Drug-Induced Gallstones (Cholelithiasis)

The gallbladder is a small organ located under the liver on the right side of the body. It stores bile, a fluid that is produced by the liver, until it is released into the intestines to help in the digestion of dietary fat.

Gallstones — stones in the gallbladder (a condition known as cholelithiasis) — affect at least 10% of adult Americans.[1] Although 80% of individuals with gallstones are asymptomatic, the remaining 20% eventually develop complications caused by gallstones obstructing the ducts (tubes) that drain bile from the gallbladder. The most common of these complications is acute cholecystitis (inflammation of the gallbladder), which often requires removal of the gallbladder (cholecystectomy).

The main risk factors for developing gallstones are genetic factors, female sex, increased age, rapid weight loss, obesity, pregnancy and prolonged fasting.[2]

In addition, several drugs can induce cholelithiasis as an adverse effect in adults and children. We discuss this condition, the major drugs implicated in it and what you can do about it.

Mechanisms of drug-induced cholelithiasis

Certain drugs promote gallstone formation in various ways.[3] For example, some drugs precipitate in the gallbladder, forming gallstones.

Other drugs change the composition of bile, leading to cholesterol gallstones. Drugs also can reduce gallbladder contraction, resulting in bile stagnation and gallstone development.

For many drugs, however, it is not known how they induce cholelithiasis, and their involvement can only be confirmed by chemical analysis of gallstones.[4]

Commonly implicated drugs

Certain anti-infective and acromegaly (a condition caused by abnormally high levels of growth hormone in adults) drugs as well as hormone-therapy and certain lipid-lowering drugs top the list of medications that can induce cholelithiasis (see Table, below, for a list of these drugs and others).

Anti-infective drugs

Use of the injectable cephalosporin antibiotic ceftriaxone (available in generic only) is associated with sludge (a suspension of mucus, cholesterol crystals and calcium salts in the gallbladder) formation, even in children.[5],[6],[7] This effect is reversible after the drug is discontinued. When ceftriaxone is taken at high doses for prolonged periods (three weeks or longer), it can cause gallstones.[8]

The antifungal drug voriconazole (VFEND) can cause cholelithiasis between the first and sixth months of therapy.[9] Furthermore, certain antiviral drugs for HIV infection, mainly atazanavir (EVOTAZ, REYATAZ), can trigger the formation of gallstones.[10]

Certain acromegaly drugs

Somatostatin analogues, most of which are given by injection, are primarily used to treat acromegaly. Use of these medications, including lanreotide (SOMATULINE DEPOT) and octreotide (MYCAPSSA, SANDOSTATIN), is a cause of gallstones.[11],[12]

Another somatostatin analogue, pasireotide, causes gallstones in up to 33% of users[13],[14] and is available in two brand-name formulations: SIGNIFOR (used to treat Cushing’s disease, a condition involving an excess of the adrenal gland hormone cortisol in the blood) and SIGNIFOR LAR (used to treat acromegaly and Cushing’s disease).

Estrogen and progesterone therapy

Long-term use of oral estrogen, progesterone or their combinations in postmenopausal women increases the risk of gallstones and gallbladder disease requiring surgery, but this risk appears to be highest with estrogen-only therapy.[15],[16],[17]

Oral contraceptives appear to be implicated in gallstones mainly in women younger than 40 years, with those taking high-dose estrogen-containing products (such as those containing more than 50 micrograms of ethinyl estradiol) having the highest added risk.[18],[19] Notably, most currently available oral contraceptives contain low-dose estrogen and do not carry such risk.

Lipid-lowering drugs

Gallstones have been reported with use of fibrates, medications that mainly reduce the production of triglycerides in the liver.[20] Examples of these drugs include fenofibrate (ANTARA, FENOGLIDE, LIPOFEN, TRICOR, TRIGLIDE, TRILIPIX)[21] and gemfibrozil (LOPID).[22]

Among other lipid-lowering drugs, only ezetimibe (NEXLIZET, ROSZET, VYTORIN, ZETIA), which inhibits the absorption of cholesterol from the intestines, carries a risk of gallstone formation.[23]

Other drugs

The antiplatelet drug dipyridamole (AGGRENOX, PERSANTINE)[24] and glucagon-like peptide analogues — including liraglutide (SAXENDA, VICTOZA) — which are used to treat type 2 diabetes or obesity,[25] increase the risk of gallstones.

Other drugs commonly associated with gallstones include deferasirox (EXJADE, JADENU, JADENU SPRINKLE), an iron chelator that is used to treat patients with too much iron in their bodies due to repeated blood transfusions; febuxostat (ULORIC), a uric-acid–lowering drug for treating gout; and teduglutide (GATTEX), which is used in patients with short bowel syndrome.[26]

Examples of Drugs That Can Cause Gallstones

†Combination product that contains one or more other active ingredients
*Designated as Limited Use by Worst Pills, Best Pills News
**Designated as Do Not Use Except After Heart Valve Replacement by Worst Pills, Best Pills News
***Designated as Do Not Use by Worst Pills, Best Pills News

What You Can Do

Before you take any drug discussed in this article, ask your doctor about the risk of gallstones. If treatment with a drug that can cause gallstones is necessary, your doctor may order an ultrasound before you start taking it and periodically thereafter to monitor your gallbladder. Your doctor also may give you a lower dose of the drug if you are at high risk of developing gallstones.

If you experience symptoms related to gallstones (including episodes of severe pain in the right upper abdomen, usually at night or following a high-fat meal, along with nausea and vomiting), ask your doctor to consider whether it could be drug-related.

If your doctor suspects that one of your medications may be causing gallstones, they will likely discontinue that drug — which may lead to resolution of the gallstones[27] — and monitor your condition. Do not stop any medication you are taking without consulting your doctor.

Report all serious adverse events related to drug-induced gallstones to the FDA’s MedWatch adverse event reporting program by visiting http://www.fda.gov/MedWatch or by calling 800-FDA-1088.
 

References

[1] Gallaher JR, Charles A. Acute cholecystitis: A review. JAMA. 2022;327(10):965-975.

[2] Afdhal NH, Zakko SF. Gallstones: Epidemiology, risk factors and prevention. UpToDate. September 30, 2020.

[3] Drug-induced cholelithiasis. Prescrire Int. 2019;28(201):42-44.

[4] Alušík Š, Paluch Z. Drug-induced cholelithiasis. Curr Rev Clin Exp Pharmacol. 2021;16(4):300-305.

[5] Alušík Š, Paluch Z. Drug-induced cholelithiasis. Curr Rev Clin Exp Pharmacol. 2021;16(4):300-305.

[6] Afdhal NH, Zakko SF. Gallstones: Epidemiology, risk factors and prevention. UpToDate. September 30, 2021.

[7] Gallaher JR, Charles A. Acute cholecystitis: A review. JAMA. 2022;327(10):965-975.

[8] Afdhal NH, Zakko SF. Gallstones: Epidemiology, risk factors and prevention. UpToDate. September 30, 2021.

[9] Alušík Š, Paluch Z. Drug-induced cholelithiasis. Curr Rev Clin Exp Pharmacol. 2021;16(4):300-305.

[10] Ibid.

[11] Ipsen Biopharmaceuticals, Inc. Label: lanreotide (SOMATULINE DEPOT). April 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022074s024lbl.pdf. Accessed April 7, 2022.

[12] Chiasma, Inc. Label: octreotide (MYCAPSSA). June 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208232s000lbl.pdf. Accessed April 7, 2022.

[13] Novartis Pharmaceuticals Corporation. Label: pasireotide (SIGNIFOR). January 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/200677s006lbl.pdf. Accessed April 7, 2022.

[14] Recordati Rare Diseases Inc. Label: pasireotide (SIGNIFOR LAR KIT). June 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203255s008lbl.pdf. Accessed April 7, 2022.

[15] Alušík Š, Paluch Z. Drug-induced cholelithiasis. Curr Rev Clin Exp Pharmacol. 2021;16(4):300-305.

[16] Martin KA, Barbieri RL. Menopausal hormone therapy: Benefits and risks. UpToDate. August 31, 2020.

[17] Marjoribanks J, Farquhar C, Roberts H, et al. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2017;1(1):CD004143.

[18] Afdhal NH, Zakko SF. Gallstones: Epidemiology, risk factors and prevention. UpToDate. September 30, 2020.

[19] Drug-induced cholelithiasis. Prescrire Int. 2019;28(201):42-44.

[20] Afdhal NH, Zakko SF. Gallstones: Epidemiology, risk factors and prevention. UpToDate. September 30, 2020.

[21] Lupin Pharmaceuticals, Inc. Label: fenofibrate (ANTARA). June 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021695s022lbl.pdf . Accessed April 7, 2022.

[22] Pfizer Inc. Label: gemfibrozil (LOPID). December 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/018422s059lbl.pdf. Accessed April 7, 2022.

[23] Drug-induced cholelithiasis. Prescrire Int. 2019;28(201):42-44.

[24] Ibid.

[25] Alušík Š, Paluch Z. Drug-induced cholelithiasis. Curr Rev Clin Exp Pharmacol. 2021;16(4):300-305.

[26] Drug-induced cholelithiasis. Prescrire Int. 2019;28(201):42-44.

[27] Drug-induced cholelithiasis. Prescrire Int. 2019;28(201):42-44.