Anemia associated with Alinia monotherapy when used longer than FDA-approved duration
Alinia, the first thiazolide, was approved in 2002 by the FDA for the treatment of protozoal and helminthic infections. It was hypothesized that the drug may have possible antiviral activity by increasing the phosphorylation of double-stranded RNA-dependent protein kinase and the induction of eukaryotic-initiation of factor 2-alpha, which is an important factor in the innate immune response against hepatitis C infection.
Before the introduction of the direct-acting antiviral agents in 2011, treatment for HCV consisted of combination therapy using ribavirin (RBV) and pegylated interferon (PEG-IFN). Treatment therapy of nonresponders, relapsers or patients who were not candidates for combination therapy with RBV and PEG-IFN were often offered salvage therapy with experimental drugs in an attempt to suppress the HCV and thus, halt the development of hepatocellular carcinoma.
This case series documents severe anemia secondary to off-label use of Alinia (nitazoxanide, Romark Laboratories; NTZ) in two patients undergoing salvage therapy for HCV infection. At the time the documented cases occurred, neither Victrelis (boceprevir, Merck), Incivek (telaprevir, Vertex Pharmaceuticals), nor the recently approved protease inhibitors-based oral therapy were approved by the FDA or available for use in the United States. Results from our two case studies included patients who were treated with NTZ monotherapy for HCV infection, both of whom experienced symptomatic anemia requiring discontinuation of the drug. These laboratory abnormalities, along with reported symptoms associated with anemia, resolved once NTZ was discontinued.
A 56-year-old white male with a history of hypertension presented to the infectious disease clinic for the management of his HCV infection. Of note, the patient was treated with PEG-IFN and RBV 2 years earlier for a total of 7 weeks. Combination therapy was discontinued due to the patient developing several adverse events, including severe nausea and loss of appetite, which did not respond to conservative medical management. Given the intolerance to the previous treatment, the patient was agreeable to be started on salvage therapy with oral NTZ 500 mg twice daily in an effort to suppress his HCV infection. The patient’s medications at the time of initiation of NTZ included amlodipine and lisinopril. Both were well tolerated over the 1 year since they were started. Baseline laboratory tests before starting NTZ included: a complete blood count (CBC) with a red blood cell count (RBC) of 3.96 M/μL, white blood cell count (WBC) of 8.8 K/µL, hemoglobin (Hgb) of 13.2 g/dL, and a hematocrit (Hct) of 38.2%. Prior Hgb levels ranged from 13 g/dL to 14 g/dL during the previous 12 months before initiation of NTZ. After 8 weeks on NTZ, the patient presented for follow-up with a chief complaint of intermittent abdominal cramps and bloating. Two weeks later at the next visit, the patient reported sporadic tarry stools. A CBC reflected a drop in RBC to 3.28 M/µL, along with a decrease in Hgb and Hct to 10.4 g/dL and 31.5%, respectively. Platelets were in the range of 163 K/µL and did not change throughout the treatment course with NTZ. No additional medications had been started during the preceding 8 weeks except for NTZ. The decision was made to discontinue the NTZ and obtain a fecal occult test to rule out a possible gastrointestinal (GI) source. Subsequently, the fecal occult test confirmed the presence of blood in the stool (three out of three cards were positive). The patient’s CBC reflected a further drop in RBC to 3.11 M/µL with a continued drop in Hgb and Hct to 9.5 g/dL and 29.5%, respectively, over a 12-week period. A colonoscopy revealed a normal mucosa except for minimal proctitis. Endoscopy was not performed because from the time of discontinuing the NTZ therapy and after the colonoscopy, the patient’s CBC began to return to baseline. Since this episode of anemia, the patient did not have any further incidents of anemia after discontinuation of NTZ therapy.
A 54-year-old white male with a history of seasonal allergies was diagnosed with HCV infection. The patient had a history of thrombocytopenia (platelet count was 55 K/µL), which was thought to be secondary to cirrhosis. The patient was deemed not to be a candidate for standard treatment with PEG-IFN and RBV due to thrombocytopenia and subsequently was offered NTZ therapy at 500 mg twice daily. Medications at the time of initiation of NTZ therapy included loratadine. Baseline labs done 1 month before initiation of NTZ reflected a normal Hgb of 15.4 g/dL, Hct of 43.9%, platelets at 55 K/µL, alanine transaminase of 85 U/L, and aspartate aminotransferase of 82 U/L. After 4 weeks of salvage monotherapy with NTZ, showing a drop in Hgb to 13 g/dL and Hct to 39.4%, the platelet count did not change. A follow-up CBC on week 7 of NTZ therapy demonstrated a further drop in Hgb to 9.7 g/dL and Hct to 30.3%, resulting in discontinuation of the NTZ. It was felt that the anemia was associated with the long-term use of NTZ, thus an anemia workup was not initiated but would have been considered if the blood count had not improved. However, the patient’s Hgb and Hct subsequently returned to baseline over the next few weeks after discontinuation of NTZ therapy.
The Cochrane Database of Systematic Reviews in 2014 reviewed seven randomized clinical trials with chronic HCV patients (all genotype 1 or 4). While only one study examined NTZ plus PEG-IFN and RBV vs. no intervention plus PEG-IFN and RBV, no deaths were noted and side effects associated with NTZ were uncertain. NTZ might have sustained virological and end-of-treatment responses, but because of concern over random error, the Review found a lack of information on genotypes 2 and 3 infections associated with chronic HCV. While the major side effect with NTZ is diarrhea, our two cases documented significant anemia. Anemia is listed as a rare side effect in the package insert occurring in less than 1% of cases. This is the first case series of documented anemia secondary to NTZ use, something that has not been well defined in prior literature. In addition, the limited described risk for anemia associated with NTZ usage is important to highlight when considering its use for FDA-approved (cryptosporidiosis and giardiasis), non-FDA–approved (Clostridium difficile colitis, infection by Fasciola, intestinal parasitism, and viral gastroenteritis due to rotavirus), and off-label treatments (HCV, Crohn’s disease and leishmaniasis), especially if prolonged duration is considered. Currently, the specific dosage of NTZ causing toxicity has not been determined, and there is no known antidote, supporting the importance of monitoring for adverse events.
These case reports only included the patients who were on NTZ monotherapy, but similar results have been seen in patients on NTZ with PEG-IFN and RBV. The described cases presented here were selected as they did not include any other possible offending medications such as PEG-IFN or RBV. Standard therapy for HCV infection with RBV and PEG-IFN are known to cause bone marrow suppression and hemolysis. NTZ is FDA-approved for the treatment of Cryptosporidium and Giardia for the duration of 3 days, which may not be sufficient time to achieve such drops in Hgb and Hct. The aim of publishing these findings is to help alert clinicians to monitor for anemia, which could be overlooked with potential non-FDA–approved, long-term use of NTZ.
We believe the most likely mechanism of NTZ causing anemia is a GI source. In one study aimed at evaluating the safety and efficacy of NTZ monotherapy compared with placebo, the authors indicated only two serious events occurred; one in the placebo group, which involved a patient experiencing hematemesis, and one in the NTZ group, with a patient experiencing melena that later revealed a duodenal ulcer.
Long-term use of NTZ beyond the currently approved duration should be used with caution due to possible side effects, including anemia. Monitoring the blood count on a regular basis is strongly recommended. Clinicians should be aware that anemia can be a significant side effect of this medication if it is used longer than the FDA-approved length of therapy.
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Roula Baroudi, MD, is a clinical assistant professor at the University of South Florida and an attending infectious disease physician at Bay Pines VA Healthcare System in Bay Pines, Florida. She can be reached at Roula.Baroudi@va.gov.
Marquetta Flaugher, PhD, ARNP, is from the division of medicine service, Bay Pines VA Healthcare System, Bay Pines, Florida.
Edward Grace, PharmD, is an associate professor in the department of pharmacy practice at Presbyterian College School of Pharmacy in Clinton, South Carolina.
Disclosures: Baroudi, Flaugher and Grace report no relevant financial disclosures.