Milena Miljkovic ([email protected]):

In selection of antibiotics, along with their efficacy and harm, antibiotic resistance should be also taken into consideration, as well as seriousness of an infection to be treated. In serious otitis media, oral cefixime (a third generation cephalosporin) is recommended in combination with clindamycin (a lincosamide antibiotic), but as a second-line therapy after treatment failure with initial antibiotics. It is known that cefixime may causes hepatic enzyme increased (frequency is uncommon) and also hepatitis or jaundice (frequency is very rare). Clindamycin may also cause jaundice and abnormalities in liver function (frequency is also very rare). However, if an infection is serious and treatment with oral cefixime in combination with clindamycin is medically justified, liver enzymes should be monitored during this treatment to minimize the risk of liver injury (for example, by reducing the dose of clindamycin if liver enzymes increase ≥5 times of ULN).

I concur with what Milena said. Additionally, I would also look at the patient's underlying medical/medication history- any history of alcohol use, hepatitis, use of other hepatotoxic agents? These can further complicate the picture if there is an increase in LFTs. Limiting the use of acetaminophen to less than 3-4 grams/day (in all of its combined forms if it is being used in multiple medication combinations) may also be helpful in preventing drug-induced liver injury.

I fully agree with Donna.

Milena M Miljkovic Where did you get this info. from ( It is known that cefixime may causes hepatic enzyme increased (frequency is uncommon) and also hepatitis or jaundice (frequency is very rare). Clindamycin may also cause jaundice and abnormalities in liver function (frequency is also very rare) ) ? Livertox or other resource that can help me identify the frequency of ADR?

Milena Miljkovic ([email protected]):

Cefixime and clindamycin have been used for many years in clinical practice so the source document for health -care professionals to see their safety profiles should be last version of the product information, such as Summary of Product Characteristics (SmPC) and United States Prescribing Information (USPI). USPIs can be find at DailyMed website (https://dailymed.nlm.nih.gov/dailymed/), while SmPCs at eMC website (https://www.medicines.org.uk/emc) or at Irish Drug Agency (HPRA) website (https://www.hpra.ie/homepage/medicines/medicines-information/find-a-medicine), or other regulatory authority websites. Adverse reactions are presented in section 4.8 of the SmPC, per System Organ Class and per frequency category (these categories are explained at the beginning of section 4.8 Undesirable effects). Please, see the SmPC for Clindamycin 150mg/ml soluton for injection at website: https://www.medicines.org.uk/emc/product/3350. However, for Cefixim, there is no data on frequency of hepatic events neither in the SmPC nor in the USPI, but it is well-known that hepatic injury (drug-induced liver injury - DILI) is very rare, while ALT, AST, ALP elevations occur more often (but mostly as temporary events). Although all medicines approved by regulatory authorities are accompanied by prescribing information and adverse liver reactions are often mentioned as a part of the prescribing information, it is not always clear whether this is related to enzyme elevations and/or clinically apparent liver injury.

Milena M Miljkovic Dr.Donna wrote an article explaining that as Pharmacists we should use other resources like Livertox when it comes to assessing medication effect on the liver (I agree with regard to adverse events on other organ systems but the liver?) because she said there is variation among standard drug compendia.

Reference of the image:

https://www.uspharmacist.com/article/druginduced-liver-injury-an-overview

Thank you for quoting my paper. While I am advising to routinely consult LiverTox for information on drug-induced liver disease, I don’t preclude also consulting other sources. As with all published information, there can be lag times in dissemination of information.

It’s interesting because this is the actual disclaimer on LiverTox

Information presented in the LiverTox database is derived from the scientific literature and public databases and reflects professional expertise of the authors.  Such information does not represent official policy of the U.S. Government or any agency thereof.  The information in LiverTox is not meant as a substitute for FDA approved product labeling and professional judgment in the diagnosis and treatment of drug induced liver injury.  The U.S. Government and its individual agencies, including the NIDDK, NLM and NIH, does not warrant or assume any legal responsibility for the accuracy, completeness, or usefulness of the information contained on this Site.

So when assessing the medication effect on the liver, how should I proceed? Check Livertox first or SmPC & USPI? I already check the latter resources for adverse events on the rest of organ systems but my Q is asking with regard to the hepatic adverse events? I saw inconsistency among different references with regard to severity and frequency and management.

Milena Miljkovic ([email protected])

Many pharmacists, physicians, and scientists use LiverTox, due to valuable information and especially due to listed references (scientific publications). However, it is recommended to use approved SmPC or USPI (last approved version) in everyday clinical practice, due to specific clinical and other data relevant for the treatment of patients (such as approved therapeutic indications, contraindications, warnings and precautions, interactions with other medicines, adverse reactions, etc). USPIs and SmPCs are approved by the regulatory authority (FDA, and EMA, respectively), based on submitted dossiers for marketing authorization, but later these documents can be change based on new scientific knowledge (e.g., new adverse reactions are added based on sufficient evidences on their causal association with specific medicinal product/group of products). These changes in SmPC and USPI of medicines are also approved by the corresponding regulatory authority.

Dr.Milena, in your opinion how can I go about evaluating hepatic adverse reactions? Just check the frequency and if it is common, read more?

Milena Miljkovic ([email protected]):

If you would like to evaluate whether the combination cefixime + clindamycin or any other treatment will be safe for your patient (in terms of hepatotoxicity), you have to know whether any hepatic disorder is included in the patient's ongoing/recent medical history, as well as whether any drug that can cause liver injury is included in the patient's concomitant medications. You may use this combination or any other potentially hepatotoxic medicine only if it is medically justified (i.e., if the benefits expected from the use of such combination of medicines or single medicine significantly outweigh potential risks for the individual patient, in the approved indication), along with the liver enzymes monitoring (to minimize the risk of liver injury), as I have already mentioned in my first answer.

Thanks Dr.Milena!

LiverTox’s Disclaimer also states that the database is not meant as a substitute for FDA approved product labeling and professional judgment in the diagnosis and treatment of drug induced liver injury.  However, the information included in prescribing information may be observational without establishment of causality. LiverTox and other databases reference assimilate and evaluate the information and attempt, in many case, to try to establish causality.

The LiverTox database was last updated 11-1-18. Having said that, in the US at least a half-dozen drugs have been approved since 1/1/19. https://www.centerwatch.com/drug-information/fda-approved-drugs/

I agree with previous comments, that LiverTox is a great resource for information on DILI, but that LiverTox does not claims to answer all questions.

Still it is a very good starting point.

When it comes to the question if any drug is safe to use, DILI is unlikely to occur, usually only in the range of 1 in 1000 or fewer people (Exceptions are ie Isoniazid [INH] where monitoring is recommended).

If a patient had a DILI reaction in the past to a certain medication, I would avoid such medication, unless clinically absolutely necessary due to lack of alternative therapies.