Generic Anti-epileptic Drugs and Persons with Epilepsy

EPILEPSY is the most common chronic brain disorder. In the Philippines, there are nearly a million individuals with epilepsy. Epilepsy is a chronic condition, whereby control of recurrent unprovoked seizures may require continuous intake of anti-epileptic drug (AED) for two to five years. Control may be achieved with AED medication in 60-80 percent of cases. For some, AED is taken for longer periods due to the refractoriness of their recurrent seizures.

The primary determinant in what AED a person with epilepsy (PWE) takes is the seizure type or types of the patient. There are other factors that influence the medication prescribed and taken and in our country, cost is an important determining factor. AED cost is especially important in societies where patients or their families need to spend for the medication. The Philippines is one such nation and this also happens in countries such as Indonesia, Cameroon, and Ethiopia.

Since cost is a major factor in determining the AED prescribed, the use of generic AEDs have been a major issue in the care of patients. The price of generic AEDs compared to the innovator in general is cheaper by half. Generic drugs imply that such can be produced, manufactured, and distributed due to the loss of any patent protection. Companies that make generic drugs do not incur the high cost of drug discovery, including the cost of clinical trials. Instead, they can reverse-engineer known drug compounds to allow them to manufacture versions that are said to be equivalent. There is, though, the issue whether generic AEDs have the same seizure control compared to the innovator brand.

It is said that generic drugs that are deemed “THERAPEUTICALLY” equivalent to the innovator are expected to have the same clinical effect and are thus approved by the FDA. Thus, it is not surprising to see brand substitution at the pharmacy level. This topic of “therapeutic” equivalence is a thorny issue. Generic drugs that are “therapeutically” equivalent are pharmaceutically equivalent as well as being bioequivalent. Pharmaceutical equivalence means that the generic drug has the same active ingredient in the same amount or dose, that also meets the same standard for quality and purity. It may, however, differ in shape, configuration, scoring, packaging, release formulation, and excipients. It is questioned, however, if drug degradation is also addressed by pharmaceutical equivalence.

For bioequivalence, a test drug is compared to a reference drug. The parameters tested include the extent or degree or percentage of drug absorption, the rapidity of drug absorption, and the maximum drug concentration in relation to the time of drug intake. The acceptability of a test drug’s result compared to the reference drug is arbitrarily set. For a generic product to be approved as bioequivalent to the innovator, the 90 percent confidence interval (CI) for each of the said parameters has to fall between the 0.8 to 1.25 range of log-transformed data. It means that for the test drug to be acceptable as bioequivalent, its maximum drug concentration for instance, as well as the other two parameters, has to fall within the acceptable range of 80-125 percent. If the test drug’s maximum drug concentration is less that 80 percent against the comparator standard, then the drug is not labeled as bioequivalent since it would be less efficacious. If the test drug’s maximum drug concentration is more than 125 percent of the standard drug, it is also not labeled bioequivalent since this increases the chances of a patient receiving the drug to develop adverse effects even at the lowest dosages. This set boundary, however, is based on probability and there are no controlled tests that have tested to support such a range. Currently, it is what is available and is what is being used.

It is due to this wide range of variability of comparing the generic drug to the innovator product that presents with differences in how patients benefit from generic AEDs, as well as how it is perceived by the patient and their physicians. A generic drug that is approved and determined to be bioequivalent may fall within the 80-125 percent acceptable range for the said parameters but it can either fall towards the lower end or the higher end of the spectrum. This leads to some patients who get switched from the innovator product to the generic brand AED with an acceptable bioequivalence but with values at the lower end of the spectrum to have breakthrough seizures. It has to be stated that some AEDs, especially the older generation AEDs whose patent protection expectedly have already expired and are the AEDs with both innovator and generic brands in the market, have narrow therapeutic indices (amount of AED in the blood that has been determined to be effective in exerting it’s therapeutic effect of controlling seizures without too much of the adverse effects) and any small decrease in levels would greatly affect clinical efficacy which in this case would be seizure breakthroughs. At the opposite side of the spectrum, it would not be surprising if adverse effects are easily felt or seen in patients receiving a bioequivalent AED but whose accepted values fall more towards the 125 percent range for bioequivalence testing.

If one looks through the medical journals, one would realize that there are numerous reports of seizure breakthroughs as well as toxic side effects in nations where generic substitution is allowed. What makes things more dangerous is that only generic drugs are compared to the innovator drug and there are no generic-generic comparisons. Generic to generic substitution thus showcases a magnified difference in bioavailability between generic formulations. Imagine if generic A is bioequivalent to the innovator in all three parameters at 90 percent. A patient then gets switched from generic A to generic B because of cost. Generic B, however, has bioequivalence test values within the acceptable 80-125 percent range but is even less than the 90 percent of generic A at say 82 percent. What would one expect in such a scenario? It wouldn’t be surprising if the patient would either have breakthrough seizures or if the patient would actually experience less seizure control. It is the same principle towards the other end of the spectrum but only this time, seizures may be controlled but the adverse effects might be too limiting for it to be used.

This begs the question, are pharmaceutically equivalent and bioequivalent drugs truly “THERAPEUTICALLY” equivalent? Currently, when a drug is labeled to be bioequivalent, such a drug is not tested for their therapeutic effect on patients. It is assumed that since the generic AED has satisfied the standards set for pharmaceutical equivalence and bioequivalence, ergo, then the generic AED has to have the same therapeutic efficacy as the innovator drug. If so, then why are there numerous reports in the journals regarding generic AEDs being less efficacious? Why are some patients themselves deciding to switch back to their original brand of AED?

There is also the issue regarding excipients affecting the AED’s clinical performance. Our own DFA has not addressed this query.

These are the issues that are being raised. Generic drugs are welcomed. However, there is a question as to whether these are actually doing more harm to the patients they are supposed to be helping.

In our country, the position of physicians caring for PWE regarding generic AED mirrors those in the United States, France, and Italy. Possible adverse consequences of switching AED formulations must be drilled into everyone. In the Philippines, the practice of AED substitution at the point of sale is rampant. The autonomy of the prescription is not respected at the pharmacy level and AED switching is done without the prescribing physician’s knowledge. This is not true for all pharmacies and it is quite reassuring that there remains a stalwart of a pharmacy older than myself that does respect this and dutifully informs both the physician and the patient of a potential switch particularly in cases where the prescribed AED is unavailable or if cost suddenly became a bigger limiting factor in the purchase and procurement of their maintenance AED. The prescribing of generic AEDs is rational. It hardly raises eyebrows especially if it is the medication started in virgin untreated cases of epilepsy. Caution is advised, however, when switching AEDs in a PWE with a controlled state who is on an innovator AED but who is switched to a generic AED for reasons already elucidated earlier. When switching from one generic AED to another, the possibility of seizure breakthroughs and drug adverse effects being easily felt have to be understood by the patient or the patient’s family or caretaker. Switching of AEDs with different release mechanisms is also not advised as this may either alter seizure control and may also cause patients to easily experience the AED’s adverse effects easily.

Generic AEDs are a very welcome addition to the armamentarium of PWE treatment and management. However, the stories and issues inherently attached to generic drugs may not be well understood for most resulting in disagreement and wars in the medical, allied medical, and political arena. The perceived resistance to generic drugs in general is, in my opinion, largely due to the still unanswered question as to whether they truly are “THERAPEUTICALLY” equivalent. Perhaps it is time to answer this by requiring generic brands to also be tested in the field.