Generic antidepressants; why 'same but not the same' might not be good enough.
Are ‘same but not the same’ generic antidepressants adding to the complex issues of antidepressant harm and dependence? An emerging danger to the health of patients, why might those taking generic antidepressants be particularly at risk?
Lack of innovation meaning fewer new drugs and patents expiring on blockbuster drugs means the generic drug market is growing rapidly. Generic drugs must demonstrate bioequivalence to the brand-name original, however, two pills with the same amount of the same active therapeutic ingredient can cause different effects on the human body if they dissolve at different times in the stomach, if their active principles appear at different rates in the bloodstream, or if their excipients (binders, fillers, dyes and shellac coatings which are often of lower quality) influence the human body in different ways.
Generic medicines applications do not make use of any data from the originator registration file. The data of originator products are never revealed to third parties so cannot be used by generic medicines researchers. Instead, generic medicines producers research and develop their own formulation of the product. In fact, a generic requires reverse engineering and the result is an approximation rather than a duplicate of the original. Regulators do not specifically regulate how quickly the medicine must reach maximum concentration in the blood which is an important aspect of time-released medication that can impact its effectiveness.
Unlike most of the rest of Europe, the majority of generic medicines in the UK are marketed by the generic name or International Non-proprietary Name (INN). GPs are trained at medical school to write prescriptions by INN except where there is a clinical reason for doing otherwise. GPs have incentives to prescribe generics and pharmacists have incentives to dispense them. Generics can cost 20% to 90% less than the original price of their brand-name equivalents and now account for more than 40 per cent of the money spent on drugs in primary care in the UK,
The British Generic Manufacturers Association (BGMA) stress generic medicines meet the same standards of quality, safety and efficacy as originator brands. They add that the significant use of generics within the NHS delivers a range of benefits including: cost containment, enhanced patient access to treatment, promotion of innovation, enhanced security of supply and increased efficiency in Pharmaceutical spending.
The interchangeability of some types of medication has been straight-forward but for some it has been complicated and contested. Why do the BGM say ‘proceed with caution’ with certain classes of drugs? Why do they state making the switch with certain classes of drugs, and with drugs that have a narrow therapeutic range can pose potential problems and must be done with caution—if at all? Why are patients not informed one of the drug classes is psychotropic agents which includes antidepressants?
A generic drug company’s scientists have to figure out how a molecule operates in the body but antidepressants’ mechanisms of action are not well understood and scientists still do not fully understand how these drugs work on a molecular level. The generic drug company only needs to test to prove it performs ‘similarly’ to the brand drug. This needs to be done on only a few dozen healthy volunteers. The concentration of the drug in their blood is mapped to prove bio-equivalence.
The inert ingredients in the generic version do not have to be the same as those in the brand name drug (although the ratio of inert to active compound must be similar) Because drugs tested in bioequivalence studies are administered in single doses, many experts wonder whether the inert compounds used in the generics may affect the distribution, metabolism, or absorption of a drug when it is administered in multiple doses, or whether the serum concentration of the generic drug may be elevated when it is taken for long periods.
We are told Eli Lilly’s Prozac, as an example, is interchangeable with generic fluoxetine which costs a fraction of the price. The generic capsules may contain 20mg of fluoxetine but it is different in name, where it was made, size, shape, colour and most importantly price. Unlike the brand-name drug, generic fluoxetine is approved only on the basis of similarity, no clinical trials necessary; generic drugs are not ‘identical’ but sufficiently ‘similar’. The similarities and differences of the drugs has long been a contentious issue.
In October 2009, the FDA declared that a generic drug it had previously approved, a generic version of the popular antidepressant Wellbutrin was not in fact “bioequivalent” to the name-brand version. Complaints by patients the drug budeprion XL 300 mg. didn’t work as effectively and made them feel sick had been dismissed for years by The FDA. However, an independent consumer laboratory tested the generic and found that it dumped the active ingredient into the bloodstream at four times the rate of the branded drug. The FDA took a highly unusual step and it withdrew approval for the generic. It required other generic companies to retest their versions.
In 2008, a study ‘Did a switch to a generic antidepressant cause relapse?’ was undertaken. (Rosenthal, Jessica & Kong, Brian & Jacobs, Leslie & Katzman, Martin. (2008). The Journal of family practice. 57. 109-14.) They concluded,‘a switch to a generic form of an antidepressant, antipsychotic, mood stabilizer, or benzodiazepine, maintaining a concentration of only 80% of the original brand, might result in a sudden change in efficacy yielding an increased risk of withdrawal symptoms or even a relapse of a previously well-treated illness. Alternatively, if a patient is switched to a generic drug that maintains a 120% bioequivalence, there could be a sudden increase in adverse events. This could lead to a decrease in compliance and potentially prompt a clinician to misread the specific symptomatic presentation as a worsening of the symptoms. Considering such risks, it is disconcerting to note that patients and their physicians may not always realize that a switch has been made from a brand-name drug to a generic.’
In fact, the FDA cites some psychotropic drugs for which generic formulations may not be interchangeable—including amitriptyline/ perphenazine and venlafaxine—and others for which generic formulations may not be bioequivalent at all doses. It says the type of salt used to form a compound is also important and to avoid problems, physicians should prescribe generics containing the same salt as their brand-name counterpart!
The BGM are already quietly warning about Psychotropic generics. I increasingly hear complaints ’they do not work as well’ when patients are switched from their usual brand to endless boxes of unfamiliar cheaper generic drugs but I suggest the issue is one more complex and more dangerous than ‘they do not work as well’. Could the problem with generic antidepressants be an under-recognised ticking time bomb confounding the growing antidepressant crisis?
Anecdotal evidence tells us from switch to switch of generic drug, adverse effects can appear and disappear. We know antidepressants ‘create’ a chemical imbalance rather than ‘cure’ one and It is at times of starting medication or increasing or decreasing doses the imbalance most often occurs. The question is, could the changes of generic drugs also be causing an imbalance? What role could generic drugs be playing in causing adverse effects? Could some reports of nightmares, vomiting, anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, and mania in any way be linked to the quality, safety or ability of generic to create chemical imbalances?
For some it seems certain generics make them feel as if they have suddenly commenced an involuntary tapering of their medication. This is dangerous, as we know these drugs should not be stopped or reduced without supervision of a medical professional. Failure to recognise switching between generics might cause symptoms similar to withdrawal is alarming. Are generic antidepressants putting those dependent on medication at more risk of adverse effects and might those attempting to withdraw from antidepressants be particularly at risk? As an Antidepressants half-life is a crucial factor in managing withdrawal, do we need to be vigilant about prescribing different generics during tapering?
If generic antidepressants are ‘the same but not the same’ as brand name antidepressants it is time we understood the consequences of the strengths and limitations of the generic concept. We might choose a breakfast cereal with less fruit and plain packaging to save money, but it’s not the same as having generic drugs chosen for us which causes intolerance, psychological and physical adverse effects. In an age of consumer choice is it acceptable to live in a ‘you get what you are given’ world when it comes to pharmaceuticals?
More research and patient and prescriber awareness will enable us to determine under what circumstances is it safe to prescribe generics or to substitute a generic for a brand-name drug. Is this just one more issue to be added to the growing list of complexities associated with antidepressants?
Note: GPs will write generic prescriptions (INN) except where there is a ‘clinical reason’ for doing otherwise. Patients must be aware of any changes when they take a newly prescribed generic and report their ‘clinical reason’ for not being prescribed a specific generic drug.
Take a note of generic drugs you are intolerant to and those your body tolerates
Notify your GP or Prescriber and ask them to note this on their system
Ask the pharmacies you use to note the generic drugs you are intolerant to on their system
If you receive a generic you are intolerant to call you pharmacist and request a replacement immediately
Do not switch brand / generic during a taper. Wherever possible take the same medication as prior to commencing.