FDA Issues Guidance for Developers of Chloroquine and Hydroxychloroquine

Pharmacy Times, June 2020, Volume 88, Issue 6

In response to high demand for the unproven COVID-19 treatments, chloroquine and hydroxychloroquine, the FDA has issued 2 product-specific guidance documents for manufacturers.

Editor's Note: The FDA revoked Emergency Use Authorization for chloroquine and hydroxychloroquine on June 15, 2020, and no longer recommends related dosing regimens for treatment of COVID-19. This article was printed in Pharmacy Times prior to the revocation.

In response to high demand for the unproven coronavirus disease 2019 (COVID-19) treatments, chloroquine and hydroxychloroquine, the FDA has issued 2 product-specific guidance documents for manufacturers.1

Both drugs are approved as antimalarial treatments, but there were some hopes that they may be effective in patients with COVID-19, despite the fact that clinical trial data have been scarce and noted significant risks. A study based in Brazil was stopped early, because of safety concerns, when patients receiving high doses of chloroquine developed irregular heart rates.2

Other research has suggested that treatment with either chloroquine or hydroxychloroquine in combination with azithromycin could, in fact, be harmful for patients. Potentially harmful effects could include cardiac arrhythmias, drug-drug interactions, hypoglycemia, metabolic variability, neuropsychiatric effects, and overdose.2

“Despite optimism [in some, even enthusiasm] for the potential of chloroquine or hydroxychloroquine in the treatment of COVID-19, little consideration has been given to the possibility that the drugs might negatively influence the course of the disease,” David Juurlink, MD, PhD, FRCPC, head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto, Ontario, said in a statement. “This is why we need a better evidence base before routinely using these drugs to treat patients with COVID-19.”2

Despite these concerns, demand for these drugs has been high. Multiple manufacturers have reported shortages in recent months, creating concerns for patients with lupus who need the medications.3 In anticipation of continued shortages and increasing demand, the FDA has taken several steps to ensure adequate supply, including publishing guidance to support generic drug development.1

Manufacturers have taken actions to address the shortages, including massive donations. Sandoz has donated 30 million doses of hydroxychloroquine to the federal government, and Bayer Pharmaceuticals has donated 1 million doses of medical-grade chloroquine phosphate. Sanofi has announced donations to more than 50 countries, as have manufacturers Amneal Pharmaceuticals, Sun Pharmaceutical Industries, Ltd, and Teva Pharmaceutical Industries, Ltd.4

The FDA issued an emergency use authorization on March 30, 2020, allowing the US Biomedical Advanced Research and Development Authority to begin distributing the donated doses.4

Manufacturers looking to develop generic hydroxychloroquine tablets have 2 options to complete the required studies. They can complete the Biopharmaceutics Classification System—based biowaiver or perform an in vivo study. A waiver request would be considered, provided that the appropriate documentation regarding high solubility, the test product formulation, and very rapid dis- solution is qualitatively the same as the standards detailed in the Guidance for Industry.5

Manufacturers performing in vivo studies for generic hydroxychloroquine can either use fasting or fed participants, and all studies must have single-dose, 2-treatment, randomized, parallel in vivo designs.5

For manufacturers looking at generic chloroquine, there is a notable difference. The guidance clarifies that the product is AA-rated in the Approved Drug Products With Therapeutic Equivalence Evaluations publication, which means that there are no known or suspected bioequivalence problems, and no in vivo studies are necessary. Based on this, the guidance says that in vitro dissolution profiles of the proposed products are comparable to the reference products.6

In addition to streamlining the manufacturing process for generic drugs, the FDA has also increased opportunities for developers and scientists to send inquiries and requests, provided resources to health care providers to help them submit emergency requests to use investigational products, and redeployed medical and regulatory staff for review teams dedicated to COVID-19 therapies.7

“Accelerating the investigation of products that could potentially benefit people affected by the COVID-19 pandemic is one of the FDA’s highest priorities,” FDA Commissioner Stephen M. Hahn said in a statement. “We want to help patients by expediting promising treatments and are committed to maximizing our regulatory flexibility and proactively bringing the best innovators together to ensure we are getting the right treatments to the right patients at the right time.”7


  • Product-Specific Guidelines for Chloroquine Phosphate and Hydroxychloroquine Sulfate [news release]. FDA; April 13, 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/product-specific-guidances-chloroquine-phosphate-and-hydroxychloroquine-sulfate. Accessed April 21, 2020.
  • Hippensteele, A. COVID-19 Treatment With Chloroquine, Hydroxychloroquine, Azithromycin May Be Harmful. Pharmacy Times; April 14, 2020. https://www.pharmacytimes.com/news/covid-19-treatment-with-chloroquine-hydroxychloroquine-azithromycin-may-be-harmful. Accessed April 21, 2020.
  • Nessel, J. Patients with Lupus Experiencing Difficulties Accessing Hydroxychloroquine, Chloroquine. Pharmacy Times; April 15, 2020. https://www.pharmacytimes.com/news/patients-with-lupus-experiencing-difficulties-accessing-hydroxychloroquine-chloroquine. Accessed April 21, 2020.
  • Brennan Z. FDA offers guidance for generic drug developers of hydroxychloroquine, chloroquine. Regulatory Affairs Professionals Society; April 13, 2020. https://www.raps.org/news-and-articles/news-articles/2020/4/fda-offers-guidance-for-generic-drug-developers-of. Accessed April 21, 2020.
  • FDA Guidance on Hydroxychloroquine Sulfate. FDA website; finalized April 2020. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_009768.pdf. Accessed April 21, 2020.
  • FDA Guidance on Chloroquine Phosphate. FDA website; finalized April 2020. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_006002.pdf. Accessed April 21, 2020.
  • Coronavirus (COVID-19) Update: FDA Continues to Accelerate Development of Novel Therapies for COVID-19 [news release]. FDA website; March 31, 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-continues-accelerate-development-novel-therapies-covid-19. Accessed April 21, 2020.