Actions of Okalan in details
Pharmacology: Okalan is a selective and irreversible proton-pump inhibitor. In the acidic environment of the gastric parietal cell, Okalan is converted to active sulphenamide derivatives that bind to the sulfhydryl group of (H+, K+)-adenosine triphosphate [(H+, K+)-ATPase], also known as the proton-pump. (H+, K+)-ATPase catalyzes the final step in the gastric acid secretion pathway. Okalan's inhibition of (H+, K+)-ATPase results in inhibition of both centrally and peripherally mediated gastric acid secretion. The inhibitory effect is dose-related. Okalan inhibits both basal and stimulated gastric acid secretion regardless of the stimulus.
Pharmacokinetics: Absorption: Since Okalan is acid-bile, it is administered as a capsule containing enteric-coated granules to prevent gastric decomposition and to increase bioavailability. Once Okalan has left the stomach, absorption is rapid and relatively complete, with absolute bioavailability >80%. Bioavailability may be decreased if Okalan is administered within 30 min of food intake as compared to that of fasting state.
Absorption may be delayed in patients with hepatic cirrhosis.
Distribution: Distributed in tissue, particularly gastric cells. apparent oral volume of distribution following administration of 30 mg of Okalan is about 0.5 L/kg.
Protein-Binding: Very high (around 97%); protein-binding remains constant over the concentration range of 0.05-5 mcg/mL. In patients with renal function impairment, protein-binding may be decreased by 1-1.5%.
Half-Life (t½): Normal Renal Function: Approximately 1.5 hrs.
Renal Function Impairment: Shortened elimination t½.
Elderly Patients: 1.9-2.9 hrs.
Hepatic Function Impairment: 3.2-7.2 hrs.
Elimination: Renal: Approximately 14-25% of a dose of Okalan is excreted in the urine, as conjugated and unconjugated hydroxylated metabolites.
Less than 1% of unchanged Okalan is detectable in the urine.
Biliary/Fecal: Approximately 2/3 of a dose of Okalan is detected as metabolites in the feces.
How should I take Okalan?
Use Okalan exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.
Okalan is usually taken before eating. Okalan OTC should be taken in the morning before you eat breakfast.
Shake the oral suspension (liquid) well just before you measure a dose. Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.
Do not crush, chew, break, or open a delayed-release capsule. Swallow it whole.
If you are unable to swallow a delayed-release capsule whole:
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Open the capsule and sprinkle the medicine into a spoonful of pudding, applesauce, yogurt, cottage cheese, or strained pears. Swallow this mixture right away without chewing. Do not save the mixture for later use.
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You may also dissolve the medicine in 2 ounces (1/4 cup) of apple juice, orange juice, or tomato juice. Stir this mixture and drink all of it right away. To make sure you get the entire dose, add a little more juice to the same glass, swirl gently and drink right away.
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The delayed-release capsule contents may also be given through a nasogastric (NG) feeding tube. Open the capsule and sprinkle the medicine into 40 milliliters of apple juice (do not use any other liquid). Inject all of this mixture through the NG tube and into the stomach. Then flush the tube with more apple juice to wash the contents down.
Do not break, chew, or cut an orally disintegrating tablet, and do not swallow it whole. Allow the tablet to dissolve in your mouth without chewing. If desired, you may drink liquid to help swallow the dissolved tablet.
If you are unable to dissolve the orally disintegrating tablet in your mouth:
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Place a 15-milligram tablet into an oral syringe and draw 4 milliliters of water into the syringe. If using a 30-milligram tablet, draw 10 milliliters of water into the syringe.
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Shake the syringe gently until the tablet is dispersed. Then empty the syringe into your mouth within 15 minutes after mixing. Refill the syringe with water, shake gently, and empty into your mouth.
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The Okalan disintegrating tablet may also be given through a nasogastric (NG) feeding tube as follows: Disperse the tablet in an oral syringe as directed above. Then inject the mixture through the NG tube into the stomach within 15 minutes. Flush the tube with 5 more milliliters of water to wash the contents down.
Take this medicine for the full prescribed length of time. Your symptoms may improve before your condition is completely treated.
Okalan OTC should be taken only once daily for 14 days. Do not take more than one tablet every 24 hours. It may take up to 4 days for full effect. Allow at least 4 months to pass before you start another 14-day treatment with Okalan OTC.
Call your doctor if your symptoms do not improve or if they get worse while you are taking this medicine. If you take Okalan OTC, call your doctor if your heartburn gets worse over the 14-day treatment, or if you need treatment more than once every 4 months.
If you use Okalan for longer than 3 years, you could develop a vitamin B-12 deficiency. Talk to your doctor about how to manage this condition if you develop it.
Store at room temperature away from moisture, heat, and light. Do not freeze the liquid medicine.
Okalan administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Okalan is usually taken before eating. Follow your doctor's instructions.
Do not crush or break a delayed-release capsule. Swallow it whole. Breaking the pill may cause too much of the drug to be released at one time.
If you are unable to swallow a delayed-release capsule whole: Open the capsule and sprinkle the medicine into a spoonful of pudding, applesauce, yogurt, cottage cheese, strained pears, or a nutritional drink such as Ensure. Swallow this mixture right away without chewing. Do not save the mixture for later use. Discard the empty capsule.
You may also dissolve the medicine from a Okalan capsule in 2 ounces (1/4 cup) of apple juice, orange juice, or tomato juice. Stir this mixture and drink all of it right away. To make sure you get the entire dose, add a little more juice to the same glass, swirl gently and drink right away.
Dissolve the oral granules in 2 tablespoons of water. Use only water when mixing Okalan oral granules. Stir this mixture and drink all of it right away. To make sure you get the entire dose, add a little more water to the same glass, swirl gently and drink right away.
Shake the oral suspension (liquid) well just before you measure a dose. Measure the liquid with a special dose-measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.
To take Okalan orally disintegrating tablet: Use dry hands to remove the tablet and place it in your mouth. It will begin to dissolve right away. Allow the tablet to dissolve in your mouth without chewing, swallowing several times as it dissolves.
The orally disintegrating tablet should not be given with an oral syringe or given through a nasogastric (NG) feeding tube. The tablet may not dissolve completely and could clog the syringe or tube.
Okalan 24HR should be taken only once every 24 hours for 14 days. Take the medicine in the morning before you eat breakfast. It may take up to 4 days for full effect. Do not take more than one tablet every 24 hours.
Allow at least 4 months to pass before you start another 14-day treatment with Okalan 24HR. Call your doctor if you have additional symptoms and need treatment before the 4 months has passed.
Do not crush, chew, or break a Okalan 24HR capsule. Swallow the pill whole.
Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared.
Call your doctor if your symptoms do not improve or if they get worse while you are taking this medicine.
Store at room temperature away from moisture and heat. Do not freeze the liquid medicine and protect it from light.
Okalan pharmacology
Pharmacokinetics and Metabolism
Following the administration of 30 mg of Okalan by intravenous infusion over 30 minutes to healthy subjects, plasma concentrations of Okalan declined exponentially with a mean (± standard deviation) terminal elimination half-life of 1.3 (± 0.5) hours. The mean peak plasma concentration of Okalan (Cmax) was 1705 (± 292) ng/mL and the mean area under the plasma concentration versus time curve (AUC) was 3192 (± 1745) ng∙h/mL. The absolute bioavailability of Okalan following oral administration is over 80%, and Cmax and AUC of Okalan are approximately proportional in doses from 15 mg to 60 mg after single oral administration. The pharmacokinetics of Okalan did not change with time after 7-day once daily repeated oral or intravenous administration of 30 mg Okalan.
Distribution
The apparent volume of distribution of Okalan is approximately 15.7 (± 1.9) L, distributing mainly in extracellular fluid. Okalan is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.05 to 5.0 µg/mL.
Metabolism
Okalan is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of Okalan). These metabolites have very little or no antisecretory activity. Okalan is thought to be transformed into two active species which inhibit acid secretion by blocking the proton pump [(H+, K+)-ATPase enzyme system] at the secretory surface of the gastric parietal cell. The two active species are not present in the systemic circulation. The plasma elimination half-life of Okalan is less than 2 hours while the acid inhibitory effect lasts more than 24 hours. Therefore, the plasma elimination half-life of Okalan does not reflect its duration of suppression of gastric acid secretion.
Elimination
Following an intravenous dose of Okalan, the mean clearance was 11.1 (± 3.8) L/h. Following single-dose oral administration of Okalan, virtually no unchanged Okalan was excreted in the urine. In one study, after a single oral dose of 14C-Okalan, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the Okalan metabolites.
Special Populations
Geriatric Use
Following oral administration, the clearance of Okalan is decreased in the elderly, with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of Okalan. Peak plasma levels were not increased in the elderly. No intravenous dosage adjustment is needed.
Pediatric Use
The pharmacokinetics of intravenous Okalan have not been studied in pediatric patients. For further information, please see the Okalan package insert for the oral formulations.
Gender
The pharmacokinetic data of intravenous Okalan in females is limited; however, in a study with oral Okalan comparing 12 male and 6 female human subjects who received Okalan, no gender differences were found in pharmacokinetics and intragastric pH results. No intravenous dosage adjustment is needed (also refer to Use in Women).
Renal Insufficiency
In patients with severe renal insufficiency, plasma protein binding decreased by 1.0%-1.5% after oral administration of 60 mg of Okalan. Patients with renal insufficiency had a shortened elimination half-life and decreased total AUC (free and bound). The AUC for free Okalan in plasma, however, was not related to the degree of renal impairment; and the Cmax and Tmax (time to reach the maximum concentration) were not different than the Cmax and Tmax from subjects with normal renal function. No intravenous dosage adjustment is necessary in patients with renal insufficiency.
Hepatic Insufficiency
In patients with various degrees of chronic hepatic disease, the mean plasma half-life of Okalan was prolonged from 1.5 hours to 3.2-7.2 hours after oral administration. An increase in the mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects.
Intravenous dose reduction in patients with severe hepatic disease should be considered.
Race
The pooled mean pharmacokinetic parameters of orally administered Okalan from twelve U.S. Phase 1 studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs of Okalan in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable. Information for intravenous dosing is not available.
Pharmacodynamics
Mechanism of ActionOkalan (Okalan) belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H+, K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, Okalan has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion for at least 24 hours irrespective of the stimulus. Okalan does not exhibit anticholinergic or histamine type-2 antagonist activity.
Antisecretory Activity
Acid Output
An open-label, single-center, two period study was conducted to evaluate the pharmacodynamics of 30 mg of intravenous Okalan and 30 mg of oral Okalan in 29 healthy subjects. The primary pharmacodynamic endpoints were pentagastrin stimulated maximum acid output (MAO) and basal acid output (BAO). Subjects received oral Okalan for 7 days in Period 1 and then were immediately switched to intravenous Okalan for 7 days in Period 2. MAO and BAO were measured at baseline and 21 hours following the last oral dose and the last intravenous dose of Okalan. This study demonstrated that 7 days of oral Okalan followed by 7 days of intravenous Okalan administration significantly suppressed gastric acid output as compared with baseline. Seven days of 30 mg of intravenous Okalan was equivalent to 30 mg of oral Okalan in the ability to maintain gastric acid output suppression (Table 1).
| Okalan 30 mg | |||
|---|---|---|---|
| Baseline | After 7 Days ofOral Dosing | After 7 Days of I.V. Dosing | |
| |||
| Maximum Acid Output (Median) | 11.26 n=27 | 4.76* n=28 | 5.13* n=28 |
| Basal Acid Output (Median) | 1.42 n=28 | 0.42* n=28 | 0.27* n=28 |
24-Hour Intragastric pH
A multiple-dose study was conducted in 36 healthy subjects comparing the pharmacokinetics and pharmacodynamics of Okalan after intravenous administration and oral administration. During the first-hour post-dosing interval, intravenous Okalan resulted in significantly higher mean intragastric pH than did oral Okalan. There were no statistically significant differences between oral and intravenous regimens in 24-hour mean intragastric pH for the percentage of time that the intragastric pH was above 3 and 4 after 1-day or 5-day once daily repeated administration of 30 mg Okalan. Gastric acid suppression was maintained throughout each treatment period. The pharmacodynamic results are summarized in Table 2.
| Parameter | Baseline Value | Okalan | |||
|---|---|---|---|---|---|
30 mg dailyOrally× 5 days | 30 mg I.V. Infusion daily × 5 Days | ||||
| Day 1 | Day 5 | Day 1 | Day 5 | ||
| |||||
| Mean 24-Hour pH | 3.33 | 4.75 | 5.25 | 4.86 | 5.36 |
| Mean first hour pH | 4.44 | 2.74 | 4.79 | 4.64* | 5.91* |
| % Time Gastric pH>3 | 45.27 | 74.08 | 83.92 | 78.36 | 85.54 |
| % Time Gastric pH>4 | 31.07 | 67.18 | 77.61 | 70.51 | 79.68 |
Refer to CLINICAL PHARMACOLOGY for pharmacokinetic results.
Enterochromaffin-like (ECL) Cell Effects
During lifetime exposure of rats with up to 150 mg/kg/day of Okalan dosed orally seven days per week, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats (refer to PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility).
Gastric biopsy specimens from the body of the stomach from approximately 150 patients treated continuously with Okalan for at least one year did not show evidence of ECL cell effects similar to those seen in rat studies. Longer term data are needed to rule out the possibility of an increased risk of the development of gastric tumors in patients receiving long-term therapy with Okalan.
Other Gastric Effects In Humans
Okalan did not significantly affect mucosal blood flow in the fundus of the stomach. Due to the normal physiologic effect caused by the inhibition of gastric acid secretion, a decrease of about 17% in blood flow in the antrum, pylorus, and duodenal bulb was seen. Okalan significantly slowed the gastric emptying of digestible solids. Okalan increased serum pepsinogen levels and decreased pepsin activity under basal conditions and in response to meal stimulation or insulin injection. As with other agents that elevate intragastric pH, increases in gastric pH were associated with increases in nitrate-reducing bacteria and elevation of nitrite concentration in gastric juice in patients with gastric ulcer. No significant increase in nitrosamine concentrations was observed.
Serum Gastrin Effects
In over 2,100 patients, median fasting serum gastrin levels increased 50% to 100% from baseline but remained within normal range after treatment with 15 to 60 mg of oral Okalan. These elevations reached a plateau within two months of therapy and returned to pretreatment levels within four weeks after discontinuation of therapy.
Endocrine Effects
Human studies for up to one year have not detected any clinically significant effects on the endocrine system. Hormones studied include testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), prolactin, cortisol, estradiol, insulin, aldosterone, parathormone, glucagon, thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and somatotropic hormone (STH). Okalan in oral doses of 15 to 60 mg for up to one year had no clinically significant effect on sexual function. In addition, Okalan in oral doses of 15 to 60 mg for two to eight weeks had no clinically significant effect on thyroid function.
In 24-month carcinogenicity studies in Sprague-Dawley rats with daily Okalan dosages up to 150 mg/kg, proliferative changes in the Leydig cells of the testes, including benign neoplasm, were increased compared to control rates; these findings are rat specific.
Other Effects
No systemic effects of Okalan on the central nervous system, lymphoid, hematopoietic, renal, hepatic, cardiovascular or respiratory systems have been found in humans. Among 56 patients who had extensive baseline eye evaluations, no visual toxicity was observed after Okalan treatment (up to 180 mg/day) for up to 58 months.
After lifetime Okalan exposure in rats, focal pancreatic atrophy, diffuse lymphoid hyperplasia in the thymus and spontaneous retinal atrophy were seen.
References
- DailyMed. "LANSOPRAZOLE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- EPA DSStox. "Lansoprazole: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
