Experts skeptical of compounding pharmacy practices

Pharmaceutical compounding, defined as the combining or mixing of pharmaceutical ingredients to create a customized medication for a patient, has recently come under fire due to sterility issues. Now, controversial regulatory issues and recent legislative action have caused experts to speak out about the clinical implications of compounded thyroid agents and the controversies surrounding this typically unchartered territory for clinicians.

“The bottom line with compounding pharmacies is that they are state regulated and the regulation is not very rigid. In theory, it’s a custom prescription for each patient,” James V. Hennessey, MD, associate professor of medicine at Harvard Medical School and clinical director of the division of endocrinology, diabetes and metabolism at Beth Israel Deaconess Medical Center, told Endocrine Today. “I’m primarily convinced that levothyroxine is the mainstay of therapy, and I’m underwhelmed with the literature that tells me [triiodothyronine] compounds are of predictable benefit to patients. I’m willing to read about it and I’m willing to look at the evidence; however, at this time, I’m not anticipating that I will be using compounding pharmacies.”

Regulatory issues

In October, the New England Compounding Center (NECC) of Framingham, Mass., shipped more than 17,000 vials of preservative-free methylprednisolone 80 mg/mL, intended for epidural use, to doctors’ offices and clinics in 23 states. Some of the vials were contaminated with fungal species, including Exserohilum rostratum and Aspergillus. The CDC reported that fungal meningitis was the most commonly reported illness to result from the outbreak that killed 53 patients and made 700 sick.

According to a report from the US Senate Committee on Health, Education, Labor and Pensions (HELP), at least 48 compounding pharmacies have been discovered to produce and sell medications that have been contaminated or compounded in unsafe conditions in the 8 months after the NECC-linked meningitis infections.

As of May 17, the CDC reported that E. rostratum was identified in 152 patients and continues to be the predominant fungal infection in this outbreak.

Could such an outbreak occur due to a lack of sterility in thyroid compounds? It is not likely, Jacqueline Jonklaas, MD, MPH, PhD, associate professor of endocrinology and metabolism at Georgetown University, and endocrinologist at the Center for the Study of Sex Differences (CSD) in Health, Aging and Disease and of the research faculty at the Lombardi Cancer Center, told Endocrine Today.

“An infectious agent is less likely, given that these are oral medications, but you have to entertain that it may be a possibility. If a contaminant gets into these drugs it would not be detected by the usual regulatory process,” Jonklaas said. “It’s definitely a concern in the back of any clinician’s mind whose patient tells them they’re getting drugs from a compounding pharmacy. It’s not going to be a zero risk.”

The HELP committee, in acknowledging all of the risks, voted favorably May 22 for the passage of the Pharmaceutical Compounding Quality and Accountability Act, which will distinguish oversight of pharmaceutical compounding. Traditional pharmacies (ie, retail drug stores) will remain under the supervision of state regulatory pharmacy boards. However, compounding manufacturers that make sterile products without or in advance of a prescription and sell the products across state lines will now be required to register with the FDA and be subject to regular inspections.

Additionally, the committee voted favorably for the Drug Supply Chain Security Act, which will essentially create a “track and trace” program, enabling the FDA to track prescription drugs once they leave the manufacturer so that clinicians, patients and regulators can trace the drugs’ safety. According to a press release, the legislation is expected to be brought to the floor of the full US Senate at an unknown date in June or July.

“The basic premise under which compounding proceeds is that specific patients may require medicines in a form otherwise unavailable. This may not be construed as formulating and manufacturing medicines in advance for prospective patients. The latter is a traditional pharmaceutical role for regulation, and supervision already exists. These disparate functions must continue to exist, but under appropriate regulation. This bill attempts to re-establish the needed supervision,” Chief Medical Editor Alan J. Garber, MD, PhD, told Endocrine Today.

Jonklaas said she accepts the idea that some patients may need doses that are otherwise harder to administer; some patients may prefer certain inert ingredients or prefer not to have certain colorations.

“The concept is fine. The problem is the lack of oversight and having no idea what patients are receiving. When patients go to a compounding pharmacy they believe they’re getting a specific amount of T3. But we can’t be sure what they’re truly getting on a day-to-day basis,” Jonklaas said. “Obviously, fluctuations are a concern with any patient, but we worry more about our thyroid cancer patients and elderly patients who we’re trying to titrate to a specific goal in terms of their thyroid function tests.”

Implications of thyroid compounds

Compounding pharmacies have reported that they can currently formulate strengths in T3 and thyroxine combinations that are not commercially available; compound thyroid medications when there is a manufacturer’s back order; compound sustained-release thyroid preparations; and eliminate ingredients that patients may be allergic to (such as color additives).

One clinician who chose not to be mentioned due to patient confidentiality told Endocrine Today that one of his patients who saw both her endocrinologist and another specialist who prescribed a compounded agent developed symptoms of thyrotoxicosis, and, upon exploration, the patient’s T3 and T4 components had been reversed. She was found to have a suppressed thyroid-stimulating hormone of 0.01 mIU/L and free T4 of 0.4 ng/dL with a lower normal of 0.89 ng/dL and a free T3 of 9.2 pg/mL, with an upper normal of 4.2 pg/mL. At that time, she was supposed to be on a slow-release formulation combination of 130 mcg T4 and 1.5 mcg of T3. Ultimately, the patient was switched back to the combination recently titrated to a dose of 140 mcg of T4 and 1.9 mcg of T3. The clinician said the patient continues to use the same compounding pharmacy.

“According to the American Association of Clinical Endocrinologists, American Thyroid Association and Endocrine Society’s perspective, any change in thyroid hormone preparation should be met with caution, and the patient should be reassessed 6 to 8 weeks later with reassessment of outcome measures such as TSH because of the known differences among the various preparations,” Hennessey said.

Anne R. Cappola, MD, ScM, associate professor of medicine at Penn Medicine and physician at Perelman Center for Advanced Medicine in Philadelphia, spoke to Endocrine Today about compounding pharmacies and extracts.

“Before World War II, this was the only way you could get your medication. Your local pharmacy would make it up for you. It was during WWII that they needed to mass produce medication for the troops, and suddenly these companies who would mass produce certain medications came into being and then evolved with the FDA regulation, and these compounding pharmacies tended to dwindle,” Cappola said. “But they’ve had resurgence with an interest in more ‘natural’ or ‘bioidentical’ hormones.”

Cappola told Endocrine Today that the problem with switching formulations is that the bioavailability or stability of the drug is uncertain.

“One study in the literature found that a liquid preparation of levothyroxine at 25 mcg/L had less than 90% of its initial potency after 14 days,” she said.

Benefits include the exclusion of excipients that some patients may be allergic to, Cappola added. However, she said the T3 and T4 ratios of Armour Thyroid (Forest Laboratories) are far different compared with the T3 and T4 ratios produced by a human, and the high concentrations and short half-life of T3 in these desiccated preparations is of concern for clinicians.

Effect of Levoxyl recall

In March, the ATA and Pfizer reported in a letter to health care providers and pharmacists that the manufacturer had halted shipping of all strengths of levothyroxine (Levoxyl) as of Feb. 13, and the back-order situation was currently being discussed with the FDA.

Another letter to health care providers from King Pharmaceuticals, a subsidiary of Pfizer, reported that the recall of levothyroxine sodium had begun at retail pharmacies due to complaints from pharmacists and patients of an “uncharacteristic odor” emanating from some bottles.

“The odor is related to the oxygen-absorbing canister that is packaged in the 100-count and 1,000-count bottles. Pfizer has conducted a careful health assessment and has concluded that the odor is not likely to cause any adverse health consequences. However, the company discussed this situation with the FDA and decided, out of an abundance of caution, to voluntarily recall all strengths of Levoxyl to the retail level. There is no need for patients to return or discard the medication they have, as they may continue to take the medication in accordance with their health care provider’s prescribed directions,” the manufacturer wrote.

The drug may not be available until 2014, according to the FDA.

At the office of Jeffrey R. Garber, MD,Endocrine Today Editorial Board member, chief of endocrinology at Harvard Vanguard Medical Associates, immediate past-president of the American College of Endocrinology and associate professor of medicine at Harvard Medical School, the staff has felt the effect of the recall.

“We have been so inundated with this because so many patients were on Levoxyl that we had to hire an interim part-time person to deal with all of the transitions. The switch involves much more than just writing a prescription. It involves explaining the transition to the patient, followed by them making a choice, issuing a new prescription, collecting blood work and ordering follow-up blood work,” he said. “It’s been an enormous drain.”

Hennessey said he has also experienced an influx of transitions at his practice.

“In the first couple of weeks of the shortage and subsequent recall, I was switching 10 to 15 patients from Levoxyl to other preparations each day,” Hennessey said.

Higher-risk patients, such as those with thyroid cancer, those who are elderly or with underlying cardiac disease, have been switched to another consistently available brand name drug for eventual same source consistency, whereas low-risk patients are allowed to transition to generic equivalents. He said all have been asked to return for follow-up testing on the new preparations. However, a patient’s preference regarding price is frequently the ultimate deciding factor.

Cappola also noted increased calls to her office due to the recall. “We have a choice to make. The data behind sticking with a brand name drug and the decision of whether to retest the TSH 6 weeks after the brand change is due to concerns in differences of absorption based on the brand,” she said.

Moving forward

Despite the burdens of transitioning patients from Levoxyl to other equivalents, the recall has not persuaded endocrinologists to use compounding pharmacies as an alternative at this time.

“Traditional endocrinologists are even less likely to go to compounding pharmacies now, based on the recent negative news,” Cappola said.

David S. Cooper, MD, of the division of endocrinology and metabolism, and professor of medicine at The Johns Hopkins University School of Medicine, said compounding pharmacies are not a consideration for his patients, adding that what matters for patients are consistencies from refill to refill.

“There are legitimate reasons why a patient might think that having a medicine made especially for them by a compounding pharmacy that either tastes better, comes in a different form or doesn’t have excipients in it might be ‘better.’ On the other hand, the problem is when we see patients that come to us with medicine from a compounding pharmacy, we never know whether this medicine has the actual potency and stability and how the manufacturing techniques are conducted,” Cooper said. “We have no idea whether these are medications we can trust or not, and that’s the bottom line.”

At the ATA Spring Symposium and Research Summit in Washington, D.C., Cooper spoke about biochemical and cardiac parameters associated with thyroid hormone. He said thyroid function tests may appear normal in a patient. However, when other measurements are collected from the blood, that patient may still appear to be hypothyroid biochemically or still have hypothyroid symptoms.

Similarly, Jeffrey Garber said more treatment options are needed.

“In theory, if one truly had a slow-release T3 agent that does not have a marked post-absorptive peak, and it was tested for safety and efficacy, there would be a level of enthusiasm about employing that. However, producing such a formulation remains a challenge,” he said. “In theory, an agent that does what it claims to do [slow-release T3] would be a potentially nice addition to our armamentarium, but efficacy cannot be determined without studies and quality control.” – by Samantha Costa

Disclosure: Hennessey reports consultancy for Akrimax Pharmaceuticals and AbbVie Inc. Cooper and Jonklaas report no relevant financial disclosures. Jeffrey Garber reports no relevant financial disclosures.

Could compounded therapies, with proper regulation, have a role in treatment?

Yes

I frequently write prescriptions for compounded time-release T₃ or natural thyroid extract. The only way to ensure the dose of T₃/T₄ is correct is to use compounding.

Negative studies exist within the literature on T₃ due to dosages. Patients were given far too much T₃ (approximately 10 to 20 times the appropriate dose). There is no benefit when a patient is given too much of a physiologic hormone. Thus, the data reported are true, but the studies were done incorrectly.

The controversy about compounding pharmacies relates to the sterility of agents administered by injection, and that is a completely different area than oral thyroid medications.

I’ve written tens of thousands of compounded T₃ or thyroid extract prescriptions since 1996, and I have yet to see a problem.

Kenneth R. Blanchard, PhD, MD, is a private practice endocrinologist specializing in thyroid disease and menopausal hormone replacement therapy in Newton, Mass. Disclosure: He reports being on the speakers’ bureau for Akrimax Pharmaceuticals.

No

Thyroid hormone replacement medications have been available for more than 100 years, initially using desiccated animal thyroid gland, then the introduction in 1958 of synthetic levothyroxine (T₄) therapy. Currently, the primary options for thyroid hormone replacement therapy include levothyroxine, liothyronine or a desiccated porcine thyroid product. The 2012 AACE/ATA guidelines for hypothyroid management emphasize that the standard of care is levothyroxine therapy alone, and there is inadequate evidence for the addition of liothyronine (T₃) for most patients. There are no published data supporting the use of routine T₄-T₃ therapy or the use of desiccated porcine thyroid products. The synthetic levothyroxine is a bioidentical (chemical duplicate) of the T₄ hormone that is produced by the thyroid. While desiccated thyroid hormone may come from a “natural” source, it is not bioidentical to human thyroid hormone content.

Compounded medications are best suited when medications are not readily available to meet the patient’s needs. In the case of thyroid hormone replacement, there are high-quality, synthetic, FDA-approved pharmaceutical-grade products that are available and have safely been used for decades. The most common thyroid compounded product is desiccated porcine thyroid, which comes in a fixed T₄:T₃ ratio of 4.2:1, which is much lower than the natural physiologic human thyroid production of these hormones, meaning that there is a non-physiologic excess of T₃ in porcine thyroid products. There are synthetic T₄ and T₃ ingredients available for compounding that are not desiccated and can be customized, but, again, there has been no randomized controlled clinical trial proving superiority of the combination of T₄ and T₃ therapy for the majority of hypothyroid patients. In cases where T₃ therapy is added to T₄, liothyronine can be readily used and the dose can be titrated as needed without requiring compounding.

Compounded medications typically come in capsules, meaning that the dose cannot be customized by taking one-half of a tablet, more or less, on any given day. With 12 different strengths of levothyroxine available from most manufactures, as well as the ability to cut tablets in half, small changes in dosage can be easily made to optimize a patient’s hypothyroid replacement treatment. Customized dosing is therefore not required.

Sensitivity to fillers and dyes is another reason that patients often turn to compounded products. With the availability of the levothyroxine gel cap — Tirosint (Akrimax Pharmaceuticals) — this is not as much of an issue with the rare exception of gelatin sensitivity.

The cost of compounded medication also tends to be much greater than the pharmaceutical equivalent.

Even with proper regulation of compounded therapy, with the variety of synthetic products currently available, the lack of evidence supporting combination T₄/T₃ therapy and the non-physiologic ratio of T₄:T₃ in desiccated porcine thyroid, there is no compelling reason to include compounded thyroid therapy as a treatment option for the vast majority of patients with hypothyroidism.

Mark Armin Lupo, MD, FACE, ECNU, is the founder and medical director of the Thyroid & Endocrine Center of Florida. He can be reached at 3050 Bee Ridge Road, Sarasota, FL 34239; email: lupomd@hotmail.com. Disclosure: He reports honoraria from AbbVie Inc. and Akrimax Pharmaceuticals.