stated that interchanging products used to treat seizures can lead to toxic adverse events or loss of seizure control. They presented simulation data suggesting that on average, 46% of phenytoin patients switching to a generic would no longer receive enough active drug for effective seizure control. They cited these findings as illustrative of problems with FDA generic drug policies. In this case, they claimed that to ensure proper drug levels, more mon- itoring is required. This additional cost may exceed the savings offered by using the generic drug product (AAN, 2001). A number of similar arguments were made, all suggesting that the use of generic drugs could be inappropriate for patients with epilepsy. Likely based on the totality of these arguments, in 2007, the American Epilepsy Society (AES) adopted an official position opposing the substitution of generic epilepsy medications with- out the consent of both patients and physicians. Despite this, according to the FDA, no scientifically rigorous clinical trials had been conducted to support these anti-generic sentiments. In an effort to control this narrative, since 2010, FDA has taken the lead in a collaborative effort to address these concerns. To this end, at least three pivotal clinical trials have been conducted in patients with epilepsy. These important trials were designed, executed, and analyzed in collaboration with academic medical centers, the National Institute of Neurological Disorders and Stroke (NINDS), and AES to ensure diverse expertise and perspective. Although all these studies had slightly different approaches, a common finding was that in all cases, FDA bioequivalence criteria were achieved and there were no findings of increased seizure activ - ity or incidence of adverse events when generic products were compared to other generics or innovator brand-name products. (FDA, 2019a). In 2016, AES issued a new position paper on the topic of generic substitution of epilepsy medications. They state that the results of recent clinical trials supported the validity of FDA bioequivalence standards. As a result, they concluded that FDA generic standards are appropriate for epilepsy medications. Further, this body of re- search also provided practical recommendations for prescribers and dispensers of generic anti- epileptic medications (Vossler et al., 2016). Another argument against substitution is founded on inferior ge- neric drug quality. FDA has imposed strict regulations designed to ensure that all drug products, branded or generic are of high qual- ity and deliver consistent blood concentrations. These guidelines are designed to ensure that patients can expect consistent results regardless of whether they use a brand-name or generic product. Because of these regulations, manufacturers must exhaustively test their product and destroy any batches that do not adhere to the prescribed standard. A manufacturer’s ability to meet and maintain these standards are a prerequisite to approval. Nonethe- less, according to White, foreign manufacturers have generated a variety of subpar generic products that have been subsequently marketed in the U.S. He posits that if FDA had conducted the robust inspection protocols that domestic manufacturers are sub- jected to, many of these issues would have been discovered ear- Case study: Tina Pharmacist Timothy is the proud third generation owner and op- erator of Thomas’ Uptown Pharmacy. Over the years, Thomas has earned the trust of the community. As a result, many people from the neighborhood come to the pharmacy to get friendly, but sol- id, well-founded advice. One day as Timothy was preparing to close the pharmacy for the evening, a new customer that he was not familiar with entered the store. Timothy greeted her as was his practice. Rather than approach him right away, the lady browsed aimlessly, as if she had no clear objective. Timothy suspected that this was not the case, rather from her behavior, he sensed that she had something on her mind to discuss. He stepped out from behind the counter and approached her slowly, introducing him- self and asking if there was anything that he could do to help. She hesitated a bit, seeming to be gathering her courage. Although Timothy was anxious to close the pharmacy and go home, he re-
lier. Although he stated that FDA is now increasing the rigor of their inspections, room for improvement remains. (White, 2019). Evidence-based practice! In order to try and resolve this con- troversy, the American Epilepsy Society, the Epilepsy Founda- tion, and US Food and Drug Administration funded a critical clin- ical trial: The Equivalence among Generic Antiepileptic Drugs (EQUIGEN) chronic-dose study. This trial was a double-blind crossover study that enrolled 33 adult patients with epilepsy. All patients received 14-day courses of treatment consisting of 100-400 mg immediate release, oral lamotrigine. Two different brands of generic lamotrigine were tested. Administered treat- ments were assessed for bioequivalence. Further to that, the frequency of seizures and adverse events were recorded. Data obtained in this study demonstrated that there was no statis- tical difference between the blood levels of the two different generic drug products. Further to that, there were no significant differences in the frequency of seizures or incidence of adverse events. Investigators concluded that the two different lamotrig- ine products were bioequivalent with no detectable differences in clinical effects. Based on these findings, it was concluded that FDA bioequivalence standards are appropriate to assess lamo- trigine generic drug products (Privitera et al 2016). As an example, in July 2018, FDA announced recalls of sever- al lots of products containing valsartan, losartan and irbesartan manufactured in China. Impacted lots were found to be contami- nated with carcinogenic compounds. Upon further investigation, the number of companies with affected products and subsequent recalls grew to at least 10 (ACC, 2019). Another recent case was illustrated by an FDA inspection of an In- dian pharmaceutical company responsible for the manufacture of biosimilars of important cancer drugs. FDA noted that their review of video showed workers shredding papers that appeared to be manufacturing documents at 1 am four days in advance of an FDA inspection. Although the company did not respond to requests for comment, an FDA spokeswoman stated that such practices raise questions about the accuracy, reliability, and truthfulness of all the data and information collected and reported. Further, she stated that while some Indian companies meet U.S. quality stan- dards, others are challenged by them (Palmer, 2017). Another quality issue regarding active drug ingredient contami- nation may provide some useful perspective. In September 2019 FDA learned that some ranitidine medications contain low levels of a cancer-causing nitrosamine impurity called N-nitrosodime- thylamine (NDMA). FDA did not state if this contamination was limited to generic drug products, or if it impacted both brand and generic formulations. It is critical to note that although NDMA is classified as a probable human carcinogen, it is a known envi - ronmental contaminant sometimes found in water and commonly consumed foods. The amount of NMDA found in ranitidine barely exceeded the amounts found in foods. As such, FDA stated that the benefits of taking these medications currently outweigh the risks of consuming the contaminant (FDA, 2019b). alized that he had a new patient in need. He tried to get her to warm to him by introducing himself using his first name and iden - tifying himself as the pharmacist. This approach seemed to work. The lady became a bit more ani- mated, and told Timothy that her name was Tina, and she had a problem that she needed help with. Timothy invited her to have a seat in the patient counseling area. She sat down and appeared to become more at ease. She stated that she had recently been laid from her job and had to move in with her daughter. Timothy did not interrupt her as she went on explaining the financial hard - ships that she was experiencing. Every now and then, Timothy would nod or verbally validate her problems. This non-threaten- ing and accepting interplay seemed to be working. Tina was now ready to discuss the problem at hand.
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