Nitazoxanide

Nitazoxanide is a broad-spectrum thiazolide antiparasitic agent that is approved by the Food and Drug Administration (FDA) for the treatment of Cryptosporidium parvum and Giardia duodenalis infections in children aged ≥1 year and adults. Nitazoxanide is rapidly metabolized to its active metabolite, tizoxanide, and has in vitro antiviral activity against a range of viruses, including influenza viruses, hepatitis B and C viruses, norovirus, rotavirus, Ebola virus, Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2.^1-3 The mechanism of antiviral activity is not fully characterized. Nitazoxanide inhibits host enzymes, which impairs the posttranslational processing of viral proteins. It also has inhibitory effects on proinflammatory cytokines. With the exception of a Phase 2b/3 trial for uncomplicated influenza, the evidence for clinical activity of nitazoxanide against other viruses is limited or of low quality.⁴

Recommendation

• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of nitazoxanide for the treatment of COVID-19, except in a clinical trial (BIIa).

Rationale

Two randomized controlled trials that were conducted in Brazil and the United States did not find a significant clinical benefit for nitazoxanide treatment in nonhospitalized adults with COVID-19 when treatment was initiated within 2 to 5 days after illness onset.^5,6 One of these trials, which has not yet been published, reported that fewer patients in the nitazoxanide arm progressed to severe COVID-19 than in the placebo arm. However, the study was underpowered to detect a difference, and this finding was not statistically significant.⁶ Additional small, unpublished studies were reviewed; however, due to their limitations, they did not provide support for the use of nitazoxanide.^7,8 Nitazoxanide was well tolerated in these trials. The Panel concluded that results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of nitazoxanide in the treatment of COVID-19.

Please see the clinical data table for more information.

Monitoring, Adverse Effects, and Drug-Drug Interactions

• Nitazoxanide is generally well tolerated. The most commonly reported side effects include abdominal pain, diarrhea, headache, nausea, vomiting, urine discoloration, and, rarely, ocular discoloration.
• Nitazoxanide is a highly plasma protein-bound drug (>99.9%). Drug-drug interactions may occur when nitazoxanide is administered concurrently with other highly plasma protein-bound drugs due to competition for binding sites. If nitazoxanide is coadministered with other highly protein-bound drugs with narrow therapeutic indices, monitor the patient for adverse drug reactions.
• Please see Table 4d for more information.

Considerations in Pregnancy

According to the animal study data included in the product label, nitazoxanide does not appear to affect fertility, nor does it cause fetal toxicity.⁹ There are no data on using nitazoxanide to treat COVID-19 in pregnant people.

Considerations in Children

Nitazoxanide is approved by the FDA for use in children aged ≥1 year old to treat Cryptosporidium parvum and Giardia duodenalis infections. Dosing for the nitazoxanide suspension or tablets is available for children that provides exposure that is similar to the approved adult dose of oral nitazoxanide 500 mg twice daily. There are no data on using nitazoxanide to treat COVID-19 in children.

Clinical Trials

Several clinical trials that are evaluating the use of nitazoxanide for the treatment of COVID-19 are currently underway or in development. Please see ClinicalTrials.gov for the latest information.