WHAT HAPPENED TO KETOCONAZOLE (KETAZOLE)?

QUE PASO CON EL KETOCONAZOL (KETAZOL) ?

WHAT HAPPENED TO KETOCONAZOLE (KETAZOLE)?

KETOCONAZOLE TABLETS

SOURCE: LAPROFF.COM

UPDATED 2026

NOTE: The popular KETOCONAZOLE or KETAZOL (antifungal), as it has been known worldwide, and still in the national and world market, in its oral presentation, that is tablets, was PROGRESSIVELY REMOVED from WORLD MARKETS a partir del July 26 year of 2013 due to its toxicity FATAL HEPATIC TOXICITY AND CARDIAC ARRHYTHMIAS fulminant, in addition to other side effects.

EDITORIAL ENGLISH:

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In this work I bring you the HISTORY of the RISE and FALL de this molecule, which today still remains very POPULAR, mechanisms of action dose, adverse effects, uses, warnings, that forced its WITHDRAWAL in its version ORAL from the market, and why STILL it is sold, exists that presentation in tablets, which you get practically in all pharmacies.

This is explained because its WITHDRAWAL in its ORAL version was not TOTAL, its use is limited to certain conditions that we will explain later.

The topical versions (creams, 2% shampoo and vaginal suppositories ) still available due to minimal systemic absorption, that is, they are not harmful, they have no side effects. (1-3).

1.) HISTORY AND DISCOVERY:

The KETOCONAZOLE was discovered and synthesized in 1976 by the researcher Paul Janssen and his team in the laboratory Janssen Pharmaceutical, (laboratory Belgian). In September 2023, Johnson & Johnson unified its business segments and the Janssen brand is now Johnson & Johnson Innovative Medicine. (1). Its introduction was a PHARMACOLOGICAL HIT, consolidating itself as the FIRST antifungal of the imidazole family (azoles) with broad spectrum of action administrable by oral route (2).

The formal approval of KETOCONAZOLE by the FDA of the United States occurred in 1981, under the name of NIZORAL of Janssen Pharmaceuticals marking a significant change in the outpatient treatment of mycosis "FUNGUS" (2).

2. PHARMACOLOGICAL MECHANISM OF ACTION:

2.1 Antifungal Action:

At the cellular level, the KETOCONAZOLE potently inhibits the enzyme 14-alpha-demethylase (enzymatic system dependent on cytochrome P450 in fungi) (3). This enzyme converts lanosterol to ergosterol, fundamental structural component of the cell membrane of fungi (equivalent to cholesterol in human cells) (3).

At blocking its production, the fungal membrane weakens, increasing its porosity and permeability, losing intracellular components, causing the death of the fungus, in a few words the molecule promotes the DESTRUCTION of the membrane cell of the pathogen (3).

2.2 Limited Selective Toxicity:

The critical biological problem that occurred with the KETOCONAZOLE is the lack of perfect selectivity: upon entering the bloodstream, the molecule also blocks enzymes of the human cytochrome P450 (specifically CYP3A4), this fact caused:

- Alteration of metabolism of other drugs in the liver.

- Blocking the synthesis of hormones steroids and testosterone in adrenal glands and testicles; here was when the PROBLEMS of this medicine began (4,17).

3.) THERAPEUTIC ORIGINAL USES:

Since its approval in the 1980s, the drug was authorized for treating multiple diseases as first-line therapy, being highly popular, with ASTRONOMIC sales in the world market (5):

3.1.) Skin and Superficial Conditions:

- Dermatophytosis: (mycosis) severe (body ringworm, athlete's foot), practically ALL the variants of ringworm.

- Onychomycosis: (fungi in the nails): in this condition it was one of the most used.

- Candidiasis: oral or vaginal recurrent.

- Pityriasis versicolor: (5)

3.2.) Endemic and Deep Systemic Mycosis:

- Histoplasmosis.

- Blastomycosis.

- Coccidioidomycosis.

- Paracoccidioidomycosis. (5)

4.) ADVERSE EFFECTS IN GENERAL OF KETOCONAZOLE:

A.) Gastrointestinal disorders:

1.- Frequent nausea.

2.- Persistent vomiting.

3.- Mild to moderate abdominal pain.

4.- Clinical diarrhea (6).

B.) Hepatotoxicity (Liver damage):

5.- Asymptomatic elevation of liver enzymes (serum transaminases).

6.- Severe hepatitis and jaundice (yellowish coloration of skin and eyes).

7.- Acute and fulminant hepatic failure (7).

C.) Cardiovascular disorders:

8.- Pathological prolongation of QT interval in electrocardiogram.

9.- Fatal ventricular arrhythmias, including the dangerous condition of torsades de pointes (7,12).

D.) Endocrine and reproductive system disorders:

10.- Gynecomastia (enlargement of breast tissue in males) (4,6,14).

11.- Oligospermia (low sperm production) and transient sexual impotence (4,6).

12.- Acute adrenal insufficiency due to blockage in the production of endogenous cortisol (4,6,14).

5.) OVERALL ADVERSE EFFECTS OF SYSTEMIC (ORAL) KETOCONAZOLE:

ADVERSE EFFECTS OF THE SYSTEMIC KETOCONAZOLE

SYSTEM	ADVERSE EFFECTS	NUMBER	REFERENCE
Gastrointestinal	Frequent nausea	~20-30%	(6)
Gastrointestinal	Persistent vomiting	~10-15%	(6)
Gastrointestinal	Mild-moderate abdominal pain	~5-10%	(6)
Gastrointestinal	Clinical diarrhea	~3-5%	(6)
Hepatic	Asymptomatic elevation of transaminases	~10-15%	(7)
Hepatic	Severe hepatitis with jaundice	- 1% Rare cases	(7)
Hepatic	Acute fulminant hepatic failure	- 0.1% Rare cases	(7,11)
Cardiovascular	Pathological prolongation of QT interval	~2-5%	(7,12)
Cardiovascular	Ventricular arrhythmias (torsades de pointes)	-0.1%	(7,12)
Endocrine	Gynecomastia in males	~10-20%	(4,6,14)
Endocrine	Oligospermia and transient impotence	~5-10%	(4,6)
Endocrine	Acute adrenal insufficiency	- 1% Rare cases	(4,6,14)

Brief Notes: the greatest side effects reported were deaths by acute hepatic failure, with 30-40 deaths reported, and severe cardiac arrhythmias (torsades de points) 15 deaths, including healthy people.

6.) FDA AND EMA REGULATORY ALERTS:

6.1.) Critical Point in 2013: (37 years later):

The fall of systemic use of this drug reached its critical point in July 2013, when both the FDA in United States and the European Medicines Agency (EMA) issued massive health warnings after analyzing decades of pharmacovigilance data (8,15,16).

FDA ordered to modify the product labeling to include its most severe warning: the FAMOUS black box, or (Black Box Warning). This regulatory alert was motivated by the discovery that the KETOCONAZOLE caused LETHAL HEPATIC TOXICITY —even in young and healthy patients without history taking it for banal conditions like fungi in the nails— and because its severe enzymatic inhibition caused fatal drug interactions when combined with other common drugs, triggering untreatable cardiac arrhythmias (8,15,16).

6.2.) FDA BLACK BOX WARNING: "THE BLACK BOX":

What does this mean ?. The black box or black container, is a "LABEL" that the FDA obligates to place on products that have SEVERE WARNINGS regarding their use, cannot be sold freely (OTC), and that there must be strict surveillance over their potential harmful effects, that can even be fatal (8,15).

This regulatory alert was motivated by:

- Lethal hepatic toxicity: even in young and healthy patients without history (8,11).

- Use for banal conditions: (fungi in the nails) (8).

- Severe enzymatic inhibition: causing fatal drug interactions (8,17).

- Untreatable cardiac arrhythmias: when combining with common drugs (7,12).

This fact marked the beginning of the END of systemic or oral use (in tablets) of KETOCONAZOLE, after more than three DECADES (37 years) in the market without these warnings.

7.) MARKET WITHDRAWAL ORAL PRESENTATION (200 and 300 Mg):

7.1.) EMA Action (Drastic Measure):

The 2013 alerts marked the beginning of a gradual withdrawal of oral presentations (capsules and tablets) worldwide. EMA was the most drastic, recommending the immediate and total suspension of commercialization of KETOCONAZOLE oral in all member countries of the European Union that same year (9,16).

7.2.) FDA Action (Less Restrictive):

FDA DID NOT PROHIBIT IT by completely, but removed it as first-line treatment for superficial conditions, restricting its use exclusively as as last resort for patients with the so-called DEEP MYCOSIS and severe endemic that would not tolerate any other drug for their treatment; here stand out: Histoplasmosis, Blastomycosis, Coccidioidomycosis and Paracoccidioidomycosis (8,15).

Following this precedent, health authorities of countries like Australia, and gradually health ministries throughout Latin America, annulled their commercialization permits of the oral route (10,18).

8.) DOCUMENTED FATALITIES:

In the side effects of this molecule we document the main side effects of it, and as we said the use of KETOCONAZOLE via oral, under international pharmacovigilance norms, were reported multiple cases of death among them:

- Between 30 and 40 deaths direct by ACUTE FULMINANT HEPATIC FAILURE, including cases that required urgent liver transplant to save the patient's life (8,9,11).

- Additionally, were documented more than 15 deaths associated with episodes of SEVERE CARDIAC ARRHYTHMIA (torsades de pointes) derived from drug interactions with common drugs like statins, antihistamines and calcium blockers (8,9,12).

- These fatalities occurred even in young and healthy patients without medical history taking KETOCONAZOLE for banal conditions like fungi in the nails, which motivated the most severe warning of the FDA (8).

9.) TOPICAL VERSIONS (WERE NOT SUSPENDED):

It is IMPORTANT to note that the shampoo version (2%), topical creams and vaginal suppositories, remain valid and available without restrictions (10,13). This is explained because the application on skin or scalp has LOW systemic absorption, we would say it is virtually NULL, without entering the bloodstream WITHOUT HEPATIC OR CARDIAC AFFECTATION, conserving excellent local safety profile for head dandruff and seborrheic dermatitis (10,13).

10.) CONCLUSIONS:

In Venezuela it was just in the year 2020, June 02 that the Government through the Ministry of Health ORDERED, the TOTAL SUSPENSION of all presentations of KETAZOL or KETOCONAZOLE, in tablets and capsules ORAL ROUTE, except the presentation in SHAMPOO, CREAM and EGGS vaginal, that is 7 YEARS after it had already been PROHIBITED in all EUROPE (9,16,21).

The KETOCONAZOLE is a sample vivid, of how a medicine is launched to the market with great expectations, and after being tested its deleterious effects in HUMAN HEALTH, Big Pharma does EVERYTHING possible to keep them in the market, and examples like this there are a few.

Saludos a todos.

Dr. José Lapenta.

Dr. José M. Lapenta

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REFERENCIAS BIBLIOGRÁFICAS / BIBLIOGRAPHICAL REFERENCES

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1. Heeres J, Backx LJ, Mostmans JH, Van Cutsem J. Antimycotic imidazoles. Part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent. J Med Chem. 1979;22(8):1003-1005.

2. Dismukes WE, Stamm AM, Graybill JR, et al. Treatment of systemic mycoses with ketoconazole: emphasis on toxicity and clinical response in 52 patients. National Institute of Allergy and Infectious Diseases Collaborative Antifungal Study. Ann Intern Med. 1983;98(1):13-20.

3. Vanden Bossche H, Willemsens G, Cools W, Cornelissen F, Lauwers WF, van Cutsem JM. In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis. Antimicrob Agents Chemother. 1980;17(6):922-928.

4. Pont A, Williams PL, Azhar S, et al. Ketoconazole blocks testosterone synthesis. Arch Intern Med. 1982;142(12):2137-2140.

5. National Institutes of Health (NIH). LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Ketoconazole. [Actualizado en 2018; citado 10 jun 2026].

6. Sonino N. The use of ketoconazole as an inhibitor of steroid production. N Engl J Med. 1987;317(13):812-818.