Drug Labels Often Neglect to Inform About Obesity Dosing

Obesity can alter the action of many types of medications in ways affecting safety and/or efficacy, but this often isn’t mentioned in the labels.

Experts in obesity and pharmacology are trying to raise awareness about this problem, given the high prevalence of obesity in the population. With some medications, such as the antifungal posaconazole (Noxafil), obesity can increase the half-life such that the drug remains in the body longer in people with obesity than in those with normal weight and presents a drug-drug interaction risk.

With others, such as the generic antibiotic cefazolin, lower concentrations in plasma and/or tissues can result in undertreatment.

Other common medications for which obesity alters drug disposition include the antipsychotic brexpiprazole (Rexulti), the antidepressant vortioxetine (Trintellix), the immunosuppressant tacrolimus (Prograf), the emergency contraceptive levenorgestrel (Plan B), and the over-the-counter nonsteroidal anti-inflammatory ibuprofen (Advil).

In many cases, the issue can be resolved with changes in dosing or longer washout periods, but this information often isn’t included in product labels. “We need to be aware of these differences and handle these drugs differently in people with obesity,” Pharmacologist and Obesity Advocate Theodore K. Kyle, RPh, told Medscape Medical News.

Traditionally, people with obesity have been excluded from clinical trials of many drugs (other than those used to treat obesity or type 2 diabetes), in attempts to avoid heterogeneity in the data. In November 2022, the US Food and Drug Administration (FDA) held a workshop entitled Bridging Drug Efficacy and Safety to the Obese: Considerations and Scientific Approaches and the proceeds were subsequently published.

In October 2023, the American College of Clinical Pharmacology issued a “call to action” for the inclusion of people with obesity in clinical trials and for specific dosing considerations to be included in the labeling.

In November 2023, a joint statement from the American Society for Metabolic and Bariatric Surgery, the Obesity Action Coalition, the Obesity Medicine Association, the STOP Obesity Alliance, and The Obesity Society called on the FDA to “close gaps in the testing and approval process for new drugs intended for use by people with obesity.”

In a statement provided to Medscape Medical News, the FDA said that “the [2022] workshop helped the Agency highlight some of the scientific, regulatory, and practical challenges in evaluating the impact of obesity in adult and pediatric patients on safety, efficacy, drug dosing, and disposition. If a significant safety risk is identified pre-approval or post-approval, FDA can ask sponsors to generate additional data or conduct further analysis.”

Since 2022, specific language about obesity has been included in FDA guidance documents on the development of drugs for pediatric populations, and for the treatment of diabetic foot infections. And some manufacturers have begun including this information in the labeling of new drugs.

But there is no requirement for the companies to go back and gather the information for drugs already on the market, Kyle explained, noting that the available information for older drugs comes from dedicated modeling investigations. “In fact, we don’t have efficacy and safety studies. What we have are pharmacokinetic studies that tell us how these drugs behave…That information should be in the label,” said Kyle, the founder and head of the obesity advocacy and scientific consultancy at ConscienHealth.

The omission is especially striking given the routine inclusion of people with chronic kidney and liver disease as “special populations” in product labels, when they account for just 2.2% and 1.7%, respectively, of US adults compared with 42% who have obesity, Kyle and coauthors noted in a 2023 review article.

“Identifying people with obesity as a special population would speed awareness of the potential for changes in drug pharmacokinetics and pharmacodynamics and may

increase the likelihood that this information is taught and implemented as part of standard medical training,” they wrote.

The Problem With Posaconazole: Oncologists Need to Know

At the Obesity Week meeting in November 2024, Harvard Obesity Expert Caroline M. Apovian, MD, presented results of an online survey of 100 experienced oncologists who prescribe posaconazole to their chemotherapy patients for preventing and treating fungal infections. Because posaconazole is a CYP3A4 inhibitor, oncology drugs that are CYP3A substrates must be paused during posazonazole treatment, with a washout period before restarting.

The half-life of posazonazole is nearly twice as long in people with obesity, so the washout period needs to be doubled before the cancer treatment can be resumed. But this information isn’t on the label.

The research, conducted in collaboration with Emerald Lake Safety, found that less than half of the oncologists surveyed were aware of the increased half-life in people with obesity. Most (87%) said they would have expected to see that information on the label. All 100 said they would use the information going forward.

“When you have cancer and you take posaconazole, you have to wait a certain time period before you can start the chemotherapy again. And if you don’t wait long enough in a patient with obesity, the chemotherapy will be less effective. In the long run, they may end up failing the chemotherapeutic agent,” said Apovian, co-director of the Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston.

She added, “We know that patients with obesity sometimes have worse cancers. We always thought, are we not diagnosing them as early because they have a lot of fat tissue and so we can’t feel it or are patients not coming in for screening? Now we have another [potential] reason: The chemotherapeutic agents aren’t as effective because of the posaconazole.”

The Noxafil (posaconazole) label does say “Pharmacokinetic modeling suggests that patients weighing >120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections.”But it doesn’t give any alternative dosing guidance.

“Critical information needed by physicians for the safe use of posaconazole in people with obesity is not available in posaconazole’s drug label and it needs to be…All Merck has to do is put it on their label,” Apovian said.

A Merck representative told Medscape Medical News, “Merck supports the appropriate and responsible use of posaconazole based on clinically meaningful information. Drug interactions associated with posaconazole are currently well-described in the medicine’s labeling, and new data regarding product safety are reviewed on an ongoing basis by our safety teams. Additionally, the label for posaconazole includes relevant information about drug concentrations in people with obesity. We plan to share relevant data on this topic at an upcoming medical meeting.”

Actionable Changes for Other Drugs in People With Obesity

In their 2023 review article, Apovian, Kyle, and colleagues provided a table with examples of drugs with actions affected by obesity, current dosing recommendations, and suggested changes for people with obesity. Among them are the following:

• Brexpiprazole (Rexulti), an anti-psychotic with an increased half-life in people with obesity, resulting in significantly longer time to attain effective plasma concentrations.
  • Proposed change for those with obesity: For patients with schizophrenia, initiate dosing at 1 mg twice daily (as opposed to once daily in those without obesity) for 3 days, increase to 2 mg twice daily (vs daily) for 4 days, then increase to 4 mg daily thereafter as tolerated (same regardless of weight).
• Cefazolin, a first-generation cephalosporin antibiotic for which tissue concentrations are lower in people with obesity, risking undertreatment of infection.
  • Proposed change: 2 g intravenously prior to incision (vs 1-2 g), with 2 g (vs 500 mg to 1 g) every 4-6 hours (vs 6-8 hours) postoperatively.
• Levenorgestrel (Plan B): Emergency contraception is less effective in people over 70 kg, resulting in an increased risk for pregnancy.
  • Proposed change: Patients over 70 kg should use an alternative form of emergency contraception (because higher dosing doesn’t appear to help).
• Ibuprofen (Advil): A nonsteroidal anti-inflammatory agent with a higher clearance in people with obesity.
  • Proposed change: Increased doses may be necessary in people over 70 kg.

Kyle is currently engaged in a project to assess the extent of the problem in drugs already in the market. “We know this is a problem with many drugs, but because people haven’t been looking for it, we don’t know how large the problem is…When we know better, we should be doing better.”

Apovian has participated on advisory boards for Altimmune, Inc.; Arrowhead Pharmaceuticals, Inc.; BioAge; Biolinq Incorporated; Boehringer Ingelheim International GmbH; Caribou Biosciences, Inc.; Covidien LP; Form Health, Inc.; Cowen and Company, LLC; Currax Pharmaceuticals, LLC; Fractyl Health, Inc.; Lilly USA, LLC; L-Nutra, Inc.; Mediflix, Inc.; Neurocrine Biosciences, Inc.; NodThera Limited; Nutrisystem; OptumRx, Inc.; Pain Script Corporation; Palatin Technologies, Inc.; Redesign Health Inc.; ReShape Lifesciences, Inc.; Scholar Rock, Inc.; Terns, Inc.; Verily Life Sciences LLC; Veru Inc.; Vida Health, Inc.; Wave Life Sciences; Xeno Biosciences; and Zyversa Therapeutics, Inc. Kyle had received consulting fees from Emerald Lake Safety, Novo Nordisk, Roman Health Ventures, Nutrisystem, Boehringer Ingelheim, and Gelesis.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape Medical News, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker and BlueSky @miriametucker.bsky.social.