Microsoft word - 230712-generic sub antiepileptic drugs.doc

Detail-Document #230712
−This Detail-Document accompanies the related article published in− PHARMACIST’S LETTER / PRESCRIBER’S LETTER
Generic Substitution of Antiepileptic Drugs
—For a chart of state substitution laws and a list of which epilepsy drugs
are therapeutically equivalent, please see Detail-Document #220901—
Background
specific criteria are met, such as having the same Most health plans encourage the use of cheaper active ingredient, dosage form, dose, and route of generic medications by either requiring the patients to pay more for the brand-name product The potential savings from the use of generics or requiring the prescriber to seek prior is estimated to be in excess of $20 billion a year.3 authorization approval. Most state Boards of As a result, most health plans mandate the use of Pharmacy allow substitution as long as the generic generics when available and require prior product is considered therapeutically equivalent authorization when the brand-name product is (A- or AB-rated) to its brand counterpart according to the Orange Book, even if it is a mandate of generic antiepileptic drug (AED) use narrow therapeutic index drug. However, the and believes that prescribers should have American Academy of Neurology (AAN) opposes autonomy in prescribing AEDs and patients generic substitution of antiepileptic drugs for the should have access to the full range of AEDs for treatment of epilepsy without prescriber approval and patient consent.1 The AAN cites that even minor differences in the composition of generic AED Substitution Controversy
and brand-name antiepileptic drugs can cause toxic effects and/or seizures when taken by majority of the state generic substitution laws, patients with epilepsy.1 This document reviews opponents of generic substitution for AEDs the controversy over generic substitution of believe substituting generic AEDs can potentially increase healthcare costs and lead to adverse psychosocial consequences in patients with Therapeutic Equivalents
considered pharmaceutical equivalents if they bioavailability between generic and brand contain the same active ingredient(s), are of the products have been raised. According to the same dosage form and route of administration, FDA, drugs are considered bioequivalent if the and are identical in strength or concentration.2 90% confidence interval of the mean area under Bioequivalent products are products with the time absorption curve (AUC) of the test comparable bioavailability (rate and extent of product is within 80% to 125% of the reference absorption) when studied under similar product and the relative mean measure maximum experimental conditions.2 Drug products must concentration (Cmax) of the test to reference demonstrate pharmaceutical equivalence and product is between 80% and 125%.1 Furthermore, bioequivalence to be considered therapeutic bioavailability studies are carried out in healthy Substitution laws are regulated by state Boards medications, using single doses of the drug. This of Pharmacy. In most states, pharmacists cannot is different from the clinical situation where the substitute nontherapeutic equivalent products aim is to achieve steady-state conditions for the without prescriber approval. Some states allow patient.4,6 Some argue that the variability in substitution between products as long as state- bioavailability between generic and brand AEDs, Copyright 2007 by Therapeutic Research Center Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com (Detail-Document #230712: Page 2 of 4)
especially those with narrow therapeutic index Note that the generic phenytoin used in this study (e.g., phenytoin, carbamazepine, and valproate), is was recalled in December 1987 after “some enough to potentially cause toxicity or loss of batches failed dissolution specification.”4 Numerous other studies have shown significant In addition, generic AEDs usually contain differences in serum concentrations of phenytoin different colorants and excipients. The AAN between generic and brand products and among believes that even minor differences in the different generic products.4 Some of these studies composition of generic and brand-name AEDs can In a 1992 (n=12) single-blind crossover study, There is also concern that patients may not get consisting of seven 4-week treatment periods, the same generic product in month-to-month patients were treated with Epanutin capsules, refills, which can potentially increase the risk of Epanutin Infatabs, and three other generic phenytoin tablets. Serial blood samples were Bioavailability is particularly an issue if a drug taken over a 12-hour period. The difference in has low water solubility (phenytoin, bioavailabiliy compared to Epanutin capsules carbamazepine), a narrow therapeutic range ranged from 76% to 121%. Less bioavailable (phenytoin, carbamazepine, and valproate), and/or generic phenytoin preparations were subsequently nonlinear pharmacokinetics (phenytoin and withdrawn from the market. There was no valproate).4-7 Some experts suggest that generic difference in seizure control or adverse events substitutions of newer AEDs such as topiramate, among the different phenytoin formulations. lamotrigine, etc. are less likely to pose problems. However, the authors concluded that substitution There are case reports of loss of seizure control of one generic phenytoin formulation for another or toxicity resulting from changing between brand could potentially cause problems with seizure and generic products or between one generic product and another.4-9 Several reports of breakthrough seizures or increased seizure phenytoin extended-release capsules by Mylan as frequency following generic substitution with an equivalent to Dilantin Kapseals. Patients on phenytoin, carbamazepine, valproic acid, and Minnesota health plans were switched to generics primidone have been published, but it is unclear without physician notification. Shortly after, whether the increased incidence of seizure is due some of these patients began to have increased to generic substitution of AEDs or other factors.5 seizures. Over a five month period, eleven Opponents argue that although generic AEDs patients were identified as having increased are lower in price, the potential for increased side seizures requiring hospitalization, emergency effects and morbidity and the need for closer room visits, or urgent care clinic visits. Chart monitoring could offset the cost savings.4-7 reviews showed that ten of these patients were switched to the generic phenytoin formulation. Case Reports and Studies
One patient had been on the generic formulation Case reports of phenytoin toxicity or for three weeks, which was enough to reach breakthrough seizures with generic substitution of steady-state and another patient had other phenytoin were first noted in the 1960s. Most of antiepileptic drug dosage changes. Eight patients these case reports were from Australia and were had one or more phenytoin concentrations caused by a change in excipient.6,7 Since then, measured at steady-state prior to the switch to the there has been ongoing discussion about generic phenytoin, while being treated with the differences in bioavailability of generic generic, and after the switch back to brand formulations compared to brand formulations. A Dilantin. The substitution of brand for generic or retrospective chart review study conducted by the vice versa was associated with about 30% VA (n=10) showed that patients who received decrease in both total and free phenytoin generic phenytoin had a 22% to 31% lower serum concentrations. All eight patients had decreased concentration than when the patients were unbound phenytoin serum concentrations with the receiving brand name Dilantin. These patients generic and returned to similar levels when were switched to generic phenytoin in August switched back to Dilantin. Seven patients had 1987 as mandated by the VA drug formulary. decreased total phenytoin serum concentrations Copyright 2007 by Therapeutic Research Center Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com (Detail-Document #230712: Page 3 of 4)
with the generic and returned to similar levels concentration fell by around 10 mmol/L when the patient was switched to a generic formulation There are reports of recurring seizures after (Karbamazepin-DAK). The patient experienced switching from brand to generic loss of seizure control. The patient developed carbamazepine.4,7,8,10 However the differences diplopia initially after he was switched back to between generic and brand carbamazepine are less Tegretol. The author pointed out that the particle extensively studied. In a crossover study of ten size in the Karbamazepin-DAK was smaller than patients with epilepsy, the mean steady-state Tegretol and suggested that this resulted in both serum concentrations of Tegretol and generic an earlier peak concentration and greater carbamazepine were found to have no fluctuations in carbamazepine concentrations.4 differences.4 There is an anecdotal report of breakthrough seizures after switching from Depakene to generic experienced loss of seizure control three days valproic acid.7 However, in an open, randomized after he was switched to generic carbamazepine 8-week substitution study (n=64), there was no from Tegretol. For five months, beginning in statistically significant differences between May 1988, the boy was treated with Tegretol seizure occurrences or serum concentrations 600 mg twice daily and divalproex sodium 250 mg two tablets three times daily. During this It is important to note that none of these case period, he experienced two seizures and showed no signs of any adverse drug reactions. On June suggesting that switching from brand Lamictal to 12.4 mcg/mL and his valproic acid concentration generic lamotrigine could result in loss of seizure was 56.2 mcg/mL, drawn about two hours after dose administration. All AED doses remained stable and serum concentrations of both drugs had Conclusion
been within a 20% range, consistent with good AEDs are generally used to treat a potentially compliance. On November 16, three days after he serious condition. Unexpected breakthrough was switched to generic carbamazepine, the seizure in a controlled patient could lead to patient experienced nine seizures within a 30- adverse psychosocial consequence such as loss of minute period. A subsequent carbamazepine job or driver’s license, physical injury, or rarely, concentration was 6.7 mcg/mL and his valproic acid concentration was 56.5 mcg/mL. The time potentially be held legally liable for serious the blood sample was drawn relative to his last consequences arising from either a loss of seizure control or increased side effects attributable to switched back to brand Tegretol. On December 2, generic substitution in which the patient was not his carbamazepine concentration was 9.7 mcg/mL Because the consistency of antiepileptic 46.1 mcg/mL. Seizure control was improved. treatment is so important, it seems reasonable to Two months later, the frequency of the patient’s seizures increased despite stable carbamazaepine [Evidence level C; consensus].1 Decisions about switching AEDs depend on multiple clinical In another 1990 case report, a 21-year-old factors including cost. Prescribers should be pregnant woman lost seizure control when she aware of the associated costs and take that into was switched from Tegretol to generic consideration when prescribing AEDs. Consider carbamazepine. The loss of seizure control was starting a patient on a generic AED initially and associated with decreased carbamazepine avoid frequent changes between generic products concentration, though the case was complicated by other drug changes (e.g., phenobarbital Some states prohibit substitution of AEDs and/or narrow therapeutic index drugs. Others In another case, a 16-year-old Danish boy was require pharmacists to get consent from both the treated with Tegretol and reached stable prescriber and the patient or patient guardian concentrations of 34 to 42 mmol/L. The before making the switch. Pharmacists are Copyright 2007 by Therapeutic Research Center Pharmacist’s Letter / Prescriber’s Letter ~ P.O. Box 8190, Stockton, CA 95208 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 www.pharmacistsletter.com ~ www.prescribersletter.com (Detail-Document #230712: Page 4 of 4)
advised to check their state generic substitution References
laws before making a substitution and avoid 1. American Academy of Neurology. Position substituting products that are not therapeutic statement on the coverage of anticonvulsant drugs equivalents. Unless already required to do so, for the treatment of epilepsy. November 2006. http://www.epilepsyfoundation.org/generics/pdfs/A consider informing the patient and prescriber ANPositionStatement.pdf. (Accessed June 9, when switching to a different product, especially when substituting narrow therapeutic index AEDs 2. Electronic Orange Book. Approved products with (e.g., phenytoin, carbamazepine, valproic acid). therapeutic equivalence evaluation. current through May 2007. http://www.fda.gov/cder/ob/. Users of this document are cautioned to use their own 3. Anticipated availability of first-time generics. Pharmacist’s Letter/Prescriber’s Letter professional judgment and consult any other necessary or appropriate sources prior to making clinical 4. Besag, FMC. Is generic prescribing acceptable in judgments based on the content of this document. Our epilepsy? Drug Saf 2000;23:173-82. editors have researched the information with input 5. Guberman A, Corman C. Generic substitution for from experts, government agencies, and national brand name antiepileptic drugs: a survey. Can J organizations. Information and Internet links in this article were current as of the date of publication. 6. Crawford P, Feely M, Guberman A, Kramer G. Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure Levels of Evidence
In accordance with the trend towards Evidence-Based 7. Jobst BC, Holmes GL. Prescribing antiepileptic Medicine, we are citing the LEVEL OF EVIDENCE
drugs. Should patients be switched on the basis of Level Definition
Carbamazepine toxicity resulting from generic High-quality randomized controlled trial (RCT) substitution. Neurology 1993;43:2696-97. High-quality meta-analysis (quantitative 9. Burkhardt RT, Leppik IE, Blesi K, et al. Lower phenytoin serum levels in persons switched from brand to generic phenytoin. Neurology 10. Welty, TE, Pickering PR, Hale BC, Arazi R. Loss of seizure control associated with generic substitution of carbamazepine. Ann Pharmacother 11. Makus KG, McCormick J. Identification of adverse reactions that can occur on substitution of generic or branded lamotrigine in patients with epilepsy. Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8. Project Leader in preparation of this Detail-
Document: Wan-Chih Tom, Pharm.D.


Cite this Detail-Document as follows: Generic substitution of antiepileptic drugs. Pharmacist’s
Letter/Prescriber’s Letter 2007;23(7):230712.

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