US Pharm. 2014;39(6)(Generic suppl):8-12.  

Generic interchange has become routine in pharmacy practice. Over 75% of filled prescriptions are done so with a generic formulation, which has resulted in significant savings in healthcare costs.1 The FDA regulates the approval of generic drugs and ensures that generic formulations are equivalent to their brand-name counterparts. While the current regulations may be sufficient for the majority of medications, many believe that the FDA guidelines for proving bioequivalence are inadequate when it comes to narrow therapeutic index (NTI) drugs.  

According to the FDA, NTI drugs are defined as “those drugs where small differences in dose or blood concentration may lead to dose and blood concentration dependent, serious therapeutic failures, or adverse drug reactions.”2 Since there is a short interval between the dose resulting in therapeutic and unwanted toxic effects, seemingly insignificant alterations in therapy with such a drug could lead to significant consequences. Variations in therapy such as receiving different lots of a brand product, replacing a brand with a generic, or switching from one generic manufacturer to another could potentially lead to fluctuations outside the therapeutic window.3

The FDA has provided examples of NTI drugs, including warfarin, levothyroxine, carbamazepine, digoxin, lithium carbonate, phenytoin, and theophylline (TABLE 1) .2 In addition, the immunosuppressive agents cyclosporine and tacrolimus are considered to be NTI drugs. After initial approval of these drugs, several generic manufacturers entered the market, offering competitive pricing. With rising healthcare costs, it may seem economically wise for pharmacies to switch from one generic formulation to another in an effort to obtain the largest discount possible. In addition, current drug shortages may necessitate changing to a different manufacturer. However, with NTI drugs, generic interchange further adds to variability among patients in blood concentrations and requires special consideration.




The FDA publishes therapeutic equivalence evaluations for approved prescription drug products in Approved Drug Products With Therapeutic Equivalence Evaluations, commonly known as the Orange Book. According to the Orange Book, products listed with “A” codes are therapeutically equivalent to other pharmaceutically equivalent products, whereas products listed with “B” codes are not therapeutically equivalent. Drugs are designated as therapeutic equivalents after meeting specific criteria that include the requirement for bioequivalence.4 FDA regulators set a difference of 20% in the area under the curve (AUC) and peak concentration ( Cmax) between the reference and test drugs to indicate bioequivalence. Bioequivalence is thereby achieved when the mean reference to test ratio and its 90% confidence interval (CI) fall between 80% and 125%.

One limitation of this definition is that it relies on mean values. Data collected from individual subjects could fall outside this range while the mean ratio and its CI calculated from the same data could lie within the required 80% to 125% range.5 For example, if one patient had a bioavailability of 45%, although this individual concentration is below the acceptable range, the mean ratio that factors in the bioavailability of all the patients included in the study could reach at least 80% and permit the designation of bioequivalence. This variation in bioavailability becomes a greater issue when a switch from one generic manufacturer to another is attempted because of the lack of bioequivalence studies between different generic formulations. Patients switching from a generic formulation with an AUC of 80% to a different generic formulation that has an AUC of 125% may experience significantly increased drug exposure of more than 50% .6 Due to these insufficiencies as well as others in regard to establishing bioequivalence of generic drugs, Canada and the European Medicines Agency instituted stricter parameters for bioequivalence in NTI drugs, requiring no more than a 10% difference. This shrinks the acceptable CI range to 90% to 111% .7  

At the 2011 FDA Advisory Committee for Pharmaceutical Science and Clinical Pharmacology meeting, it was decided that the current regulations establishing bioequivalence were inadequate when it came to critical dose of NTI drugs and recommended a switch to stricter guidelines.2 During the 2011 committee meeting, a requirement of two-treatment, four-period crossover design for bioequivalence studies instead of the conventional two-treatment, two-period design was proposed to enhance assessment of individual subject variability in bioavailability between the brand and the generic product. In addition, narrowing of the acceptable bioequivalence range to 90% to 111% for NTI drugs was advised. Limits for acceptable potency of active ingredient determined by assay studies was also recommended to be set at 95% to 105%. 8  

NTI Drugs

The following contains a discussion of common NTI drugs and their various generic interchange and bioequivalence issues.2  

Warfarin: The first generic formulation of warfarin was approved in the late 1990s. Following its approval, case reports expressing concern about bioequivalence and international normalized ratio (INR) control after generic interchange quickly appeared.9 Observational studies have shown an increase in clinical events, INR variations, and the need for INR monitoring after generic substitution. However, results from randomized controlled trials indicate no significant differences in INR, need for dosage adjustment, or thrombotic and bleeding event rates between generic and brand warfarin. Following a change from brand to generic, it is preferred to keep patients on the same formulation to maintain a stable INR and dose. When changing manufacturers, monitoring of the INR may be needed due to individual patient variability.10  

Digoxin: Digoxin tablets were available on the market prior to the Federal Food, Drug, and Cosmetic (FD&C) Act of 1938 and therefore was a “grandfathered” drug that originally did not require bioequivalence studies or an approved Abbreviated New Drug Application (ANDA) for marketing of its generic counterparts.11 As bioavailability issues and doubt in regards to the purity and potency of generic formulations of digoxin began to arise, the FDA announced that all oral digoxin products were to be treated as new drugs, which required an ANDA for generic approval.12 The Orange Book currently lists three generic manufactured digoxin tablets with an “AB” code, meaning they have demonstrated bioequivalence under current FDA regulations. As an NTI drug, however, current regulations may not be sufficient and generic switches may potentially lead to digoxin concentrations outside the therapeutic range, which could necessitate further monitoring and alterations in the dose.11

Levothyroxine: Levothyroxine is another medication in which generic substitution is controversial. The FDA has approved several brand names for levothyroxine which include Tirosint, Levo-T, Levothroid, Levoxyl, Synthroid, and Unithroid.4 During bioequivalence studies for generic approval, levothyroxine was compared to one of these many brands and is therefore equivalent to the referenced brand, not necessarily to others.13 Following the approval of its first generic form, the American Thyroid Association, the Endocrine Society, and the American Association of Clinical Endocrinologists issued a joint statement expressing concern that differences in bioavailability of this critical dose drug may be enough to cause significant adverse events. They recommended that patients remain on the same formulation to avoid the possibility of being switched from one generic manufacturer to another upon each refill, and if a switch in therapy is made, additional thyroid function tests should be performed.14

Carbamazepine: Several case reports and studies have shown variations between generic formulations of carbamazepine to the brand Tegretol. In a study performed by the FDA, it was established that three of the tested generics exhibited significantly different absorption rates when compared with the brand; however, it was concluded that this did not translate into significant clinical differences.15 After generic interchange, increases in seizure rates and adverse events, including adrenal decompensation due to alterations in concentrations, have been reported.16

Phenytoin: Generic interchange of phenytoin is complicated not only by its NTI but also by its nonlinear kinetics. Reports of adverse events such as seizures and toxicity following generic substitution were primarily attributed to differences in excipients present in the generic product.15 In a retrospective study of clinical events following a switch from brand phenytoin to an AB-rated generic equivalent, increased rates of low phenytoin concentration were detected; however, an association between seizure rates and generic interchange was not observed. Pharmacokinetic differences between generic and brand phenytoin were reported, but the differences were insignificant and did not substantially affect clinical outcomes.17

Cyclosporine: Alterations in cyclosporine therapy could potentially result in transplant rejection when concentrations fall below the lower limit for sufficient immunosuppression, or in nephrotoxicity and neurotoxicity when concentrations are above the upper limit. It is known that transplant patients exhibit greater pharmacokinetic variability than healthy subjects in which bioequivalence studies are performed, and this variability affects their cyclosporine plasma concentrations and consequently their rejection rates.5 Individual patient age, ethnic background, and disease states as well as drug interactions usually due to multiple immunosuppressants and antibiotics further add to variations in plasma levels when a generic switch is instituted.18 Results from a retrospective study of kidney transplant patients showed higher rates of acute rejection and individual patient variability in trough level when Gengraf was compared with Neoral.5

Tacrolimus : When the first generic formulation of tacrolimus was approved by the FDA , many in the transplant community were hesitant to prescribe it due to concerns about the adequacy of FDA regulations for establishing bioequivalence. In response to these concerns and clinical reports indicating significant deficits in tacrolimus concentration when the reference listed drug was interchanged with a generic formulation, the FDA conducted in vitro studies and analytic tests comparing brand-name tacrolimus to available generic formulations.19 Results from this study showed that the mean percentage (range) of active ingredient in formulated capsules was 93% (86%-99%) for Accord, 110% (100%-120%) for Mylan, 97% (96%-99%) for Dr. Reddy, and 104% (101%-108%) for Sandoz when compared to the Astellas brand at 100% (93%-107%). Taking into account the standard deviation of these results, the investigators concluded that the differences were not statistically significant. However, to rule out potential clinical differences, in vivo studies comparing the multiple generic formulations are necessary.19

With the lack of sufficient data to support bioequivalence between generic formulations of tacrolimus, changes between generic products require close therapeutic drug monitoring. Following a change in the generic manufacturer, the transplant physician must monitor tacrolimus concentrations and, if necessary, adjust the dose to reach therapeutic goals.20


Until the FDA institutes updated regulations for determining bioequivalence in NTI drugs, special consideration may be warranted when the patient’s health insurance company or pharmacy initiates a switch in generic formulation. Pharmacists play a key role in ensuring that their patients are aware of the generic switch and are appropriately counseled on differences in appearance of the new formulation to avoid any confusion. In addition, if a conversion from one generic formulation to another is necessary, the physician may need to ensure that therapeutic drug monitoring is performed. When it comes to changes in therapy with NTI drugs, even seemingly minor generic substitutions could mean the difference between successful treatment or intolerable side effects.


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