1. INTRODUCTION

Prilosec OTC^® (omeprazole 20 mg as omeprazole magnesium 20.6 mg) has been approved by the U.S. Food and Drug Administration as an over-the-counter (OTC) medication for the treatment of frequent heartburn, defined as heartburn occurring two or more days a week. With Prilosec OTC, healthcare professionals have an OTC therapeutic option to recommend to adult patients who have frequent heartburn symptoms.

In the past, management options for self-treating consumers have included antacids and H₂-receptor antagonists (H₂RAs). However, with Prilosec OTC, consumers have access to a proton pump inhibitor (PPI), a long-lasting treatment option for controlling frequent heartburn symptoms—one dose a day works for up to 24 hours as part of a 14-day course of therapy. This section gives an overview about frequent heartburn sufferers and their treatment habits.

1.1 Characterization of Frequent Heartburn

Heartburn is described as a sensation of mid-chest discomfort moving up to the throat and neck, accompanied by a burning or painful feeling under the sternum. A 2003 survey showed that in the United States, about 65% of the total adult population experiences heartburn, with heartburn occurring daily in about 15 million adults.^1a

Slightly more women (59%) than men report frequent heartburn.^1a,2 The mean age for a consumer with frequent heartburn is 45 to 50 years,^1a and heartburn has a slight tendency to increase with age.² Geographic location, marital status, family status (children), education level, job type and level, and socioeconomic status all play a role in the tendency to develop heartburn.³

Figure 1 shows the frequency of all heartburn episodes in a 2003 survey of a representative adult heartburn population.^1a

Figure 1. Frequency of heartburn in the U.S. heartburn population^1a

Consumers with frequent heartburn reported having a long history of heartburn symptoms.

The majority of consumers with frequent heartburn have discussed their symptoms with healthcare professionals. Most consumers with frequent heartburn (62%) have reported their symptoms to their primary care physician; 16% and 2%, respectively, have seen gastroenterologists or cardiologists; and 30% have consulted with pharmacists.^1a

1.2 OTC Heartburn Medications

Most consumers with frequent heartburn self-diagnose and self-treat using available OTC medications. In a 2001 survey, about 80% of individuals with frequent heartburn reported using OTC heartburn medications.^1a

In this study, more than 70% of frequent heartburn sufferers considered their symptoms moderate to severe, and most frequent heartburn sufferers reported medicating at the first sign of symptoms to prevent them from getting worse or to relieve them. In general, consumers with frequent heartburn reported managing their heartburn by using antacids alone or in combination with OTC H₂RAs, or prescription PPIs.^1a

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2. DESCRIPTION

Prilosec OTC is supplied in 14-tablet, 28-tablet, and 42-tablet sizes. These sizes contain one, two, and three 14-day courses of treatment, respectively. Prilosec OTC is a pink-colored (salmon) tablet consisting of multiple enteric-coated pellets formulated with 20.6 mg of omeprazole magnesium, equivalent to 20 mg of omeprazole. The active ingredient is the magnesium salt of omeprazole, which allows tableting. Currently, this tablet formulation is marketed as an OTC product in Sweden and as a prescription product in more than 30 other countries.^1a

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3. COMPOSITION

3.1 Active Ingredient

The active ingredient in Prilosec OTC delayed-release tablets is omeprazole magnesium; its chemical name is di-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole magnesium. Omeprazole magnesium has a molecular weight of 713.1. Its structural formula is shown in Figure 2.⁴

Omeprazole magnesium is a crystalline substance that is freely soluble in methanol and slightly soluble in water. Omeprazole magnesium dissociates rapidly in water to form omeprazole and magnesium.⁴

Figure 2. Chemical structure of omeprazole magnesium⁴

3.2 Inactive Ingredients

Glyceryl monostearate, hydroxypropyl cellulose, hypromellose, iron oxide, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, paraffin, polyethylene glycol 6000, polysorbate 80, polyvinylpyrrolidone, sodium stearyl fumarate, starch, sucrose, talc, titanium dioxide, triethyl citrate⁵

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4. CLINICAL PHARMACOLOGY

4.1 Mechanism of Action

Omeprazole belongs to the class of drugs known as substituted benzimidazoles.⁶ Omeprazole binds irreversibly with the proton pump (H+/K+-ATPase enzyme system) at the secretory surface of the gastric parietal cell.^6-8 The binding inhibits or suppresses the ability of the parietal cell to secrete gastric acid (Figure 3).

Figure 3. Mechanism of action of omeprazole⁴

4.2 Inhibition of Gastric Acid Secretion

Reflux of gastric acid into the esophagus is the major cause of heartburn symptoms. Omeprazole inhibits both basal and stimulated acid secretion from the parietal cell, irrespective of the stimulus. At 24 hours, acid secretion by gastric parietal cells is about 50% of maximal with a single dose. When omeprazole is discontinued, the ability to secrete gastric acid returns gradually within days, as new proton pumps are generated.⁴

Pharmacodynamic data demonstrated that omeprazole 20 mg daily provides a pronounced and consistent inhibition of gastric acid secretion over 24 hours.⁴ The magnitude and consistency of this effect was significantly better for 20 mg vs. 10 mg daily doses of omeprazole. Figure 4 illustrates the superior and more consistent antisecretory effects of omeprazole administered at 20 mg or higher doses.⁹ It also shows that a daily dose of omeprazole 20 mg produces a markedly stronger and more consistent inhibition than the lower doses but not a complete blockade of gastric acid secretion over the 24-hour dosing interval.

Figure 4. Inhibitory effects of one week of treatment with daily doses of omeprazole on 24-hour intragastric acid secretion⁹

4.3 Pharmacokinetics

Bioavailability

A study involving 29 healthy U.S. subjects demonstrated that the bioavailability of Prilosec OTC tablets is similar to that of the commercially available 20 mg prescription Prilosec (omeprazole) capsules (see Figure 5).⁴ The subjects were administered the treatment product as a morning single dose under fasting conditions. The study was a randomized, open-label, crossover study with a five-day washout period between treatments. The tablet formulation is marketed in Sweden as an OTC product and in more than 30 other countries as a prescription product.^1a

Figure 5. Mean plasma concentration of omeprazole vs. time: subjects with evaluable pharmacokinetic data (n = 29)⁴

Absorption, Distribution, and Metabolism

Because the pellets that contain omeprazole magnesium in Prilosec OTC tablets are enteric coated, the tablets should not be split, as this would disturb the coating. Because of the enteric coating, absorption begins only after the pellets have entered the duodenum. This is important because exposure to the acidic environment of the stomach before entering the systemic circulation would cause degradation in the omeprazole molecule that might limit its ultimate effectiveness. Once omeprazole magnesium dissolves in this near-neutral environment of the duodenum, the omeprazole ion converts to its neutral form. The same form of omeprazole is available for absorption regardless of whether it is administered as the free form, omeprazole, or the salt, omeprazole magnesium.¹⁰ Absorption is rapid, with peak plasma levels (C_max) of omeprazole occurring within 0.5 to 3.5 hours following oral administration.⁴ In healthy adult subjects, the plasma half-life (t_1/2) is 0.5 to 1.0 hours, and the total body clearance is 500 to 600 mL/min. The duration of action of omeprazole is more than 24 hours following a single dose, since parietal cells turn over in about three to five days. Protein binding is approximately 95%. The inhibition of acid secretion is related to the area under the plasma concentration-time curve but not to the actual plasma concentration at any given time.

Omeprazole is completely metabolized in the liver by cytochrome P450 isoenzymes. At least six metabolites are formed, which have little or no antisecretory activity. Omeprazole metabolites are removed primarily in the urine and secondarily in feces.⁴

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5. CLINICAL EFFICACY STUDIES

Two well-controlled clinical studies involving 3,120 subjects support the use of a consecutive 14-day therapeutic regimen of omeprazole magnesium to treat frequent heartburn. Both studies were multicenter, double-blind, randomized, parallel, and placebo-controlled. Each study evaluated 10 mg and 20 mg doses of omeprazole magnesium for 14 consecutive days in subjects with heartburn two or more days a week.^1a

The studies had a one-week placebo run-in phase to assess heartburn frequency. Eligible subjects were randomized into a two-week double-blind treatment phase to receive a single daily dose of either omeprazole magnesium 10 mg, omeprazole magnesium 20 mg, or placebo every day. Subjects took their daily dose of study medication each morning before breakfast.^1a

The primary efficacy end point was "no heartburn over the previous 24 hours" (i.e., completely heartburn free for a full day). Efficacy was evaluated following the first dose of medication, on the last dose, and over 14 days of dosing during the double-blind phase.^1a

A number of secondary efficacy end points were also studied following the first dose of medication and subsequent doses. These included "complete prevention of nocturnal heartburn" and "occurrence of no more than mild heartburn."^1b

5.1 Primary Efficacy End Point Results (Heartburn Free for 24 Hours)

Both clinical studies showed that 20 mg of omeprazole magnesium resulted in a significant treatment effect during the first day. As shown in Figure 6, almost 50% of the subjects in the 20 mg omeprazole magnesium treatment groups were heartburn free for the full day after the first dose vs. approximately 32% of subjects in the placebo group (Figure 6).^1a

Figure 6. Percentage of subjects with no heartburn for 24 hours—Day 1^1a

On Day 14, the percentage of subjects reporting complete heartburn relief was more than 70% (Figure 7).^1a

Figure 7. Percentage of subjects with no heartburn for 24 hours—time course over 14 days^1a

5.2 Secondary Efficacy End Point Results (No Nocturnal Heartburn and No More Than Mild Heartburn)

In general, the results for these end points corroborated the findings for the primary end points.^1a

When subjects with only mild heartburn were added to the efficacy end point, more than 80% of those receiving omeprazole magnesium reported a significant therapeutic benefit on Day 1 (Figure 8).^1a

Figure 8. Percentage of subjects with no more than mild heartburn—Day 1^1a

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6. OTC LABEL COMPREHENSION AND COMPLIANCE

6.1 Compliance Study Results

Consumer behavior and understanding of the use of Prilosec OTC were evaluated in label-comprehension studies and an actual-use trial. This program of studies established the compliance with label directions and use of the product in an unsupervised setting. More specifically, the program was developed to determine whether consumers understood: 1) the population for which Prilosec OTC was best suited (self-selection based on frequency of heartburn and understanding of label warning language); 2) when and how to take Prilosec OTC (one tablet per day, 14 consecutive days); and 3) when to contact a healthcare professional (in response to specific warning language or when frequent heartburn returns). The actual-use study determined adherence to the label directions under conditions of actual use.^1a

The results of these studies strongly support the appropriate use of Prilosec OTC by the consumer with frequent heartburn and support the ability of the consumer to correctly use the product within the proposed OTC label directions (Figure 9).^1a

Figure 9. Dosing compliance^1a

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7. INDICATION AND USAGE

Prilosec OTC 20 mg tablets are indicated for the treatment of frequent heartburn, which is defined as heartburn occurring two or more days a week. The label for Prilosec OTC gives the following directions for appropriate use by consumers with frequent heartburn⁵:

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8. SAFETY

8.1 Contraindications

Prilosec OTC is contraindicated for those who are hypersensitive to omeprazole. Consumers who have certain medical conditions and/or symptoms are instructed by the label to either not use the product or to consult a doctor.⁵

8.2 Drug Interactions

The potential metabolic drug interactions with omeprazole (metabolized primarily by hepatic cytochrome P450 isoenzyme CYP2C19) have been systematically studied, especially with respect to warfarin, diazepam, digoxin, and clopidogrel.⁴

FDA Health Advisory Issued

Learn why new data recommends avoiding the combination of Prilosec OTC (omeprazole) and Plavix^® (clopidogrel).

While clinically significant interactions between warfarin or digoxin and omeprazole are unlikely, the narrower therapeutic window for these drugs led to the conservative precaution of listing them on the label for Prilosec OTC.⁴

Warfarin

Post-marketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and omeprazole therapy. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with PPIs and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Diazepam

Coadministration with diazepam was also listed in the Warnings section because omeprazole significantly reduces diazepam clearance, although the relatively wide therapeutic window for diazepam makes it unlikely that this effect of omeprazole is clinically significant.⁴

Antiretroviral Agents

Concomitant administration of omeprazole has been reported to affect the plasma levels of antiretroviral agents, thus appropriate clinical monitoring is recommended.

Tacrolimus

Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus.

Drugs with pH-Dependent Absorption

As with other PPIs and H₂RAs, omeprazole increases intragastric pH (decreases acidity), which can affect the absorption of drugs that have pH-dependent absorption, e.g., ketoconazole or itraconazole. A study demonstrated that ketoconazole absorption was greatly decreased after administration of omeprazole. Similarly, another study showed that itraconazole absorption was decreased if administered after a two-week regimen of omeprazole.⁴

Therefore, the label for Prilosec OTC lists potential drug interactions with warfarin, prescription antifungals/anti-yeast drugs, diazepam, and digoxin under the Warnings section.⁵

8.3 Special Populations

Use in Pregnancy and Lactation: The label for Prilosec OTC directs pregnant or lactating women to consult a physician before use.⁵

Use in Children: Prilosec OTC is indicated for the treatment of frequent heartburn for those aged 18 years or older. For children younger than 18 years with frequent heartburn, the label instructs consulting a physician before using.⁵

8.4 Adverse Events

Doctors have prescribed omeprazole to millions of patients to treat acid-related conditions safely.⁷

The safety of omeprazole was confirmed in 15 new OTC clinical trials with omeprazole magnesium (n > 18,000). The most common adverse events were headache and diarrhea, consistent with those in clinical trials and post-marketing surveillance for prescription Prilosec. Prilosec OTC had a similar tolerability profile to placebo.^1a

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9. AVAILABILITY AND STORAGE

Prilosec OTC tablets in a 20 mg dose are provided in blister packs. Prilosec OTC is available OTC in three different sizes⁵:

9.1 Storage Conditions

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10. REFERENCES

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