Valérie Bertrand1*
Nathalie Massy2Nancy Vegas3,4Valérie Gras5Christel Chalouhi3,4
Marie-Pierre Tavolacci6
Véronique Abadie3,4,7- 1Department of Pediatrics, Le Havre Hospital, Le Havre, France
- 2Regional Center of Pharmacovigilance, Rouen University Hospital, Rouen, France
- 3General Pediatrics Unit, Necker University Hospital, Paris, France
- 4Refferal Center for Rare Disease ≪ Pierre Robin Sequence and Sucking and Swallowing Congenital Disorders ≫, Necker University Hospital, Paris, France
- 5Regional Center of Pharmacovigilance, Amiens University Hospital, Amiens, France
- 6CIC104 Rouen University Hospital and INSERM 1073, Rouen, France
- 7Paris University, Paris, France
Objectives: Cyproheptadine is a first-generation H1-antihistamine drug first that was distributed in the 1960s. While its orexigenic effect was observed early, cyproheptadine is not yet authorized for this indication in all countries today. There is an increasing medical interest and demand for the orexigenic effect of cyproheptadine, especially in children with poor appetite. As cyproheptadine might be evaluated in future clinical trials, we wanted to assess its safety profile.
Methods: Using the French national pharmacovigilance database, we retrospectively analyzed all pediatric and adult reports of adverse effects of cyproheptadine recorded since its first distribution in France. Next, we performed a systematic review of the literature of cyproheptadine adverse effects.
Results: Since 1985, 93 adverse effects were reported in the French pharmacovigilance database (adults 81.7%, children 18.3%); these were mainly neurological symptoms (n = 38, adults 71%, children 28.9%), and hepatic complications (n = 15, adults 86.7%, children 13.3%). In the literature, the most frequent adverse effect reported was drowsiness in adults or children, and five case reports noted liver complications in adults. We estimated the frequency of hepatic adverse effects at 0.27 to 1.4/1000, regardless of age.
Conclusion: Cyproheptadine can be considered a safe drug. Mild neurological effects appear to be frequent, and hepatotoxicity is uncommon to rare. Randomized controlled trials are needed to evaluate the safety and efficacy of cyproheptadine before authorization for appetite stimulation, especially in young children as studies at this age are lacking. Possible hepatic complications should be monitored, as very rare cases of liver failure have been reported.
Introduction
Cyproheptadine (Periactine©) is a first-generation H1-antihistamine drug, that was first distributed in the 1960s. Its indications were acute or chronic allergy and pruritus in dermatologic diseases. Soon after, its effect on appetite stimulation appeared as an interesting side effect (1, 2). In 1994, Canadian authors first questioned this indication as most of the studies supporting this orexigenic effect had major methodologic flaws, and it was finally removed from the official recommendations (3). In France, the last marketing authorization date was December 1997 for “allergic pathologies such as rhinitis, conjunctivitis, urticarial” in adults or children above 6 years old. In the 2000s, cyproheptadine was evaluated again in undernourished children with cancer, cystic fibrosis and Silver-Russell syndrome, with variable but interesting results (4–6). Currently, cyproheptadine is authorized for its orexigenic effect in adults and children above 2 years old in the United States. Cyproheptadine has also been evaluated for functional digestive disorders and migraine prophylaxis (7, 8).
This renewed interest in cyproheptadine is first due to a potentially large medical demand, especially for children with insufficient or very selective appetites, or who need nutritional support. Second, there are no other drugs that can stimulate appetite and food intake without significant adverse effects (AEs). Harrison et al. recently published a systematic analysis of cyproheptadine's efficacy and concluded that “cyproheptadine appears to be a safe, generally well-tolerated medication that has utility in helping facilitate weight gain in patients drawn from a variety of underweight populations” (9). In spite of weak scientific evidence, many patients and parents are currently using cyproheptadine (or asking doctors about it) because of its positive comments on non-scientific websites and its accessibility without prescription as an “over-the-counter drug” (10–12).
First-generation H1-antihistamine drugs are known to have various AEs since H1 receptors are distributed throughout the body. These drugs interact with cerebral nervous system H1, muscarinic, serotonin, and alpha-adrenergic receptors, and interfere with cardiac ions channels. Newer-generation anti-H1 drugs have less central nervous system AEs due to lower concentrations in the brain and have superseded first-generation drugs for allergic indications (13, 14). The majority of AEs described with cyproheptadine are moderate (drowziness, dizziness) (7, 15–17), although rare cases of acute liver failure have been also reported (18). In cases of overdose, cyproheptadine was associated with anticholinergic syndrome, seizures, psychosis, and cardio-respiratory arrests (19).
Because cyproheptadine might be assessed in future clinical trials or used by patients for its orexigenic effect, we wanted to evaluate its safety profile. For this purpose, we collected all pediatric and adult reports of cyproheptadine AEs recorded in the French national pharmacovigilance database since the first distribution of cyproheptadine in France. Next, we performed a systematic (PRISMA-compliant) review of published reports of cyproheptadine AEs.
Materials and Methods
Analysis of the French Pharmacovigilance Database
We retrospectively collected and analyzed all reports of AEs involving cyproheptadine exposure, recorded between 1985 and December 31st 2020 in the French pharmacovigilance database (20). Reports were selected by using the drug name “cyproheptadine,” and only reports in which cyproheptadine was “suspected” were kept. For all patients, we recorded anonymously their age, sex, indication for cyproheptadine use, clinical characteristic of the AE, list of concomitant medications, dosage, delay between the first exposure and the occurrence of the AE, and clinical evolution.
To evaluate a potential causal relationship between the drug exposure and the occurrence of an AE, the French pharmacovigilance database uses a score, defined in the 1985 version, based on the evaluation of eight criteria divided into three groups: chronology, semiology and bibliographic data. Once combined, the chronological (C) and semiological (S) scores yield an “intrinsic” causality score ranging from 0 (unlikely) to 4 (very likely) (Table 1) (21). The eighth criterion derives an “extrinsic” or bibliographic score (B) for the reaction from a classification of the available scientific literature.
Table 1. French imputability (I) score.
To estimate the frequency of these AEs, we tried to determine how many people were exposed to the medication in France during the studied period. Since cyproheptadine is in free sale, we could not use the national social security database. We used data from OpenHealth, a private company specialized in collecting and analyzing health data. OpenHealth collects drugs sales data from approximately half of the retail pharmacies in France. We obtained data for the number of cyproheptadine boxes sold between 2008 and December 31st 2020 in France.
Literature Systematic Review of Adverse Events of Cyproheptadine
We applied the PRISMA guidelines to perform a systematic review of all the studies of cyproheptadine used as a drug and reporting adverse events. We searched for original articles, case reports, and letters to the editor that reported cases of adverse events with this drug in two electronic databases (PubMed and Web of Science) by using the following keywords (both as free text and MeSH terms): “cyproheptadine,” “adverse effect,” “hepatic,” “review.” Relevant articles were first selected according to their titles. Abstracts and full texts of selected abstracts were reviewed, and references were screened for additional articles. Searches were carried out from 1960 to December 2020. Only articles with full text available in English or French were considered (Figure 1). Descriptive analysis involved frequencies and percentages for qualitative variables and median (range) as appropriate for quantitative variables.
Figure 1. Flow chart of the search strategy for the literature review.
Results
Analysis of the French Pharmacovigilance Database
Over the 36 years of the analysis period, a total of 93 AEs were reported in the French pharmacovigilance database (Table 2). The first report dates from 1985 and the last in 2020. Patients with AEs had a median age of 61.5 years (range 2 months to 99 years), and the sex ratio (M/F) was 0.78. Overall, 76 AEs concerned adults, and 17 AEs concerned children (0–18 years old, 58.8% ≤ 4 years old).
Table 2. Cyproheptadine adverse effects (AEs) reported to the French national pharmacovigilance database between 1985 and December 31, 2020 (n = 93).
The median dosage observed was 8 mg per day (range 4–24 mg) in adults, and 4 mg per day (range 2–20 mg) in children. In France before the 1990s, the maximum recommended dosage was 20 mg per day for adults, 16 mg per day for children aged of 7 to 14 years old, and 12 mg per day for children aged of 2–6 years old. In the 2000s, the usual dosage was 20 mg per day for adults and 12 mg per day for children older than 6 years. Subsequently, the median dosage we observed was consistent with recommendations, and was higher in only four cases.
The median delay between the start of cyproheptadine treatment and the AE occurrence was 10 days (range 1–180 days). Among the 93 AEs, 40.8% were neurological symptoms (n = 38 including seven drowsiness, six confusion, five seizures, five agitation, five hallucinations, two asthenias, two paresthesias, and miscellaneous), 16.1% were hepatic lesions (n = 15), 10.7% were hemodynamic troubles (n = 10), 10.7% were hematological features (n = 10), 8.6% were dermatological symptoms (n = 8), 4.3% were urine retentions (n = 4), 2.1% were diarrheas (n = 2), and some miscellaneous (1 glaucoma, 1 hypothyroidism, 1 gynecomastia, 1 rhabdomyolysis). The most severe AEs were liver failures (n = 3), and central nervous system symptoms. Among all patients, 36 patients received cyproheptadine as a monotherapy, and 57 had a suspected concomitant treatment. Patients treated with cyproheptadine in monotherapy mainly had neurological symptoms, although one adult and one child had liver failure (Figure 2).
Figure 2. Cyproheptadine adverses effects in adults or children in the French pharmacoviligance database, with cyproheptadine (CY) as monotherapy or with concomitant medications (CYC) (data are percentage of 93 AEs).
We analyzed more thoroughly the 15 reported cases of hepatic complications. Among the three patients who had cyproheptadine as monotherapy, a 1-year-old child died from acute liver failure (but a syphilitic infection was suspected at autopsy), one adult presented moderate cytolysis, and one adult had hepatic failure that resolved. Twelve patients received cyproheptadine with other suspected concomitant drugs: among them, most had moderate hepatitis (n = 6), or cholestasis (n = 3) that resolved with cyproheptadine withdrawal, one child had acute liver failure (hepatitis B, evolution not available), and two patients had high serum alkaline phosphatase level or high gamma-glutamyl transferase levels (evolution not available).
For the 93 patients, when specified, cyproheptadine was always discontinued (n = 57). The resolution of the AE was specified for 80 patients: 91.2% of patients had total resolution (n = 73), 1.2% had partial resolution (n = 1), 3.7% had no resolution (n = 3), and 3.7% of patients died (the child with suspected syphilitic infection, and two adults died from a cause other other than cyproheptadine). According to the French causality assessment, the cyproheptadine imputability score for all 93 AEs ranged from 1 to 4 (score 1 n = 68, score 2 n = 18, score 3 n = 6, score 4 n = 1). Specifically, scores were of 1 or 2 for hepatic AEs.
We next sought to estimate the frequency of the AEs in France during the period studied. OpenHealth informed us that 2,169,221 boxes had been sold between January 2008 and December 2020, with a median of 164,054 ± 8,588 boxes were sold per year, and this number being quite stable per year. Since OpenHealth collects data on drugs sales from approximately half of the retail pharmacies in France, we could extrapolate that about 328,108 boxes were sold per year in France. A box contains 30 tablets (4 mg per tablet). Considering that a patient takes 8 mg per day on average, representing 24 boxes per year, we estimated that more than 13,672 patients took a cyproheptadine medication each year in France. Considering that the boxes sold per year were the same before 2008, we estimated that the 93 AEs occurred in more than 13,672 patients between 1985 and December 2020, which represented a frequency lower than 0.7% (7 AEs for 1,000 patients). For hepatic AEs, the frequency was about 1/1,000 patients, which is considered as an uncommon AE, according to the international classification of medication AEs (very common is ≥ 1/10, common is ≥ 1/100 to <1/10, uncommon is ≥ 1/1,000 to <1/100, rare is ≥1/10,000 to <1/1,000, and very rare is <1/10,000). Using the same method, the estimated frequency in this database was 0.3 % for neurological symptoms, 0.07% for hemodynamic symptoms, 0.07% for hematological symptoms and 0.05% for dermatological symptoms. Conversely, we also considered that a patient could take 8 mg per day for 3 months, representing 6 boxes par year, which would represent more than 54,685 patients taking cyproheptadine per year. Consequently, the estimated frequency of all AEs would be lower than 0.17%, and that of hepatic AEs would be rare, at 0.27/1,000. As such, we estimated that the frequency of hepatic AEs with cyproheptadine was probably between 0.27 and 1/1,000 in France during this period.
Literature Systematic Review of Adverse Events of Cyproheptadine
Among 8,602 articles, we selected 171 fulls text articles, which included case reports (n = 72), randomized controlled trials (n = 39), prospective trials (n = 51) and retrospective trials (n = 9) (Figure 1). Overall, 105 articles concerned adults, and 66 concerned children, which represented a total of 3,478 patients. A few studies included infants (16, 17, 22). All reports were published between 1960 and 2020, and most (74%) before year 2000. The indications for cyproheptadine therapy varied greatly as described in Table 3. The duration of treatment was heterogenous and differed according to the indication for cyproheptadine: from a single dose to extended treatment, and mainly for orexigenic effects (median duration 56 days, range 1–870). The longuest duration was of 29 months described in a pediatric case report (23).
Table 3. Indications for cyproheptadine use in the PRISMA-literature review.
Among these 171 articles, 61.4% reported some AEs, in adults (n = 53), or children (n = 52). The median cyproheptadine dosage did not differ whether reporting AEs or not: it was 12 mg per day for adults (range 2–37.5), and 0.25 mg/kg/day (range 0.1–0.8), or 7.5 mg/day (range 1–16) for children. These dosages were consistent with the French, Canadian and US recommandations (24–26). All AEs appeared within a few days after that start of cyproheptadine treatment.
For the 3,478 patients who received cyproheptadine, the exact number of patients affected by an AE was not always specified in the report, although the most frequent AE reported in publications was drowsiness (Table 4). In randomized controlled trials, drowsiness was significant in a large trial including 295 adults (15), and in a small trial (27), but was not in other trials (28–30). Weight gain and increased appetite were also reported as adverse or beneficial effects, depending on the purpose of the study. Other AEs were more rarely reported. When cyproheptadine was used to treat serotonine syndrome, it was generally well-tolerated and efficient, although tachycardia, sedation, hyperthermia, delirium, urinary retention, dilated pupils, decreased bowel movements, dry mouth and dry skin were described (31). No dermatologic or haematologic AEs were reported.
Table 4. Adverse effects (AEs) with cyproheptadine (overdose cases excluded) reported in the literature.
Five case reports describing hepatic complications were published between 1971 and 2014 (Table 5): these included four cholestatic hepatitis cases and one acute liver failure case which occured 5 to 35 days after start of cyproheptadine treatment. All patients had a favorable evolution after cyproheptadine withdrawal. No patients had any prior history of liver disease. In all other publications, hepatic blood tests were rarely performed. Only two publications reported hepatic blood tests which were normal (32), or showed isolated high serum alkaline phosphatase levels (76). Our systematic review of the literature found that hepatic complications with cyproheptadine treatment occurred in 1.4/1,000 patients (5 cases among 3,478 patients), and could be considered as an uncommon AE according to the international classification of medication AEs.
Table 5. Case reports of hepatic adverse events (AEs) with cyproheptadine reported in literature.
In cases with overdoses (n = 91), patients presented mostly with anticholinergic syndrome, within hours of cyproheptadine ingestion (19, 106–113), and with periphereal and/or central nervous system manifestations, including two deaths in adults (114, 115). Blood hepatic tests were rarely performed in these situations; in two cases, these were normal (116, 117).
Discussion
Our analysis of the cases reported in both the French pharmacovigilance database and the literature confirms that cyproheptadine is a safe drug, although physicians should be aware of potential severe hepatic complications. Also, AEs in infants may not yet be well-known due to a lack of studies in this age group. While not all side effects may have been recorded in this database or been published, it is likely that the most severe cases have been reported. Indeed, the cases recorded in the French national pharmacovigilance database are based on voluntary reports from physicians. We could not calculate a precise prevalence or risk of AEs with cyproheptadine because we do not know the exact number of AEs, of ingested cyproheptadine tablets and people who took the drug. However, it is interesting to note that the number of boxes sold per year in France has been quite stable between 2008 and 2020. This suggests that cyproheptadine is currently used mainly for its orexigenic properties, since its indication for allergy relief has been supplanted by newer-generation anti-H1 drugs.
As described in previous studies, the most frequent AEs were mild neurological complications such as drowsiness, dizziness, confusion, and agitation as all first generation H1-antagonists cross the blood-brain barrier. The AEs can be explained by cyproheptadine's antihistaminic properties (drowsiness, discomfort), anticholinergic properties with periphereal symptoms (urinary retention, tachycardia, facial flushing, hyperpyrexia, dry mucous membranes, dilated pupils, constipation) or central symptoms (dizziness, confusion, agitation seizures, athetosis, hallucination, delirium), antiadrenergic properties (orthostatic hypotension, dizziness), and antiserotoninergic properties (weight gain, augmentation of appetite). The responsibility of cyproheptadine in relation to rash, haematologic AEs, gynecomastia, and diarrhea is more doubtful: such AEs were rarely reported, and in our database, concomitant medications could have induced these effects. All of these AEs disappeared after cyproheptadine discontinuation. In in vivo and in vitro studies, cyproheptadine did not induce cardiovascular AE complications (118), which were reported mainly with other H1-antagonists such as diphenhydramine and hydroxyzine (14).
Of more concern and less well-known are hepatic complications associated with cyproheptadine, which may be severe. A total of 15 cases were recorded in our database between 1986 and 2016 and five cases were found in the literature, affecting two children and 18 adults. We estimated the frequency of hepatic AEs to be of 0.27 to 1.4/1,000 (uncommon to rare). Because patients are usually not monitored by hepatic blood tests, we cannot exclude that hepatic perturbations are underdiagnosed. When follow-up data was available, we observed that moderate cytolysis and cholestatic hepatitis resolved in 1–3 weeks and in 3 weeks to 8 months, respectively, after cyproheptadine withdrawal. As four patients had acute liver failure, including two without concomitant medications or other possible etiology, cyproheptadine should probably be contraindicated in patients with prior liver disease. For other patients, hepatic blood test monitoring should be initiated in future trials to screen for this potential complication.
Cyproheptadine hepatotoxicity could be due to its structure (tricyclic ring), which is similar to phenothiazine drugs (18, 90). The structure also contains a tertiary amine that could induce decoupling properties of oxidative phosphorylation (119). In addition, an immunoallergic process has been suspected, and in one case, hypereosinophilia was associated with the hepatic event (91). In an experimental study, rats treated with cyproheptadine had significantly elevated of hepatic microsomal cytochrome P450 levels and ultrastructural alterations to liver cells, suggesting a certain degree of hepatotoxicity with cyproheptadine (120). Accordingly, cyproheptadine is considered a potential hepatotoxic drug (121), classified as category C in LiverTox, and a probable rare cause of clinically apparent liver injury (122). The gold standard of the diagnosis of drug-induced liver injury is the recurrence of liver test abnormalities upon readministration of the drug, although in practice this is rarely done (123). Hepatic complications have also been described with second-generation H1-antihistamines: loratadine or desloratadine (124, 125), cetirizine (126), and terfenadine (127), with good evolution after drug's discontinuation.
There are very few studies evaluating infants treated with cyproheptadine. In the United States, cyproheptadine is contraindicated in infants, “because a paradoxical central nervous system stimulation and/or respiratory depression can occur,” according to the Prescribers Digital Reference (26). These recommendations are related to the reports of respiratory depression, sleep apnea, and sudden infant death syndrome in children that received phenothiazine drugs, which share a similar structure with cyproheptadine. We did not observe such AEs in our database or our literature review, although few studies included infants (16, 17, 22).
In summary, the reported AEs with cyproheptadine treatment in the French pharmacovigilance database and in the literature support the idea that cyproheptadine can be considered as a safe drug. We found that mild neurological effects were frequent, and that hepatotoxicity was uncommon to rare. However, randomized controlled trials are still needed, in terms of safety and efficacy, in order to modify the authorization of cyproheptadine for appetite stimulation, especially in young children and infants for whom studies are lacking. The prescription of cyproheptadine must follow the principles of estimating the benefit/risk ratio for each patient and should respect the classical dosage for an orexigenic indication (0.25 mg/kg/day for children, 8–12 mg/day for adults). Cyproheptadine should not be prescribed in patients with prior liver disease, and possible hepatic complications should be monitored in future trials as these may have been underdiagnosed.
Data Availability Statement
The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Author Contributions
VB conceptualized and designed the study, collected and analyzed data, performed the literature search, drafted the initial manuscript, and revised the manuscript. NM collected data, contributed to analyzing data, interpreting results, and reviewed and revised the manuscript. NV, VG, and CC contributed to analyzing data, interpreting results, and reviewed and revised the manuscript. M-PT contributed to analyzing data, and reviewed and revised the manuscript. VA conceptualized and designed the study, analyzed data, performed the literature search, reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Acknowledgments
We are grateful to OpenHealth Company for helping us in this study. OpenHealth Company, which is specialized in collecting and analyzing health data, is pleased to make available the health product consumption data available for study and research purposes. Data from the OpenHealth's real-time panel of 11,700 pharmacies in France. www.openhealth.fr. We thank Laura Smales and Melissa Taylor for her help with editing and English writing.
Abbreviations
AEs, adverse effects.
References
1. Bergen SS. Appetite stimulating properties of cyproheptadine. Am J Dis Child. (1964) 108:270–3. doi: 10.1001/archpedi.1964.02090010272008
2. Noble RE. Effect of cyproheptadine on appetite and weight gain in adults. JAMA. (1969) 209:2054–5. doi: 10.1001/jama.1969.03160260058019
4. Chinuck R, Dewar J, Baldwin DR, Hendron E. Appetite stimulants for people with cystic fibrosis. Cochrane Database Syst Rev. (2014) 27:CD008190. doi: 10.1002/14651858.CD008190.pub2
5. Couluris M, Mayer JL, Freyer DR, Sandler E, Xu P, Krischer JP. The effect of cyproheptadine hydrochloride (periactin) and megestrol acetate (megace) on weight in children with cancer/treatement-related cachexia. J Pediatr Hematol Oncol. (2008) 11:791–7. doi: 10.1097/MPH.0b013e3181864a5e
6. Lemoine A, Harbison MD, Salem J, Tounian P, Netchine I, Dubern B. Effect of cyproheptadine on weight and growth velocity in children with silver-russell syndrome. J Pediatr Gastroenterol Nutr. (2018) 66:306–11. doi: 10.1097/MPG.0000000000001708
7. Madani S, Cortes O, Thomas R. Cyproheptadine use in children with functional gastrointestinal diosrders. J Pediatr Gastroenterol Nutr. (2016) 62:409–13. doi: 10.1097/MPG.0000000000000964
8. Rao BS, Das DG, Taraknath VR, Sarma Y. A double-blind controlled study of propanolol and cyproheptadine in migraine prophylaxis. Neurol India. (2000) 48:223–6.
9. Harrison ME, Norris ML, Robinson A, Spettigue W, Morrisey M, Isserlin L. Use of cyproheptadine to stimulate appetite and body weight gain: a systematic review. Appetite. (2019) 137:62–72. doi: 10.1016/j.appet.2019.02.012
10. Arraghraghi N. Misuse of cyproheptadine and corticosteroids in morocco. Doctoral Dissert. (2017).
11. Lulebo AM, Bavuidibo CD, Mafuta EM, Ndelo JD, Mputu LC, Kabundji DM, et al. The misuse of cyproheptadine: a non-communicable disease risk behaviour in Kinshasa population, democratic republic of Congo. Subst Abuse Treat Prev Policy. (2016) 11:7. doi: 10.1186/s13011-016-0051-8
12. Spettigue W, Norris ML, Santos A, Obeid N. Treatment of children and adolescents with avoidant/restrictive food intake disorder. J Eat Disord. (2018) 6:20. doi: 10.1186/s40337-018-0205-3
13. Hu Y, Sieck DE, Hsu WH. Why are second-generation H1-antihistamines minimally sedating? Eur J Pharmacol. (2015) 15:100–6. doi: 10.1016/j.ejphar.2015.08.016
14. Simons FE. H1-receptor antagonists. Comparative tolerability and safety. Drug Saf. (1994) 10:350–80. doi: 10.2165/00002018-199410050-00002
15. Kardinal CG, Loprinzi CL, Schaid DJ, Hass AC, Dose AM, Athmann LM, et al. A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer. (1990) 65:2657–62. doi: 10.1002/1097-0142(19900615)65:12<2657::AID-CNCR2820651210>3.0.CO;2-S
16. Rodriguez L, Diaz J, Nurko S. Safety and efficacy of cyproheptadine for treating dyspeptic symptoms in children. J Pediatr. (2013) 163:261–7. doi: 10.1016/j.jpeds.2012.12.096
17. Sant'Anna AM, Hammes PS, Porporino M, Martel C, Zygmuntowicz C, Ramsay M. Use of cyproheptadine in young children with feeding difficulties and poor growth in a pediatric feeding program. J Pediatr Gastroenterol Nutr. (2014) 59:674–8. doi: 10.1097/MPG.0000000000000467
18. Chertoff J, Alam S, Clark V. Cyproheptadine-induced acute liver failure. ACG Case Rep J. (2014) 1:212–13. doi: 10.14309/crj.2014.56
19. Chu FK. Review of the epidemiology and characteristics of intentional cyproheptadine overdose in Hong Kong. Clin Toxicol. (2011) 49:681–3. doi: 10.3109/15563650.2011.602085
20. Available, online at: http://ansm.sante.fr/content/download/115483/1461439/version/1/file/BPPV-fevrier_2018.pdf (accessed December 01, 2020).
21. Miremont-Salamé G, Théophile H, Haramburu F, Bégaud B. Causality assessment in pharmacovigilance: the French method and its successive updates. Therapie. (2016) 71:179–86. doi: 10.1016/j.therap.2016.02.010
22. Merhar SL, Pentiuk SP, Mukkada VA, Meinzen-Derr J, Kaul A, Butler DR. A retrospective review of cyproheptadine for feeding intolerance in children less than three years of age: effects and side effects. Acta Paediatr. (2016) 105:967–70. doi: 10.1111/apa.13477
23. Arisaka O, Shimura N, Nakayama Y, Yabuta K. Cyproheptadine and growth. Am J Child. (1988) 142:914–5. doi: 10.1001/archpedi.1988.02150090012004
24. Available, online at: http://agence-prd.ansm.sante.fr/php/ecodex/extrait.php?specid=67231270 (accessed December 01, 2020).
25. Drug Product Database Health Canada; Editing Status 2018-08-18; re3data.org - Registry of Research Data Repositories. Available online at: http://doi.org/10.17616/R3QJ7G (accessed December 01, 2020).
26. Prescribers' Digital Referencere. Cyproheptadine. Retrieved from www.pdr.net (accessed December 01, 2020).
27. Neittaanmäki H, Myöhänen T, Fräki JE. Comparison of cinnarizine, cyproheptadine, doxepin, and hydroxyzine in treatment of idiopathic cold urticaria: usefulness of doxepin. J Am Acad Dermatol. (1984) 11:483–9. doi: 10.1016/S0190-9622(84)70196-4
28. Mahachoklertwattana P, Wanasuwankul S, Poomthavorn P, Choubtum L, Sriphrapradang A. Short- term cyproheptadine therapy in underweight children: effects on growth and serum insulin-like growth factor-I. J Pediatr Endocrinol Metab. (2009) 22:425–32. doi: 10.1515/JPEM.2009.22.5.425
29. Najib K, Moghtaderi M, Karamizadeh Z, Fallahzadeh E. Beneficial effect of cyproheptadine on body mass index in undernourished children: a randomized controlled trial. Iran J Pediatr. (2014) 24:753–8.
30. Rerksuppaphol S, Rerksuppaphol L. Effect of cyproheptadine on weight gain in malnourished children: a randomized, controlled trial. Asian Biomed. (2010) 4:977–82. doi: 10.2478/abm-2010-0130
31. Nguyen H, Pan A, Smollin C, Cantrell LF, Kearney T. An 11-year retrospective review of cyproheptadine use in serotonin syndrome cases reported to the California poison control system. J Clin Pharm Ther. (2019) 44:327–34. doi: 10.1111/jcpt.12796
32. Wortsman J, Soler NG, Hirschowitz J. Side effects of cyproheptadine. Br Med J. (1978) 1:1217. doi: 10.1136/bmj.1.6121.1217
33. Aizenberg D, Zemishlany Z, Weizman A. Cyproheptadine treatment of sexual dysfunction induced by serotonin reuptake inhibitors. Clin Neuropharmacol. (1995) 18:320–4. doi: 10.1097/00002826-199508000-00003
34. Akhondzadeh S, Erfani S, Mohammadi MR, Tehrani-Doost M, Amini H, Gudarzi SS, et al. Cyproheptadine in the treatment of autistic disorder: a double-blind placebo-controlled trial. J Clin Pharm Ther. (2004) 29:145–50. doi: 10.1111/j.1365-2710.2004.00546.x
35. Andersen JM, Sugerman KS, Lockhart JR, Weinberg WA. Effective prophylactic therapy for cyclic vomiting syndrome in children using amitriptyline or cyproheptadine. Pediatrics. (1997) 100:977–81. doi: 10.1542/peds.100.6.977
36. Asadi B, Khorvash F, Najaran A, Khorvash F. Cyproheptadine versus propanolol in the prevention of migraine headaches in children. Pak J Med Sci. (2012) 28:309–11.
37. Badihian N, Saneian H, Badihian S, Yaghini O. Prophylactic therapy of cyclic vomiting syndrome in children: comparison of amitriptyline and cyproheptadine: a randomized clinical trial. Am J Gastroenterol. (2018) 113:135–40. doi: 10.1038/ajg.2017.194
38. Bailey IS. Cyproheptadine in treatment of urticaria. Br Med J. (1961) 2:430–1. doi: 10.1136/bmj.2.5249.430
39. Boles RG. High degree of efficacy in the treatment of cyclic vomiting syndrome with combined co-enzyme Q10, L-carnitine and amitriptyline, a case series. BMC Neurol. (2011) 11:102. doi: 10.1186/1471-2377-11-102
40. Casulari LA, Naves LA, Mello PA, Pereira Neto A, Papadia C. Nelson's syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment. Horm Res. (2004) 62:300–5. doi: 10.1159/000082235
41. Comer SD, Haney M, Fischman MW, Foltin RW. Cyproheptadine produced modest increases in total caloric intake by humans. Physiol Behav. (1997) 62:831–9. doi: 10.1016/S0031-9384(97)00246-1
42. Daviss WB, Scott J. A chart review of cyproheptadine for stimulant-induced weight loss. J Child Adolesc Psychopharmacol. (2004) 14:65–73. doi: 10.1089/104454604773840508
43. Delitala G, Devilla L, Bionda S, Franca V. Suppression of human growth hormone secretion by cyproheptadine. Metabolism. (1977) 26:931–6. doi: 10.1016/0026-0495(77)90012-9
44. Epifanio M, Marostica PC, Mattiello R, Feix L, Nejedlo R, Fischer GB, et al. A randomized, double-blind, placebo-controlled trial of cyproheptadine for appetite stimulation in cystic fibrosis. J Pediatr. (2012) 88:155–60. doi: 10.2223/JPED.2174
45. Fischel T, Hermesh H, Aizenberg D, Zemishlany Z, Munitz H, Benjamini Y, et al. Cyproheptadine versus propranolol for the treatment of acute neuroleptic-induced akathisia: a comparative double-blind study. J Clin Psychopharmacol. (2001) 21:612–5. doi: 10.1097/00004714-200112000-00013
46. Gross MD, Grekin RJ, Gniadek TC, Villareal JZ. Suppression of aldosterone by cyproheptadine in idiopathic aldosteronism. N Engl J Med. (1981) 305:181–5. doi: 10.1056/NEJM198107233050401
47. Hakkou F, Jaouen C, Iraki L. A comparative study of cyproheptadine and DL carnitine on psychomotor performance and memory in healthy volunteers. Fundam Clin Pharmacol. (1990) 4:191–200. doi: 10.1111/j.1472-8206.1990.tb00487.x
48. Homnick DN, Homnick BD, Reeves AJ, Marks JH, Pimentel RS, Bonnema SK. Cyproheptadine is an effective appetite stimulant in cystic fibrosis. Pediatr Pulmonol. (2004) 38:129–34. doi: 10.1002/ppul.20043
49. Homnick DN, Marks JH, Hare KL, Bonnema SK. Long-term trial of cyproheptadine as an appetite stimulant in cystic fibrosis. Pediatr Pulmonol. (2005) 40:251–6. doi: 10.1002/ppul.20265
50. Javanbakht A. As-needed use of cyproheptadine for treatment of selective serotonin reuptake inhibitor-related female anorgasmia. J Clin Psychopharmacol. (2015) 35:91–3. doi: 10.1097/JCP.0000000000000260
51. Jensen K. The effect of antiserotonin (cyproheptadine) and antihistamine on cutaneous allergy. Acta Allergol. (1960) 15:293–305. doi: 10.1111/j.1398-9995.1960.tb03659.x
52. Kaplowitz PB, Jennings S. Enhancement of linear growth and weight gain by cyproheptadine in children with hypopituitarism receiving growth hormone therapy. J Pediatr. (1987) 110:140–3. doi: 10.1016/S0022-3476(87)80310-4
53. Kenien AG, Zeidner DL, Pang SJ, Becker DJ, Postellon DC, Gutai JP, et al. The effect of cyproheptadine and human growth hormone on adrenocortical function in children with hypopituitarism. J Pediatr. (1978) 92:491–4. doi: 10.1016/S0022-3476(78)80456-9
54. Kibel MA. Appetite and weight gain in children: a double-blind trial using cyproheptadine and methandrostenolone. Cent Afr J Med. (1969) 15:229–32.
55. Kuokkanen K. Comparison of a new antihistamine HC 20-511 with cyproheptadine (Periactin) in chronic urticaria. Acta Allergol. (1977) 32:316–20. doi: 10.1111/j.1398-9995.1977.tb02573.x
56. Lavenstein AF, Dacanet EP, Lasagna L, Vanmetre TE. Effect of cyproheptadine on asthmatic children. Study of appetite, weight gain, and linear growth. JAMA. (1962) 180:912–6. doi: 10.1001/jama.1962.03050240008002
57. Lerman-Sagie T, Mimouni M. Reversal of anorexia in a child with partial ornithine transcarbamylase deficiency by cyproheptadine therapy. Clin Pediatr. (1995) 34:163–5. doi: 10.1177/000992289503400310
58. Loli P, Frascatani F, Gelli D, Maggioni M, Muratori F, Ronzoni M. Inhibitory effect of cyproheptadine on ACTH secretion in patients with Addison's disease. Acta Endocrinol (Copenh). (1983) 102:111–5. doi: 10.1530/acta.0.1020111
59. Mercado-Asis LB, Yanovski JA, Tracer HL, Chik CL, Cutler Jr GB. Acute effects of bromocriptine, cyproheptadine, and valproic acid on plasma adrenocorticotropin secretion in Nelson's syndrome. J Clin Endocrinol Metab. (1997) 82: 514–7. doi: 10.1210/jcem.82.2.3742
60. Moertel CG, Kvols LK, Rubin J. A study of cyproheptadine in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer. (1991) 67:33–6. doi: 10.1002/1097-0142(19910101)67:1<33::AID-CNCR2820670107>3.0.CO;2-E
61. Neittaanmäki H, Fräki JE, Gibson JR. Comparison of the new antihistamine acrivastine (BW 825C) versus cyproheptadine in the treatment of idiopathic cold urticaria. Dermatologica. (1988) 177:98–103. doi: 10.1159/000248523
62. Okuma H, Iijima K, Yasuda T, Tokuoka K, Kitagawa Y. Preventive effect of cyproheptadine hydrochloride in refractory patients with frequent migraine. Springerplus. (2013) 29:573. doi: 10.1186/2193-1801-2-573
63. Rahman KM. Appetite stimulation and weight gain with cyproheptadine (periactin) in tuberculosis patients (double-blind clinical study). Med J Malaysia. (1975) 29:270–4.
64. Razzaghy-Azar M, Nourbakhsh M, Nourbakhsh M. A novel treatment for height growth in patients with growth hormone insensitivity syndrome by cyproheptadine hydrochloride. Clin Endocrinol. (2018) 88:880–8. doi: 10.1111/cen.13594
65. Riley AJ, Riley EJ. Cyproheptadine and antidepressant-induced anorgasmia. Br J Psychiatry. (1986) 148:217–8. doi: 10.1192/bjp.148.2.217
66. Silbert MV. The weight gain effect of periactin in anorexic patients. S Afr Med J. (1971) 45:374–7.
67. Silverstone T, Schuyler D. The effect of cyproheptadine on hunger, calorie intake and body weight in man. Psychopharmacologia. (1975) 40:335–40. doi: 10.1007/BF00421472
68. Smellie H, Fry L. Comparison of an antiserotonin (cyproheptadine) and a pure antihistamine chlorpheniramine in hay fever. Acta Allergol. (1962) 17:352–7. doi: 10.1111/j.1398-9995.1962.tb02962.x
69. Stiel JN, Liddle GW, Lacy WW. Studies on mechanism of cyproheptadine-induced weight gain in human subjects. Metabolism. (1970) 19:192–200. doi: 10.1016/0026-0495(70)90052-1
70. Visitsunthorn N, Tuchinda M, Vichyanond P. Cold urticaria in Thai children: comparison between cyproheptadine and ketotifen in the treatment. Asian Pac J Allergy Immunol. (1995) 13:29–35.
71. Wainberg M, Barbeau H, Gauthier S. The effects of cyproheptadine on locomotion and on spasticity in patients with spinal cord injuries. J Neurol Neurosurg Psychiatry. (1990) 53:754–63. doi: 10.1136/jnnp.53.9.754
72. Weiss D, Aizenberg D, Hermesh H, Zemishlany Z, Munitz H, Radwan M, et al. Cyproheptadine treatment in neuroleptic-induced akathisia. Br J Psychiatry. (1995) 167:483–6. doi: 10.1192/bjp.167.4.483
73. Welsh AL, Ede M. Further studies of cyproheptadine as an antiallergic, antipruritic agent. J New Drugs. (1962) 2:88–93. doi: 10.1177/009127006200200204
74. Worawattanakul M, Rhoads JM, Lichtman SN, Ulshen MH. Abdominal migraine: prophylactic treatment and follow-up. J Pediatr Gastroenterol Nutr. (1999) 28:37–40. doi: 10.1097/00005176-199901000-00010
75. Wu KG, Li TH, Wang TY, Hsu CL, Chen CJ. A comparative study of loratadine syrup and cyproheptadine HCL solution for treating perennial allergic rhinitis in Taiwanese children aged 2-12 years. Int J Immunopathol Pharmacol. (2012) 25:231–7. doi: 10.1177/039463201202500125
76. Penfold JL. Effect of cyproheptadine and a multivitamin preparation on appetite stimulation, weight gain and linear growth. A clinical trial of 40 children. Med J Aust. (1971) 6:307–10. doi: 10.5694/j.1326-5377.1971.tb50268.x
77. Benjasuwantep B. Successful treatment in a child with feeding problems and growth failure. J Med Assoc Thai. (2009) 92: (Suppl. 3):S60–4.
78. Couch RM, Smail PJ, Dean HJ, Winter JS. Prolonged remission of cushing disease after treatment with cyproheptadine. J Pediatr. (1984) 104:906–8. doi: 10.1016/S0022-3476(84)80495-3
79. Dash RJ, Ahmad J, Sethi BK, Sialy R. Failure of long-term cyproheptadine therapy in lowering growth hormone levels in acromegaly. Clin Endocrinol. (1989) 30:639–44. doi: 10.1111/j.1365-2265.1989.tb00269.x
80. D'Ercole AJ, Morris MA, Underwood LE, Van Wyk JJ, Feldman JM. Treatment of Cushing disease in Childhood with cyproheptadine. J Pediatr. (1977) 90:834–5. doi: 10.1016/S0022-3476(77)81265-1
81. Halmi KA, Eckert E, Falk JR. Cyproheptadine for anorexia nervosa. Lancet. (1982) 1:1357–8. doi: 10.1016/S0140-6736(82)92422-9
82. Halmi KA, Eckert E, LaDu TJ, Cohen J. Anorexia nervosa. Treatment efficacy of cyproheptadine and amitriptyline. Arch Gen Psychiatry. (1986) 43:177–81. doi: 10.1001/archpsyc.1986.01800020087011
83. Harris AL, Smith IE. Regression of carcinoid tumour with cyproheptadine. Br Med J. (1982) 285:475. doi: 10.1136/bmj.285.6340.475
84. Kazemi SA, MK Yekta MK, Fallah R, Diaz DN, Eftekhari K. Evaluation of cyproheptadine hydrochloride effects on weight gain in underweight children with anorexia; a randomized clinical trial. Int J Pediatr. (2017) 5:6413–9.
85. Muranjan MN, Mordekar SR, Bava HS, Alavi S, Kher AS, Nadkarni UB, et al. Cyproheptadine in severe anorexia. Indian Pediatr. (1994) 31:1429–30.
86. Najjar SS, Khachadurian AK. The effect of cyproheptadine on body weight plasma glucose and insulin. J Med Liban. (1969) 22:1–9.
87. Wanderer AA, Ellis EF. Treatment of cold urticaria with cyproheptadine. J Allergy Clin Immunol. (1971) 48:366–71. doi: 10.1016/0091-6749(71)90083-2
88. Welsh AL, Ede M. Studies of cyproheptadine combined with dexamethasone. J New Drugs. (1962) 2:223–31. doi: 10.1177/009127006200200405
89. Pontius EB. An anticholinergic crisis associated with cyproheptadine treatment of desipramine-induced inorgasmia. J Clin Psychopharmacol. (1988) 8:230–1. doi: 10.1097/00004714-198806000-00027
90. Larrey D, Geneve D, Machayekhi JP, Degott C, Benhamou JP. Prolonged cholestasis after cyproheptadine-induced acute hepatitis. J Clin Gastroenterol. (1987) 9:102–4. doi: 10.1097/00004836-198702000-00026
91. Freneaux E, Larrey D, Berson A, Pessayre D, Benhamou JP. Hepatitis caused by cyproheptadine (Periactin). A case and review of the literature. Gastroenterol Clin Biol. (1988) 12:573–5.
92. Karkalas Y, Lal H. Jaundice following therapy with imipramine and cyproheptadine. Clin Toxicol. (1971) 4:47–53. doi: 10.3109/15563657108990147
93. Henry DA, Lowe JM, Donnelly T. Jaundice during cyproheptadine treatment. Br Med J. (1978) 1:753. doi: 10.1136/bmj.1.6115.753
94. Genazzani AD, Strucchi C, Malavasi B, Tortolani F, Vecchi F, Luisi S, et al. Effects of cyproheptadine clorhydrate, a serotonin receptor antagonist, on endocrine parameters in weight-loss related amenorrhea. Gynecol Endocrinol. (2001) 15:279–85. doi: 10.1080/gye.15.4.279.285
95. Strayhorn Jr JM. Case study: cyproheptadine and aggression in a five-year-old boy. J Am Acad Child Adolesc Psychiatry. (1998) 37: 668–70. doi: 10.1097/00004583-199806000-00018
96. Kahn DA. Possible toxic interaction between cyproheptadine and phenelzine. Am J Psychiatry. (1987) 144:1242–3. doi: 10.1176/ajp.144.9.1242
97. Watemberg NM, Roth KS, Alehan FK, Epstein CE. Central anticholinergic syndrome on therapeutic doses of cyproheptadine. Pediatrics. (1999) 103:158–60. doi: 10.1542/peds.103.1.158
98. Houang M, Leroy B, Forin V, Sinnassamy P, Bensman A. Acute urine retention: a rare mode of revelation of cervico-dorsal syringomyelia caused by cyproheptadine. Arch Pediatr. (1994) 1:260–3.
99. Lappin RI, Auchincloss EL. Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med. (1994) 331:1021–2. doi: 10.1056/NEJM199410133311514
100. Poomthavorn P, Mahachoklertwattana P, Khlairit P. Childhood virilization and adrenal suppression after ingestion of methandienone and cyproheptadine. J Pediatr Endocrinol Metab. (2009) 22:459–62. doi: 10.1515/JPEM.2009.22.5.459
101. Berger M, White J, Travis LB, Brouhard BH, Cunnigham RJ 3rd, Patnode R, et al. Toxic psychosis due to cyproheptadine in a child on hemodialysis: a case report. Clin Nephrol. (1977) 7:43–4.
102. Kaya I, Suleyman F, Coskun M. Cyproheptadine-induced obsessive-compulsive symptoms in a preschool child. Klinik Psikofarmakol Bult Istanbul. (2016) 26:72–4. doi: 10.5455/bcp.20151013010412
103. Bacher NM, Sanzone MM, Kaup B. Cyproheptadine in treatment-resistant chronic schizophrenics with prior negative response to fluoxetine. J Clin Psychopharmacol. (1994) 14:424–5. doi: 10.1097/00004714-199412000-00009
104. Zubieta JK, Demitrack MA. Depression after cyproheptadine: MAO treatment. Biol Psychiatry. (1992) 31:1177–8. doi: 10.1016/0006-3223(92)90169-Z
105. Bhatia MS, Kaur J, Gautam P. A case of serotonin syndrome following cyproheptadine withdrawal. Prim Care Companion CNS Disord. (2015) 17. doi: 10.4088/PCC.14l01762
106. Baehr GR, Romano M, Young JM. An unusual case of cyproheptadine (Periactin) overdose in an adolescent female. Pediatr Emerg Care. (1986) 2:183–5. doi: 10.1097/00006565-198609000-00009
107. Blaunstein BS, Gaeta TJ, Balentine JR, Gindi M. Cyproheptadine-induced central cholinergic syndrome in a child: a case report. Pediatr Emerg Care. (1995) 11:235–7. doi: 10.1097/00006565-199508000-00012
108. Chan TY, Tang CH, Critchley JA. Poisoning due to an over-the-counter hypnotic, Sleep-Qik (hyoscine, cyproheptadine, valerian). Postgrad Med. (1995) 71:227–8. doi: 10.1136/pgmj.71.834.227
109. Craven JL, Rodin GM. Cyproheptadine dependance associated with an atypical somatoform disorder. Can J Psychiatr. (1987) 32:143–5. doi: 10.1177/070674378703200211
111. McGovern T, McNamee J, Marcus S, Kashani J. When too much is enough: pediatric cyproheptadine overdose with confirmatory level. Clin Pract Cases Emerg Med. (2017) 1:205–7. doi: 10.5811/cpcem.2017.2.33313
112. Richmond M, Seger D. Central anticholinergic syndrome in a child, a case report. J Emerg Med. (1985) 3:453–6. doi: 10.1016/0736-4679(85)90004-6
113. Yuan CM, Spandorfer PR, Miller SL, Henretig FM, Shaw LM. Evaluation of tricyclic antidepressant false positivity in a pediatric case of cyproheptadine (periactin) overdose. Ther Drug Monit. (2003) 25:299–304. doi: 10.1097/00007691-200306000-00009
114. Hargrove V, Molina K. A fatality due to cyproheptadine and citalopram. J Anal Toxicol. (2009) 33:564–7. doi: 10.1093/jat/33.8.564
115. Levine B, Green-Johnson D, Hogan S, Smialek JE. A cyproheptadine fatality. J Anal Toxicol. (1988) 22:72–4. doi: 10.1093/jat/22.1.72
116. Kano K, Yamamoto U, Yamada Y, Arisaka O. Suicide attempt with cyproheptadine. J Am Acad Child Adolesc Psychiatry. (2001) 40:994–5. doi: 10.1097/00004583-200109000-00006
117. Samie MR, Ashton AK. Choreoathetosis induced by cyproheptadine. Mov Disord. (1989) 4:81–4. doi: 10.1002/mds.870040111
118. Kobayashi K, Omuro N, Takahara A. The conventional antihistamine drug cyproheptadine lacks QT-interval-prolonging action in halothane-anesthetized guinea pigs: comparison with hydroxyzine. J Pharmacol Sci. (2014) 124:92–8. doi: 10.1254/jphs.13159FP
119. Berson A, De Beco V, Lettéron P, Robin MA, Moreau C, El Kahwaji J, et al. Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology. (1998) 114:764–74. doi: 10.1016/S0016-5085(98)70590-6
120. Unchern S, Thithapandha A. The effects of cyproheptadine hydroxhloride on hepatic drug-metabolizing enzymes in the rat. Drug Metab Dispos. (1979) 7:411–5.
121. Giri S, Nieber K, Bader A. Hepatotoxicity ad hepatic metabolism of available drugs: current problems and possible solutions in preclinical stages. Expert Opin Drug Metab Toxicol. (2010) 6:895–917. doi: 10.1517/17425251003792521
122. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda: National Institute of Diabetes and Digestive and Kidney Diseases (2012).
123. Björnsson ES. Hepatotoxicity by drugs: the most common implicated agents. Int J Mol Sci. (2016) 17:224. doi: 10.3390/ijms17020224
124. Schiano TD, Bellary SV, Cassidy MJ, Thomas RM, Black M. Subfulminant liver failure and severe hepatotoxicity caused by loratadine use. Ann Intern Med. (1996) 125:738–40. doi: 10.7326/0003-4819-125-9-199611010-00006
125. Schöttker B, Dösch A, Kraemer DM. Severe hepatotoxicity after application of desloratadine and fluconazole. Acta Haematol. (2003) 110:43–4. doi: 10.1159/000072415
126. Coskun A, Yavasoglu I, Yasa MH, Culhaci N, Yukselen V. Cetirizine induced hepatotoxicity: case series and review of the literature. Gastroenterol Rep. (2018) 6:228–30. doi: 10.1093/gastro/gow025
Keywords: cyproheptadine, adverse (side) effects, appetite, orexigenic, cholestase, liver failure
Citation: Bertrand V, Massy N, Vegas N, Gras V, Chalouhi C, Tavolacci M-P and Abadie V (2021) Safety of Cyproheptadine, an Orexigenic Drug. Analysis of the French National Pharmacovigilance Data-Base and Systematic Review. Front. Pediatr. 9:712413. doi: 10.3389/fped.2021.712413
Received: 20 May 2021; Accepted: 06 September 2021;
Published: 29 September 2021.
Edited by:
Consolato M. Sergi, Children's Hospital of Eastern Ontario (CHEO), CanadaReviewed by:
Tudor Lucian Pop, Iuliu Haţieganu University of Medicine and Pharmacy, RomaniaSravan Kumar Reddy Matta, Kaiser Permanente, United States
Copyright © 2021 Bertrand, Massy, Vegas, Gras, Chalouhi, Tavolacci and Abadie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Valérie Bertrand, valerie.bertrand@ch-havre.fr