What Are the Most Common Ketoconazole Side Effects?

Warning: The State Food and Drug Administration issued a notice on June 25, 2015, saying that ketoconazole oral preparations have been discontinued for production and sales due to severe hepatotoxic adverse reactions, and the drug approval number has been revoked; ketoconazole has been marketed orally The preparation was recalled by the manufacturer before July 30. Ketoconazole oral preparations are imidazole antifungals, and tablets and capsules are marketed in China. ^[1]

Warning: The State Food and Drug Administration issued a notice on June 25, 2015, saying that ketoconazole oral preparations have been discontinued for production and sales due to severe hepatotoxic adverse reactions, and the drug approval number has been revoked; ketoconazole has been marketed orally The preparation was recalled by the manufacturer before July 30. Ketoconazole oral preparations are imidazole antifungals, and tablets and capsules are marketed in China. ^[1]

Drug Name

Ketoconazole tablets

Drug type

prescription

Use classification

Azoles

Ketoconazole tablets ingredients

Active ingredient: Ketoconazole Chemical name: 1-Acetyl-4- [4- [2- (2,4-dichlorophenyl) -2- (1H-imidazole-1-methyl) -1,3- Dioxolane-4-methoxy] phenyl] -piperazine chemical structural formula:

Molecular formula: C ₂₆ H ₂₈ Cl ₂ N ₄ O ₄
Molecular weight: 531.44

Ketoconazole Tablet Properties

This product is white to reddish flakes.

Ketoconazole tablets indications

Ketoconazole has the risk of serious liver toxicity, so this product should only be used after considering other effective antifungal treatments and the potential benefits of this product outweigh the potential harm.
This product can only be used for the treatment of skin, hair and mucous membrane infections caused by dermatophytes and / or yeasts. Due to the infection site, area and depth, etc., the local treatment is not effective.
-Dermatomycosis-Tinea versicolor-Furionella folliculitis folliculitis-Skin candidiasis-Chronic cutaneous mucosal candidiasis-Chronic, recurrent vaginal candidiasis treatment system Fungal infection Ketoconazole cannot fully penetrate the central nervous system. Therefore, fungal encephalomyelitis should not be treated with oral ketoconazole.
-Paracoccidiosis-Histoplasmosis-Coccidioidosis-Bacterial disease

Ketoconazole tablets specifications

0.2g

Ketoconazole tablets

Skin, hair, mucous membrane infections and systemic infections caused by dermatophytes and / or yeasts, and local treatment is not effective due to factors such as infection site, area, and depth, and can be treated with this product. This product must be used under the guidance of a doctor. This product should be taken with meals to achieve maximum absorption.
Adult:
Skin, gastrointestinal and deep infections: Oral, 0.2 g (1 tablet) once a day. If necessary, it can be increased to 0.4g (2 tablets) at a time, once a day, or 0.2g (1 tablets) at a time, twice a day.
Vaginal candidiasis: Orally, 0.4g (2 tablets) once a day.
2. Children:
Children weighing 15-30 kg, 0.1 g (half tablet) once, once a day, or as directed by a doctor.
Children over 30 kg are the same as adults.
3. The usual course of treatment with this product is as follows:
Vaginal candidiasis: 5 consecutive days; skin infections caused by dermatophytes: approximately 4 weeks; ringworm variegata: 10 days; oral and skin candidiasis caused by candidiasis: 2-3 weeks; hair infections: 1 -2 months; paracoccidiosis, histoplasmosis, coccidioidosis: usually 3-6 months.
All the above indications should be treated continuously without interruption until clinical indicators or laboratory results show that the fungal infection has been cured. Insufficient treatment time will lead to recurrence of the original infection. In general, the course of treatment with this product should last at least 1 week after the symptoms disappear and the mycological examination is negative. Patients should be discontinued immediately when they develop hepatitis signs and symptoms such as loss of appetite, nausea, vomiting, fatigue, jaundice, abdominal pain, or black urine.
Special population: see [taboo] for patients with liver injury

Ketoconazole tablets adverse reactions

Clinical trials In a multicenter, open-label, multicenter, open-label study of 1361 cases of various superficial and deep fungal infections conducted in multiple countries, 149 (11%) reported adverse events. Regardless of how the researchers evaluate the relevance, the adverse events are summarized below. The most commonly reported adverse events are gastrointestinal reactions such as nausea and vomiting. Adverse events are listed in Table 1.
Table 1: Adverse events in the treatment of 1361 cases of various superficial and deep infections with this product

Post-marketing experience The adverse reactions reported spontaneously after the global listing of this product are listed in Table 2. Adverse reactions are categorized by frequency:
More common (1 / 10);
Common (1 / 100, and <1/10);
Uncommon (1 / 1000, and <1/100);
Rare (1 / 10,000 and <1/1000);
Very rare <1 / 10,000, including individual cases.
The following frequencies are derived from the reporting rate of spontaneous adverse reaction reports and do not reflect the more accurate evaluation results obtained in clinical trials and epidemiological studies.
Table 2. Post-marketing adverse reaction reports

Ketoconazole tablets contraindications

This product is banned in the following situations:
1. Known to be allergic to ketoconazole or any component of this product;
2. Patients with acute and chronic liver disease;
3. As the combination of this product with drugs metabolized by CYP3A4 will increase the plasma concentrations of these drugs, which may lead to prolonged QT interval and individual emergence of torsional VT, therefore this product is prohibited from combination with CYP3A4 substrate: benzpredil , Cisapride, propidamine, dofetilide, astemizole, halofentrazone, levomethalide (levoflavone), mizolastine, pimozide, quinidine, serindole or tefal Nadin
4. As the combination of domperidone may cause the QT interval to be prolonged, this product is prohibited from being combined with domperidone;
5. Prohibition of combined use with triazolam and midazolam oral preparations;
6. Prohibition of combination with HMG-CoA reductase inhibitors metabolized by CYP3A4 enzymes such as simvastatin and lovastatin;
7. Prohibition of combination with ergot alkaloids, such as dihydroergotamine, ergometrine, ergotamine, and ergometrine;
8. Prohibition of use with nisoldipine;
9. Prohibition of combination with eplerenone;
10. Prohibition of use with irinotecan;
11. Prohibition of use with everolimus.

Ketoconazole tablets precautions

Ketoconazole has the risk of serious liver toxicity, so this product should only be used after considering other effective antifungal treatments and the potential benefits of this product outweigh the potential harm.
Except for patients with acute or chronic liver disease, liver function tests should be performed before treatment, and regular inspections should be performed frequently during treatment to monitor the first signs and symptoms that may be caused by liver toxicity.
1. Hepatotoxicity is very rare, including severe cases of liver toxicity that are fatal or require liver transplantation. Some patients have no significant risk factors for liver disease. Cases appear within one month of starting treatment, and some within one week of starting treatment.
Accumulated dose during treatment is a risk factor for severe liver toxicity.
Patients receiving this product should consider liver function monitoring. Patients should be instructed to report to the doctor in a timely manner the signs and symptoms of hepatitis, including loss of appetite, nausea, vomiting, fatigue, abdominal pain or deeper urine. In patients with these symptoms, the drug should be stopped immediately and a liver function test should be performed.
2. Liver function monitoring Patients receiving this product should be monitored for liver function. Except for patients with acute or chronic liver disease, liver function tests should be performed before treatment, and regular inspections should be performed frequently during treatment to monitor the first signs and symptoms that may be caused by liver toxicity. If liver function tests indicate liver damage, medication should be stopped immediately.
Patients with elevated liver enzymes and active liver disease or who have experienced liver toxicity with other drugs should not use this product unless the expected benefit outweighs the risk of liver damage. Liver enzyme levels should be closely monitored during treatment. In the long-term application of this product to treat non-life-threatening diseases, the pros and cons should be weighed before administration.
3. Adrenal function monitoring In healthy subjects taking daily doses of more than 0.4g (including 0.4g), this product was found to reduce the response of cortisone to adrenocorticotropic hormone stimulation. Therefore, patients with adrenal insufficiency, as well as patients under prolonged stress (such as major surgery, intensive care, etc.) and patients who may have reduced adrenal function and symptoms should be monitored for extended treatment. Adrenal function.
4. Gastric acid reduction Patients with reduced gastric acid will affect the absorption of this product. For patients who are using gastric acid neutralizing drugs, these drugs should be taken at least 2 hours after taking this product. For patients without gastric acid, such as some AIDS patients and patients who are taking gastric acid secretion inhibitors (such as H2-receptor blockers and proton pump inhibitors), it is recommended to take them with acidic drinks such as cola.
5. No influence on the ability to drive and use the machine was found.
6. Please keep it out of reach of children.

Ketoconazole tablets for pregnant and lactating women

Pregnant women have limited experience with this product. Animal tests have shown that this product has reproductive toxicity. The potential risks of human use are unknown. Therefore, this product should not be used during pregnancy unless the potential benefits to the mother outweigh the potential risks to the fetus.
Breastfeeding women can excrete this product from breast milk, so breastfeeding women should stop breastfeeding when taking this product.

Ketoconazole tablets for children

Information on the use of this product for children weighing less than 15kg is limited, so it is not recommended for children.

Ketoconazole tablets for elderly

Use with caution in elderly patients.

Ketoconazole tablets drug interactions

1. Drugs that affect the absorption of ketoconazole cause drugs that reduce the patient's stomach acid to reduce the absorption of this product.
2. Drugs affecting ketoconazole metabolism Ketoconazole is mainly metabolized by CYP3A4. Enzyme-inducing drugs, such as rifampicin, rifabutin, carbamazepine, isoniazid, nevirapine, and phenytoin, significantly reduce the bioavailability of ketoconazole and reduce its efficacy. Therefore, it is not recommended to use in combination with strong enzyme inducers.
Ritonavir will increase the bioavailability of ketoconazole, so when the two are combined, the amount of ketoconazole should be reduced.
3. Effect of ketoconazole on metabolism of other drugs Some drugs are metabolized by liver P450 enzymes, especially CYP3A4 family enzymes. Ketoconazole can inhibit the metabolism of these drugs, resulting in enhanced effects (including side effects) and / or prolongation of these drugs including adverse reactions. E.g:
(1) While using this product, the drugs that are prohibited from being combined are:
-As the combination of this product with CYP3A4 substrate will increase the plasma concentration of these drugs, which may lead to the extension of QT interval and the emergence of apex torsional tachycardia, the combination of this product with the following drugs: terfenadine, benzepidi Al, Astemizole, Halofantrine, Levometadol (Levmethadone), Mizolastine, Cisapride, Dofetilide, Quinidine, Pimozide, Amphetamine, Sertindole;
-As the combination of domperidone may cause the QT interval to be prolonged, this product is prohibited from being combined with domperidone;
-Prohibition of combination with triazolam and midazolam oral preparations;
-Prohibition of combination with HMG-CoA reductase inhibitors metabolized by CYP3A4, such as: simvastatin, lovastatin;
-Prohibition of combination with ergot alkaloids, such as dihydroergotamine, ergometrine, ergotamine, and ergotoxine;
-Prohibition of use with nisoldipine;
-Prohibition of use with irinotecan;
-Prohibition of use with everolimus.
(2) The following drugs should be used in combination with oral ketoconazole with caution. If combined, the dose should be reduced if necessary, and the plasma concentration, efficacy or side effects need to be monitored.
-Oral anticoagulants;
-HIV protease inhibitors, such as indinavir, saquinavir;
-Some antitumor drugs, such as vinblastine, busulfan, docetaxel, erlotinib, imatinib;
-Calcium channel blockers metabolized by CYP3A4, such as dihydropyridine and verapamil (possibly);
-Some immunosuppressants: cyclosporin, tacrolimus, rapamycin;
-Some HMG-CoA reductase inhibitors metabolized by CYP3A4, such as atorvastatin;
-Some glucocorticoids, such as budesonide, fluticasone, dexamethasone, methylprednisolone;
-Digoxin (by inhibiting P-glycoprotein);
-Others: carbamazepine, buspirone, alfentanil, fentanyl, sildenafil, alprazolam, cilostazol, brotizolam, intravenous midazolam, quetiathione Ping, reglitinide, rifabutin, methylprednisolone, trimethasone, ibastine, solinacin, reboxetine, tolterodine.
4. Occasional cases have reported that this product has a similar quitting sulphur-like reaction, manifested as facial flushing, rash, peripheral edema, nausea and headache. These symptoms can completely disappear within a few hours.

Ketoconazole tablets overdose

There is no special antidote for this product. If overdose occurs, treatment including supportive care should be used. Within 1 hour after taking the medicine, gastric lavage treatment can be performed, and activated carbon can be given if necessary.

Ketoconazole tablets pharmacology and toxicology

Pharmacological action Ketoconazole is a synthetic imidazole dioxane derivative. It is effective against dermatophytes, yeasts (Candida, Malassezia, Pseudococcus and Cryptococcus), biphasic fungi and some molds. With antibacterial and bactericidal activity. Ketoconazole is less susceptible to Aspergillus, Schenckia sporophytes, certain spore fungi, and Mucor, with the exception of the genus Helminthus.
Ketoconazole exerts antibacterial effects by inhibiting the fungal ergosterol biosynthesis and changing the composition of other lipid compounds in the cell membrane.
Data from clinical pharmacology and drug interaction studies show that oral ketoconazole, 0.2 g once a day for 3-7 days, will lead to a slight extension of the QT interval: The average maximum extension is 6-12 milliseconds, but this slight extension of the QT interval is not clinically significant.
At a therapeutic dose of ketoconazole of 0.2 g per day, a transient decrease in testosterone blood concentrations was observed. Within 24 hours of ketoconazole administration, testosterone concentrations returned to pre-dose levels. Long-term treatment at this dose shows that testosterone concentrations are usually not significantly different compared to the control group.
For healthy subjects taking daily doses above 0.4g (including 0.4g), this product was found to reduce the cortisone response to corticotropin stimulation.
Toxicology studies Ketoconazole has performed a standard set of nonclinical toxicology tests.
A 12-month long-term dog toxicity test showed that ketoconazole had a hepatotoxic effect. This product can significantly increase alkaline phosphatase and degeneration of liver cells. Long-term experiments in 18-month rats documented minor pathological changes in the kidneys, adrenals, and ovaries. In addition, female rats have increased bone fragility. In the above test, the adverse reaction dose (NOAEL) was 10 mg / kg / day.
In reproductive toxicity studies, high concentrations of ketoconazole and maternal toxic doses (not less than 80 mg / kg / day) can impair fertility in female rats, produce embryotoxicity and pupal deformities [oligger (toe) and webs (Toe)]. In rats and rabbits at a dose of 40 mg / kg, ketoconazole was not embryotoxic and teratogenic, and had no effect on fertility. Ketoconazole at any dose below 160 mg / kg has no teratogenic effect on mice.
Ketoconazole is not carcinogenic and genotoxic.
Electrophysiological studies have shown that ketoconazole can inhibit the rapid activation of cells and delay the rectification of potassium currents, prolong the duration of action potentials, and possibly prolong the QT interval.

Ketoconazole tablets pharmacokinetics

Ketoconazole is a binary weak base. The acidic environment helps dissolve and absorb. Take a single dose of ketoconazole 0.2 g with meals. After 1-2 hours, the peak plasma concentration can reach 3.5 g / ml on average.
The plasma protein binding rate of ketoconazole in vitro is about 99%, and it mainly binds to albumin. Ketoconazole can be widely distributed in various tissues, but it is not easy to enter the cerebrospinal fluid.
After metabolism is absorbed through the gastrointestinal tract, ketoconazole is converted to inactive substances. Its main metabolic pathway is the oxidation and degradation of imidazole ring and piperazine ring mediated by liver microenzyme. In addition, there are oxidized -O-dehydrocarbon and aromatic ring hydroxylation. Ketoconazole does not induce its own metabolism.
Excretion During the first 10 hours and the following 8 hours after administration, the half-life of ketoconazole is 2 hours, and its elimination is biphasic.
Ketoconazole is excreted in urine at about 13% of the dose, with 2% to 4% of the original drug. Ketoconazole is mainly excreted through the bile in the gut.

Ketoconazole tablets storage

Store in a dry place at 15-30 ° C.

Ketoconazole Tablets Packaging

Packed in aluminum-plastic board, 10 pcs / board / box.

Ketoconazole Tablets

36 months

Ketoconazole Tablets

WS _1- (X-515) -2003Z