Proton Pump Inhibitors — The Drug You Can’t Stop Taking

The Package Insert series

The Prilosec label indicates the drug for short-term treatment of duodenal ulcer, gastric ulcer, GERD, and erosive esophagitis — four to eight weeks. Efficacy beyond eight weeks “has not been established.” For maintenance of healing, the label adds that controlled studies do not extend beyond 12 months. The drug has been on the US market since 1989. Tens of millions of Americans take it every day, many of them for years.

The Protonix label, in section 5.6 Tumorigenicity, states that pantoprazole was carcinogenic in long-term rodent studies and caused rare gastrointestinal tumors. The relevance to humans, the same section says, is unknown. The Prilosec and Nexium labels report a parallel finding for omeprazole — gastric carcinoid tumors and ECL cell hyperplasia in 24-month rat studies, dose-related, more frequent in females. All three labels describe the class effect: the drugs raise serum gastrin, gastrin drives ECL cell proliferation, and in rodents this proceeds to tumors. The Prilosec label adds that the human studies done so far were of insufficient duration and size to settle the carcinogenicity question. The drug is approved for short-term use. The carcinogenicity question depends on long-term use.

The Prilosec label also states that omeprazole produced “a significant increase in the intragastric concentrations of viable bacteria” — a direct admission that suppressing stomach acid changes which organisms the stomach harbors. The Protonix label warns of B-12 malabsorption with use longer than three years. All three PPI labels carry warnings for hypomagnesemia, bone fracture, atrophic gastritis, fundic gland polyps, interstitial nephritis, and Clostridium difficile-associated diarrhea. None of these warnings appeared on the original 1989 approval. Each was added later.

The Package Insert is a paid subscriber series that reads what the FDA-approved prescribing information says about the most commonly prescribed drugs in the United States. This installment draws on the labels for omeprazole (Prilosec) — the original PPI; pantoprazole (Protonix); esomeprazole (Nexium) — the s-isomer of omeprazole, approved as a separate drug; and famotidine (Pepcid) — the older H2 blocker class that PPIs largely displaced. Lansoprazole (Prevacid) and rabeprazole (Aciphex) are also widely prescribed PPIs in the same class; the findings below are class effects and apply to them as well. If you are currently taking a PPI, considering one, or have a family member on one, this is the installment to start with.

What’s behind the paywall:

• The trap by design. Why PPIs are uniquely difficult to stop, and what the labels say about gastrin, ECL hyperplasia, and acid output when treatment ends.

• The carcinogenicity question the labels do not resolve. Pantoprazole’s tumor findings, omeprazole’s rabbit embryo-lethality, and what “the relevance to humans is unknown” actually means.

• The warnings added after approval. Bone fracture, hypomagnesemia, B-12 deficiency, kidney injury, C. diff — none on the original label. They were added between 2010 and 2014.

• What suppressing 95% of stomach acid for years actually does. Bacterial overgrowth, mineral malabsorption, atrophic gastritis, fundic gland polyps. The mechanism is not in dispute.

• The patent extension nobody mentions. Prilosec’s patent was set to expire in 2001. Nexium — the s-isomer of omeprazole — was approved that same year.

• Drug interactions the patient is rarely told about. Methotrexate, clopidogrel, atazanavir, warfarin, digoxin. The mechanism, in each case, is the one the drug is designed to produce.

• Pregnancy, lactation, and pediatric use. Embryo-lethality in rabbits at clinically relevant doses. Approval for use in 1-year-olds despite the labels’ own admissions about what has not been studied.

• A consolidated 12-question list to take to your doctor.