Ketoconazole Molecular Structure

Answer

You are correct that ketoconazole is available both in oral (e.g. tablets) and topical (e.g. cream, shampoo, foam, gel, etc...) dosage forms.

Topical forms of ketoconazole are far more commonly prescribed than oral ones, but it still is given orally for certain conditions, like fungal infections that haven't responded to other treatments.

Oral ketoconazole is rarely prescribed for three main reasons:

  • It is a very strong inhibitor of the metabolizing enzyme CYP3A4 and seriously interacts with a number of medications
  • It can cause liver toxicity
  • It can cause adrenal insufficiency and inhibit the endogenous production of several hormones

I'll touch briefly on these three points below but it is first important to point out that these side effects are only a concern when taking ketoconazole by mouth, not when used topically.


Drug Interactions

CYP3A4 is one of the significant drug-metabolizing enzymes in our body, responsible for processing at least 30-50% of all prescribed drugs.

Inhibition of metabolizing enzymes (especially CYP3A4) is a major mechanism behind drug interactions.

Ketoconazole has been confirmed to be a strong inhibitor of CYP3A4.

If it is taken with another drug that is a substrate for CYP3A4 (i.e. is also metabolized by CYP3A4), concentrations of that drug in our body can be increased to dangerous levels, increasing the risk of side effects and toxicity.

Ketoconazole is actually contraindicated (i.e. should not be used) with a number of drugs due to this interaction. This includes:

  • Several 'statin' drugs, such as lovastatin and simvastatin. Taking ketoconazole with these increases the risk of rhabdomyolysis.
  • Several different benzodiazepines, such as alprazolam, triazolam, and midazolam. Combining ketoconazole with these can significantly increase the risk of central nervous system depression.

This is only a small sampling of potential drug interactions with ketoconazole. Since it interacts with just so many drugs, it isn't often used.

Liver Toxicity

Ketoconazole can not be used in those with liver disease since it has been reported to cause liver toxicity.

In fact, if you are prescribed ketoconazole, it is strongly recommended to have liver tests done before taking the drug. Per the prescribing information for ketoconazole:

At baseline, obtain laboratory tests (such as SGGT, alkaline phosphatase, ALT, AST, total bilirubin (TBL), Prothrombin Time (PT), International Normalization Ratio (INR), and testing for viral hepatitides). Patients should be advised against alcohol consumption while on treatment. If possible, use of other potentially hepatotoxic drugs should be avoided in patients receiving NIZORAL® Tablets.

Adrenal Insufficiency

Ketoconazole inhibits our body's production of several hormones with long term use, including testosterone and cortisol. This, obviously, can lead to many problems.


Topical Absorption

I've spent a good portion of this answer discussing all the dangers of oral ketoconazole, and of course, the potential side effects are a bit scary.

However, when it comes to topical dosage forms, there is much less concern since it is not well absorbed through the skin.

In fact, systemic exposure (i.e. the amount of drug that gets into the bloodstream) for ketoconazole is hundreds of times lower with topical administration versus taking it by mouth.

The prescribing information for one ketoconazole topical product, Xolegel, states the following:

The plasma levels from an oral dose of 200 mg ketoconazole taken with a meal are approximately 250 times higher than the resulting plasma levels of ketoconazole following topical application of XOLEGEL.

The side effects of using ketoconazole topically are generally limited to mild skin reactions, including:

  • Burning
  • Redness
  • Itching
  • Dryness

In your question, you stated that you were prescribed ketoconazole 2% cream. As long as you use it as directed, it should be fairly well tolerated and you needn't be concerned with all of the potential side effects of oral ketoconazole.

In terms of whether or not there are other topical antifungal options, there certainly are, but the choice of a particular drug depends on many factors including what you are treating, the cost of drug and ease of administration.

Topical ketoconazole is a perfectly fine and safe drug to use for many conditions, but if you are concerned with this choice, be sure to discuss it with your doctor.


Summary

  • Oral ketoconazole has a number of potentially dangerous side effects (e.g. liver toxicity) and is associated with numerous drug interactions. Due to these issues, it isn't commonly prescribed.
  • Topical ketoconazole, such as in a cream or gel form, is not well absorbed through the skin and is not associated with the serious side effects or interactions as oral ketoconazole products are.

  • References
    1. Nizoral Prescribing Information. AccessFDA
    2. XOLEGEL® Prescribing Information. AccessFDA
    3. Basic Review of the Cytochrome P450 System. PubMed