI for Barr's product was found to be within a 95% to 105% range of the mean pharmacokinetic parameters reported with Coumadin.²⁶

FDA has not developed a separate standard to determine bioequivalence in drugs with a narrow therapeutic index. FDA's official position is that no clinical data has shown that a problem exists with generic substitution of narrow therapeutic index drugs utilizing the -20% to +25% rule.^20,25 In addition, FDA states that generic products that have been found to be bioequivalent may be substituted for each other without an adjustment in dose or the need for added monitoring.^19,22,26 Any difference that could exist between products should not be any greater than what would be expected when switching between lots of the innovator brand.²² FDA says that the differences between AB-rated products is no greater than the variation between different batches of Coumadin.

Clinical Trials

Several trials have compared the clinical efficacy of brand-name warfarin to generic versions. Witt et al conducted the largest of these trials, which analyzed 2,299 patients receiving warfarin anticoagulation.²² Patients currently treated with brand-name warfarin were switched to the Barr generic product. International normalized ratio (INR) values were compared 90 days before and after the switch. The majority of patients, 72% had an INR change greater than 10% (33.1% experiencing better INR control and 38.9% experiencing worsening INR control). In 13% of patients, INR control varied by greater than 50%. The mean INR value changed from 2.54 + 0.51 before the switch to 2.41 + 0.45 after the switch. This was statistically (p < 0.05) but not clinically significant. No difference was noted in the number of nonfatal anticoagulation-related adverse events after the switch.²²

Additional smaller trials comparing brand-name warfarin to generic have found little difference in INR when switching between products.^27-29 A study funded by Barr pharmaceuticals found no significant difference in INR in 39 patients that were switched from the innovator brand to generic warfarin.^22,26-30 However, a bias in this analysis is that 15 of the original 55 enrollees were excluded from analysis due to the need to make adjustments in dosage.^22,26,30

A randomized, crossover trial by Weibert et al compared equivalent anticoagulation of brand-name to generic warfarin in patients with atrial fibrillation.²⁸ Patients included in the analysis had stable INR control and a low risk of adverse events. Of the 1,181 patients initially screened, 113 met study inclusion criteria. Patients were initially treated with one product for four weeks and then crossed over and treated with the other product for an additional four weeks. No significant differences in INR values, warfarin dosage, or adverse events were noted between groups.

Milligan et al²⁷ (n=182) and Swenson et al²⁹ (n=210) also compared the therapeutic efficacy of brand to generic warfarin substitution in HMO and managed care settings, respectively. Both studies demonstrated no difference in INR and adverse event rate in patients who switched to generic warfarin.^27,29

Bioequivalence trials have found comparable bioavailability between brand and generic warfarin products.^24,29 Several smaller trials have found negligible difference in INR when patients were switched.^27-29 However, a few case reports have demonstrated either under or over coagulation when generic warfarin was substituted for the brand name.^30,31 In the Witt et al trial, the global change in INR before and after switching from brand to generic warfarin was relatively small and not clinically significant.²² However, the majority of patients had a >10% change in INR after switching from brand to generic warfarin.

Whether the changes in INR in this trial represent real differences between products or just the inherent variability associated with warfarin therapy is unknown. There are many other factors which can play a critical role in INR control. These include dietary vitamin K intake, drug interactions, herbal interactions (e.g., ginkgo, ginseng), alcohol use, laboratory error, noncompliance, and other disease states (e.g., congestive heart failure).^19,23

The best way to keep INR stable is with consistency. Patients should be reminded to be consistent with dietary vitamin K intake (e.g., green leafy vegetables). If changes in drug therapy (including OTC products or herbal remedies) take place, patients should notify their provider. Providers should also be notified if patients become ill or acute changes in present disease states occur.

Remind patients that fluctuations in INR are very common and can be caused by other factors. For example, eating more green leafy vegetables...or by interactions with other drugs or supplements. Keep in mind that patients on any brand of warfarin are hard to dose and monitor. Lots of variables can affect clotting times...diet...other drugs...other diseases, etc. In fact, these variables may create more variation in warfarin needs than small differences in tablet bioavailability.

For more on warfarin food interactions, see "What You Should Know About Your Diet and Warfarin," Detail-Document #210507.

There's some evidence to suggest that augmenting vitamin K intake can help reduce INR variability in patients. For more, see "Use of Low-Dose Vitamin K to Stabilize INR," Detail-Document #220303.

Current Status

Controversy continues to exist regarding the substitution of generic warfarin for the innovator product (or vice versa). Recommendations used to vary from an affirmative "yes" from FDA to "no" from anticoagulation therapy guidelines from such organizations as the Institute for Clinical Systems Improvement (ISCI).^19,22,24,32 Currently, ISCI recommends not switching between brand and generic or between generics, but acknowledges that generic warfarin may show "equivalent anticoagulation response."³³

Based on bioequivalence studies, generic warfarin can be used safely at the initiation of therapy.^20,24 Brand warfarin can also be safely switched to generic warfarin (or vice versa) in most patients.^{22-24,27-29,34} FDA says the AB-rated warfarin is perfectly safe to substitute. But a pharmacist's ability to substitute will depend upon state regulations. Currently, warfarin is available as brand-name Coumadin from Bristol-Myers Squibb, as brand-name Jantoven from USL Pharma, and as generics from Barr, Taro, Genpharm, etc.²⁴

FDA does not recommend any additional monitoring when switching between brand-name and AB-rated generic drugs or among AB-rated generics (including narrow therapeutic index drugs).^19,22,26,35 And now most experts DON'T recommend testing after a switch. However, some experts do recommend more frequent monitoring after substitution.^22,34 Patients in which more monitoring may be especially necessary after switching include those with a history of unstable INRs, patients taking concomitant therapy that may interact with warfarin, and those at high risk for bleeding. Explain to these patients that they might need to get a blood test a week or two after the switch to check their INR.

Question #5
Concerns over generic warfarin arose partly because:
	a. Generic warfarin has many food interactions not seen with Coumadin.
	b. The availability of lower cost generic warfarin might enable too many patients to use a potentially risky medication.
	c. Amorphous warfarin, an alternative to crystalline warfarin, increased patient risk for bleeding.
	d. Brand name warfarin, Coumadin, does not require careful monitoring but generic warfarin does.

Question #6
When treating patients with warfarin, it's good to:
	a. Not switch between brand and generic or between generics with each refill.
	b. Remind patients at each visit that consistency is key with warfarin including consistency with dietary vitamin K, OTCs, or supplements.
	c. Realize that FDA rates several generic warfarins as therapeutically equivalent to Coumadin.
	d. All of the above

Levothyroxine

Levothyroxine has been on the market for 50 years, since the introduction of Synthroid in 1955. Thyroid hormone, prepared from desiccated ground thyroid glands of cows, had been on the market for decades previously. Levothyroxine, classified with thyroid hormone, was not considered to be a new drug by the 1962 amendments to the Food, Drug and Cosmetic Act. So NO efficacy, safety, or bioequivalency studies were required for levothyroxine products.^36,37

For more than 40 years, Synthroid controlled 85% of the levothyroxine market. The manufacturer, Knoll Pharmaceuticals (now Abbott Laboratories), took advantage of the lack of an FDA-approved standard for bioequivalence. Synthroid promotional materials proclaimed, "No proven bioequivalence product" and "There's no substitute for Synthroid."^36,37

In the late 1980s, researchers at the University of California, San Francisco (UCSF) conducted a study comparing the bioequivalence of Synthroid, Levoxyl, and two generic levothyroxine products. Their research showed that all four products were bioequivalent. The industry sponsor, Knoll, refused to allow publication of the study, which had been accepted by JAMA.^36,37

After a huge spate of controversy and lawsuits, the study was eventually published in JAMA in 1997, seven years after the research was completed.^38,39 At the urging of the consumer advocacy group Public Citizen, and citing reports of product inconsistencies, FDA ruled that no levothyroxine products were generally recognized as safe and effective in 1997.^36,40 All levothyroxine products would be required to file a new drug application (NDA) within three years to show safety and efficacy.⁴⁰

Since then, several levothyroxine products have been approved by FDA.^41,42

Unithroid, August 2000
Levoxyl, May 2001
Levo-T, March 2002
Novothyrox, May 2002 (not marketed)
Synthroid, July 2002
levothyroxine sodium, June 2002 (Mylan)
Levolet, June 2003 (not marketed)
levothyroxine sodium, June 2004 (Sandoz)

As described earlier, FDA's Orange Book designates AB ratings for products that are therapeutically equivalent. BX ratings are assigned to drug products for which FDA has insufficient information to determine therapeutic equivalence.

For the purposes of the Orange Book, BX drugs are considered to be therapeutically inequivalent until proven equivalent.⁴³ Clinically, a BX rating doesn't necessarily imply inequivalence. The BX rating simply says studies haven't been done to prove a product is equivalent to another product. For some products, such research is fiscally unwise and unlikely to be done.

Multisource drug products, meaning multiple companies produce a version, with an AB rating may have an additional number added to their rating. FDA usually decides equivalency ratings by comparing a generic drug to one brand name reference drug. In the case of levothyroxine the situation gets complicated...because there are three brand name reference drugs...Synthroid, Levoxyl, and Unithroid. That's why you'll see ratings like AB-1, AB-2, and AB-3. AB1 means that the generic product is equivalent to Unithroid, AB2 means it's equivalent to Synthroid, and AB3 means it's equivalent to Levoxyl. Three-character codes are assigned only in situations when more than one reference-listed drug of the same strength has been designated. If a study is submitted that demonstrates bioequivalence to a specific listed drug product, the generic product will be given the same three-character code as the reference-listed drug it was compared against.⁴³

Current Status

Levothyroxine has a long history of fierce competition for market share. Clinical studies suggest that levothyroxine may be consistent among brands.^39,44

As discussed earlier, FDA compiles the Orange Book, but leaves substitution rules up to state regulation. Most states allow pharmacists to freely substitute generics. Pharmacists practicing in these states can consider levothyroxine product cost as an important factor when recommending or substituting levothyroxine, as inter-and intra-product variability has improved since FDA required new drug testing of levothyroxine products.

For states that rely on the Orange Book for generic substitution decisions, only AB-rated products can be substituted. All other levothyroxine products that are BX rated require the prescriber's permission for substitution.

Package labeling for levothyroxine products recommends obtaining a thyroid-stimulating hormone (TSH) level within eight to 12 weeks of changing a levothyroxine dose or brand, and every six to 12 months thereafter. And many endocrinologists still want a thyroid test after any switch. Tell the prescriber about any switch you make...so he or she can decide whether retesting TSH is warranted. You can also mention to the prescriber that the cost differences of long-term therapy among the various brands of levothyroxine are substantial. Even the added expense of a TSH level to verify the therapeutic equivalence of a less expensive product may be cost-effective.

The following chart covers which levothyroxine products are bioequivalent and therefore can be substituted.

Table 2: Levothyroxine Substitution
Product	Rated by FDA as Bioequivalent to:
*Unithroid** Manufactured by: Jerome Stevens Rated by FDA as: AB1 and AB3	Levothyroxine (Mylan) Levoxyl
*Synthroid** Manufactured by: Abbott Rated by FDA as: AB2	Levothyroxine (Mylan) Levothyroxine (Sandoz)
*Levoxyl** Manufactured by: Jones Pharma Rated by FDA as: AB1 and AB3	Levothyroxine (Mylan) Levothyroxine (Sandoz) Unithroid
Levothyroxine (Mylan) Manufactured by: Mylan Rated by FDA as: AB1, AB2, and AB3	Levothyroxine (Sandoz) Levoxyl Synthroid Unithroid
Levothyroxine (Sandoz) Manufactured by: Sandoz Rated by FDA as: AB2 and AB3	Levothyroxine (Mylan) Levoxyl Synthroid
*Levolet* (not marketed) Manufactured by: Vintage Rated by FDA as: BX	None
*Levothroid* Manufactured by: Lloyd for Forest Rated by FDA as: BX	None
*Novothyrox* (not marketed) Manufactured by: Genpharm Rated by FDA as: BX	None

*Levothyroxine bioequivalence rating has created a unique situation. FDA recognizes THREE reference drugs. For purposes of rating bioequivalence, FDA has compared certain products to certain other products. In the chart above, " * " designates one of the Reference Products to which FDA compared other products. Products rated AB1 are bioequivalent to Unithroid. Products rated AB2 are bioequivalent to Synthroid. Products rated AB3 are bioequivalent to Levoxyl. Products rated BX are not rated bioequivalent to any other product. Some states only allow substitution between products that are rated bioequivalent by FDA. Some states allow substitution between any of the above products as long as state-specific criteria are met, such as having the same dose, form, and strength.

Some patients are trying to improve their weight loss efforts by using "thyroid boosting" products. For more see, "Thyroid Boosters for Weight Loss," Detail-Document #220209.

Question #7
A prescription is written for levothyroxine. Which of these substitutions is NOT appropriate based on FDA ratings? (HINT: see Table 2.)
	a. Levothroid for Synthroid
	b. Generic levothyroxine by Sandoz for Synthroid
	c. Levoxyl for Unithroid
	d. Generic levothyroxine by Mylan for Unithroid

Question #8
Important considerations for thyroid replacement therapy include:
	a. Clinicians have the most experience with Unithroid because it was the first levothyroxine approved by FDA.
	b. There are cost differences between levothyroxine options. It may be cost-effective to switch, even with the expense of additional TSH levels.
	c. Levothyroxine products rated BX are not FDA approved.
	d. Synthroid can not be substituted for because there are no bioequivalent products available.

The Bottom Line

The availability of a generic drug is not always based on the brand-name drug's patent(s) expiration. The generic drug approval process is complicated when litigation is involved. Often, the approval of a generic product is tied up in court for years. These products are tentatively approved by FDA and will not gain final approval until litigation issues are resolved or patents expire. In some cases, even once they are approved, generic medications can take awhile to gain acceptance in the clinical community, especially if they are drugs with an NTI.

References

Simons J. Blockbusters to the Rescue! Can anything go right for Big Pharma? With a crop of mega-selling meds set to roll out, the industry may be on the mend. Fortune 2006;153(1):31.
Agovino T. Generic drug sales boosting retail pharmacies. Inside Bay Area - Business News. Available at: http://www.insidebayarea.com/businessnews/ci_3388004 (Accessed January 11, 2006).
FDA Center for Drug Evaluation and Research. The FDA Process for Approving Generic Drugs. Presentation Transcript. http://www.connectlive.com/events/genericdrugs/pdf-GenericsScriptFINAL.pdf (Accessed December 3, 2005).
Express Scripts. Study reveals $20 billion untapped generic drug savings. http://phx.corporate-ir.net/phoenix.zhtml?c=69641&p=irol-newsArticle_print&ID=772056&highlight= (Accessed December 6, 2005).
Anon. FDA's budget proposal for FY 2004. FDA Talk Papers. February 3, 2003. http://www.fda.gov/bbs/topics/Answers/2003/ANS01195.html (Accessed December 6, 2005).
Improving the approval process for generic drugs. Pharmacist's Letter/Prescriber's Letter 2001;17(7):170715.
Mossinghoff, GJ. Overview of the Hatch-Waxman Act and its impact on the drug development process. Food Drug Law J 1999;54:187-94.
Hathaway CR, Manthei JR. Market exclusivity options under the FFDCA: Strategic opportunities for innovators of pharmaceutical products. Pharmaceutical Law and Industry Report 2004;2(7). http://www.lw.com/resource/Publications/_pdf/pub924_1.pdf (Accessed December 5, 2005).
Dickinson EH. FDA's role in making exclusivity determinations.
Food Drug Law J 1999;54:195-203.
Abood, Richard. Pharmacy Practice and the Law. 4th ed. Sudbury, MA: Jones and Bartlett Publishers, 2005. 40.
Goldenberg M. Medicare and the new generic drug legislation. P&T 2004;29:89-94.
Federal Trade Commission. Generic drug entry prior to patent expiration: An FTC Study. July 2002. http://www.ftc.gov/os/2002/07/genericdrugstudy.pdf (Accessed December 4, 2005).
Buehler G. Statement before the U.S. Senate Committee on the Judiciary. May 24, 2001. http://www.fda.gov/ola/2001/generic0524.html (Accessed December 3, 2005).
Meadows MM. Greater access to generic drugs. New FDA initiative to improve drug reviews and reduce legal loopholes. FDA Consumer Magazine. September-October 2003 Issue. Pub No. FDA04-1328C. http://www.fda.gov/fdac/features/2003/503_drug.html (Accessed December 4, 2005).
Buehler G. Approval Letter for Ramipril ANDA 76-559. October 24, 2005. http://www.fda.gov/cder/foi/appletter/2005/076549ltr.pdf (Accessed October 27, 2005).
Abood, Richard. Pharmacy Practice and the Law. 4th ed. Sudbury, MA: Jones and Bartlett, 2005. 287.
Abood, Richard. Pharmacy Practice and the Law. 4th ed. Sudbury, MA: Jones and Bartlett, 2005. 117-119.
Abood, Richard. Pharmacy Practice and the Law. 4th ed. Sudbury, MA: Jones and Bartlett, 2005. 141.
Henderson JD, Esham RH. Generic substitution: issues for problematic drugs. South Med J 2001;94:16-21.
Banahan BF, Bonnarens JK, Bentley JP. Generic substitution of NTI drugs: issues for formulary committee consideration. Formulary 1998;33:1082-96.
DeCara JM, Croze S, Falk RH. Generic warfarin: A cost-effective alternative to brand-name drug or a clinical wild card? Editorial. Chest
1998;113:261-3.
Witt DM, Tillman DJ, Evans CM, et al. Evaluation of the clinical and economic impact of a brand name-to-generic warfarin sodium conversion program. Pharmacotherapy 2003;23:360-8.
Hirsch J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119:8S-21S.
Food and Drug Administration Center for Drug Evaluation and Research. Approved Drug Products with Therapeutic Equivalence Evaluations. Electronic Orange Book. Current through January 2006. http://www.fda.gov/cder/ob/default.htm (Accessed August 17, 2003).
Williams RL. NTI Letter. Therapeutic equivalence of generic drugs response to National Association of Boards of Pharmacy. Food and Drug Administration Center for Drug Evaluation and Research. April 16, 1997. http://www.fda.gov/cder/news/ntiletter.htm (Accessed August 17, 2003).
Basskin L. A pharmacoeconomic analysis of Coumadin versus generic warfarin. Formulary 1998;33:573-87.
Milligan PE, Banet GA, Waterman AD, et al. Substitution of generic warfarin for Coumadin in an HMO setting. Ann Pharmacother 2002;36:764-8.
Weibert RT, Yeager BF, Wittkowsky AK, et al. A randomized, crossover comparison of warfarin products in the treatment of chronic atrial fibrillation. Ann Pharmacother 2000;34:981-8.
Swenson CN, Fundak G. Observational cohort study of switching warfarin sodium products in a managed care organization. Am J Health Syst Pharm 2000;57:452-5.
Hope KA, Havrda DE. Subtherapeutic INR values associated with a switch to generic warfarin. Ann Pharmacother 2001;35:183-7.
Wagner JL, Dent LA. Epistaxis associated with elevation of INR in a patient switched to generic warfarin. Pharmacotherapy 2000;20:240-3.
Institute for Clinical Systems Improvement. Health Care Guideline Supplement: Anticoagulation Therapy Supplement. September 2001. Available online at: www.icsi.org.
Institute for Clinical Systems Improvement (ICSI). Anticoagulation therapy supplement. 4th ed. Bloomington (MN): Institute for Clinical Systems Improvement (ICSI); 2005 Apr. Available at: http://www.icsi.org/
display_file.asp?FileId=140&title=Anticoagulation%20Therapy%
20Supplement (Accessed March 7, 2006).
Schulman S. Care of patients receiving long-term anticoagulant therapy. N Eng J Med 2003;349:675-83.
Nightingale SL. Therapeutic equivalence of generic drugs letter to health practitioners. FDA Center for Drug Evaluation and Research. January 28, 1998. http://www.fda.gov/cder/news/nightgenlett.htm (Accessed July 21, 2003).
Lurie P, Wolfe SM. Letter to FDA Commissioner David Kessler urging him to begin a safety and efficacy review of all pharmaceuticals marketed in the U.S. prior to 1938 (including Synthroid). May 29, 1996. Public Citizen. Available at: http://www.citizen.org/ publications/release.
cfm?ID=6035 (Accessed July 21, 2003).
King R. Bitter pill: how a drug company paid for university study, then undermined it. Wall Street Journal 1996;April 25:1.
Rennie D. Thyroid storm. JAMA 1997;277:1238-43.
Dong BJ, Hauck WW, Gambertoglio JG, et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA 1997;277:1205-13.
Food and Drug Administration. Prescription drug products; levothyroxine sodium. Fed Regist 1997;62:43535-8.
Food and Drug Administration, Center for Drug Evaluation and Research. "CDER New and Generic Drug Approvals: 1998-2004." http://www.fda.gov/cder/approval/index.htm (Accessed September 17, 2004).
Food and Drug Administration, Center for Drug Evaluation and Research. "Drugs@FDA." http://www.accessdata.fda.gov/scripts/cder/
drugsatfda/index.cfm (Accessed September 17, 2004).
Food and Drug Administration, Center for Drug Evaluation and Research. "Approved drug products with therapeutic equivalence evaluations." http://www.fda.gov/cder/ob/docs/preface/ecpreface.
htm#Therapeutic%20Equivalents (Accessed September 17, 2004).
Escalante DA, Arem N, Arem R. Assessment of interchangeability of two brands of levothyroxine preparations with a third-generation TSH assay. Am J Med 1995;98:374-8.