The dark side of generic medications. My personal experience.
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The plan was to fly to Mexico on Monday, January 15th, 2024, so that Chloe could meet her great grandma (maternal) and so that I could say my goodbyes while she was still with us.
Towards the end of 2023, my grandma was found to have shortness of breath with a hemoglobin of 6 g/dl and an oxygen saturation of 88%. She’s 92 years old and resides in a skilled nursing facility. I let my aunt (who lives in Mexico) know she should have her sent to the hospital. She was sent but, to my surprise, was immediately discharged with oral iron supplementation.
A week later, she suffered an ischemic stroke.
Up until her 80s, my grandma was incredibly healthy. She didn’t have a medical diagnosis and didn’t take any prescription medication. My grandfather passed away at 99 years of age, and the only non-communicable disease we were aware of was dementia. As far back as I can remember, they were always focused on their health. They were intentional with what they put in their body and with what they kept out.
At the time, it all seemed so pointless. It wouldn’t be until the last 12 months that I would realize why they did what they did. Although they may not have known the mechanisms behind nutrition and health, they certainly did everything right.
In any event, my grandma’s health didn’t look too promising. But the problem was I couldn’t fly out due to our issue with Chloe.
Something didn’t make sense.
If you’ve read my previous posts, you’re aware Chloe has been on Sirolimus since May 2023. We have been titrating very slowly and looking at her trough level with every increase. One odd thing to me was how the trough didn’t correlate with her increasing dose adjustments; it acted almost independently. In other words, there were times the trough increased appropriately, but there were equal amounts of times it stayed the same or even decreased. Our hematologist attributed this to her changing metabolism. Something didn’t make sense, but I didn’t know what.
On November 22, 2023, we increased her dose from 2mg to 2.3 mg. During this increase, I realized we had Sirolimus from a new manufacturer. Then, on December 11th, I saw progressive changes in Chloe. She started having loose stools, a maculopapular rash (self-resolved after a few hours), increased appetite, early morning awakenings (3 am and unable to fall back asleep), and a .5 lb weight loss. We also noticed a recurrence of the staring spells (possible absence seizures) she hadn’t had in months.
On December 29, 2023, we did blood work, and labs returned two days later:
Ferritin dropped from 26 → 18 (even though iron supplementation was unchanged).
RDW increased from 23% → 27% (microcytosis and macrocytosis noted).
Triglycerides increased from 129 → 606 (TC, HDL, and non-HDL decreased).
LDL couldn’t be calculated but was previously 150 mg/dl (occurs in mitochondrial patients)
Platelets increased from 8 → 13.
The good news is that her platelets have been consistently increasing since September 28th, 2023. However, I was worried about Chloe’s behavioral changes and shifts in her labs, specifically the increased risk of pancreatitis due to the rapid increase in triglycerides. Unfortunately, fibrates and statins negatively affect mitochondrial function. At the same time, a high dose of fish oil increases Chloe’s risk of bleeding (which we noticed when we tried supplementation early on, albeit her platelets were lower).
The metabolic effects from Sirolimus
From my reading, the metabolic side effects of sirolimus come from daily chronic use, as MTORC2 is eventually affected. It also appears that the hypertriglyceridemia may be secondary (at least in part) to insulin insensitivity (which seems to coincide with her behavior). The metabolic derangement looks to self-resolve reasonably quickly after sirolimus is discontinued. Metformin has been used to mitigate these adverse effects, but metformin negatively affects mitochondrial function.
Because of all this, we opted to stop the sirolimus.
It appears as if her platelets were finally improving, but the primary mitochondrial disease prevents her from using the adjunctive medications typically offered to patients in this situation.
In the longevity space, it’s believed that the metabolic effects can be mitigated by giving a higher-than-usual dose once a week (theoretically, it spares MTORC2). We have a different goal, as we are looking to treat an autoimmune disease, and that dosing regimen hasn’t been studied in this patient population. Instead, we are looking for an immunomodulatory effect without causing frank immunosuppression.
While researching various options, Chris sent me an interesting podcast episode that discussed FDA regulations regarding generic medications. This led me to a surprising discovery.
Brand name vs. generic
I was taught that generic medications are as effective as the brand name. While this may be true, there are some significant caveats we all need to be aware of, especially for those taking a drug with a narrow therapeutic index.
Here is what is required by the FDA for a generic medication to get approved:
Requirement: Generic drugs must have the same active ingredient, strength, dosage form, and route of administration as the brand-name drug.
My thoughts: This doesn’t necessarily mean the formulation needs to be the same; the “inactive” ingredients can differ; although these ingredients might be nonconsequential for most, they can lead to various reactions in others.
Requirement: Generic drugs must be bioequivalent to the brand-name drug.
My thoughts: Bioequivalence is tricky because the entire definition put forth by the FDA is to conclude that two medications are not different. The goal is not to conclude that they are the same—a small but important distinction.
Bioequivalence has traditionally been assessed in healthy adult (18 - 24 years of age) males (it’s only been a few years since trials began to include women) by administering both medications (at different times) to the same adult under the same conditions. The peak plasma concentration (rate of absorption) and area under the curve (extent of absorption) between the generic and brand names are then compared.
Each value for the generic must fall between 80% and 125% of the values put forth by the brand name with a 90% confidence interval (90 out of 100 times the area under the curve, and peak plasma concentration will fall between 80% and 125%).
After the math is said and done, there can be a 10% difference between a generic and a brand name. This also means there can be as much as a 20% difference between a generic on one side of the spectrum and a generic on the opposite end of the spectrum.
For most drugs, this difference is probably insignificant. But it matters a lot more if you use the area under the curve as your north star (which we are) and have a narrow therapeutic index where this unpredictability could lead to toxicity or a lack of efficacy.
Why not just request the same generic?
Alright, so we know there’s a 10% difference from the brand name and a possible 20% difference from one generic to another. Why not just stick to one generic and call it a day?
Unfortunately, many pharmacies don’t dispense the same generic medication each month. The manufacturer they dispense depends on the pharmacy’s distributor and the shipment received; you can’t ask for a specific generic as you can ask for a particular brand name.
In other words, you may get a generic medication from a different manufacturer each month.
Does this matter?
Bioequivalence testing is done with young, healthy male adults; they do not have the same metabolism seen in pediatrics, geriatrics, women, or those with non-communicable diseases (I can’t help but feel this is common sense). Bioequivalence only considers the data points, not outcomes (which is what we ultimately care about).
We now know that those inactive ingredients aren’t so inactive; they influence the physiology and metabolism of patients and can also lead to adverse reactions.
A generic medication is not required to go through clinical trials to demonstrate efficacy or safety. This is because the active ingredient is already deemed safe and effective, and inactive ingredients are believed to have no clinical significance.
Active vs. inactive ingredients
Anything classified by the FDA that carries a medical claim is, by definition, an active ingredient. If it is not classified as a drug and doesn’t make a medical claim, then it is considered inactive. Food, fillers, emulsifiers, binders, dyes, flavors, preservatives, and products that help increase absorption and stability are all considered inactive ingredients.
I find it hard to believe everything on that list isn’t expected to influence a medication. I believe the opposite so much that I’m pursuing another degree in nutrition.
A study from MIT and Brigham and Women’s Hospital found that nearly all medications contain inactive ingredients that can lead to adverse reactions; the ingredients often make up more than half of the medication’s mass but can be up to 99%. The study found that 93 percent of the medicines contained peanut oil, lactose, dyes, gluten, and sugars classified as FODMAP (especially bothersome for patients with IBS).
Giovanni Traverso is an assistant professor in MIT’s Department of Mechanical Engineering, a gastroenterologist at Brigham and Women’s Hospital, and the study's senior author. Here’s a quote from MIT News regarding Dr. Traverso:
“Traverso began looking into this issue about five years ago following an experience involving a patient he was helping to look after. The patient, who had celiac disease, reacted poorly to omeprazole, a common acid suppressant used to treat stomach ulcers.
The specific formulation of omeprazole the patient had obtained contained ingredients derived from wheat products (potentially containing gluten). This information was only available from the manufacturer at the time. A week after obtaining the medication the patient had reported feeling sick from taking the medication.
‘That really brought it home to me as far as how little we know about tablets and the potential adverse effects they might have,” Traverso says. “I think there’s a tremendous underappreciation of the potential impact that inactive ingredients may have.’”
The dark side of generic manufactures
After learning this information, I decided to look up the ingredient list for the generic we last gave Chloe. I was disheartened by what I found when researching the manufacturer.
The FDA has issued warning letters for over ten years regarding their manufacturing process, quality control process, and falsifying data. They deleted the data of failed test results and only reported the batches that passed the required tests. The company was banned from importing medications into the United States for two years. The FDA allowed them back, but they were still hit with warning letters year after year. Then, in 2019, the FDA pulled approval for more than 30 of their medications.
Yet, for reasons unbeknownst to me, they are still allowed to import medications to pharmacies all over the United States. It’s one thing to mess with an adult’s antihistamine. But, it’s something entirely to do this to a medication used by children to prevent organ transplant rejections.
Unfortunately, this isn’t isolated to this manufacturer. With so many medications manufactured overseas, it is hard to enforce quality control measures from a logistical standpoint.
I have personally experienced this with our daughter; with every dose adjustment, a serum drug level was measured, and without fail, there were drastic variations in her trough when switched to a different manufacturer. However, the last manufacturer led to more than just variations in the data, which forced us to stop the medication.
We then spent two weeks fighting with our insurance to approve the brand name Rapamune. We were denied three times before we got the go-ahead. Because of this, I had to cancel our flights to Mexico. The last thing I wanted was for us to be in a different country, with a platelet count of 3,000, without medication, and the possibility of having our flight canceled because of the Boeing 737 fiasco.
I couldn’t imagine the difficulties a parent has to face when put in this situation when they don’t have the medical knowledge or resources to stay persistent.
We’re back on track.
Chloe has now been on Rapamune for three weeks. Her labs have returned to baseline, and all the adverse reactions described above have resolved. It’s interesting; we titrated down her dose, but her trough increased to 12 microg/L (the therapeutic range is 5-12 microg/L).
The bad news is her platelets dropped back down to 3,000. The good news is that despite being at this level, we don’t have any bleeding.
Now that we are back on track, I’ve been searching for a flight to Mexico to say my goodbyes. However, Boeing has made finding a direct flight that works with our schedules incredibly difficult.
Because we canceled our flights, I had some time on January 18th to register for the nutrition classes I expected to start in April. To my surprise, classes began on January 16th, and the last day to register was January 19th. Oops!
Thankfully, the universe had my back. So, I’m officially one month into my master’s program in personalized nutrition.
Cheers to the journey!