DailyMed Label: Konvomep

DailyMed Label: Konvomep

2023

DailyMed Prescription

Konvomep

omeprazole and sodium bicarbonate

Azurity Pharmaceuticals, Inc.

NDC: 65628-272

NDC: 65628-272

NDC: 65628-272

NDC: 65628-272

KONVOMEP (omeprazole and sodium bicarbonate for oral suspension) is a combination of omeprazole, a PPI, and sodium bicarbonate, an antacid. Omeprazole is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1 H -benzimidazole, a racemic mixture of two enantiomers that inhibits gastric acid secretion. Its empirical formula is C 17 H 19 N 3 O 3 S, with a molecular weight of 345.42. The structural formula is: Omeprazole is a white to off-white crystalline powder which melts with decomposition at about 155°C. It is a weak base, freely soluble in ethanol and methanol, slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of omeprazole is a function of pH; it is rapidly degraded in acid media but has acceptable stability under alkaline conditions. Sodium bicarbonate raises the gastric pH and protects the omeprazole from acid degradation. Sodium bicarbonate is a white crystalline powder. It is soluble in water and insoluble in alcohol. One gram of sodium bicarbonate dissolves in 12 mL of water at 25ºC. The pH of a freshly prepared 0.1 molar aqueous solution is 8.3 at 25ºC. Aqueous solutions slowly convert to sodium carbonate through loss of carbon dioxide. The molecular formula is NaHCO 3 and the molecular weight is 84.01. The structural formula is: KONVOMEP is supplied as a kit. Each kit is comprised of 1 bottle of pre‑weighed omeprazole powder and 1 bottle of pre‑measured strawberry‑flavored diluent to be reconstituted for oral administration. The strawberry‑flavored diluent contains sodium bicarbonate and the following inactive ingredients: benzyl alcohol, carboxymethylcellulose sodium, FD&C Red No. 40, poloxamer 188, purified water, simethicone emulsion, sodium citrate (dihydrate), sorbitol solution, strawberry flavor (natural and artificial flavors, propylene glycol, and glycerin), and sucralose. After reconstitution each mL contains 2 mg omeprazole and 84 mg sodium bicarbonate. Omeprazole Structure Sodium Bicarbonate Structure

KONVOMEP is indicated in adults for: • short-term treatment (4 to 8 weeks) of active benign gastric ulcer. • reduction of risk of upper gastrointestinal (GI) bleeding in critically ill adult patients. KONVOMEP is a combination of omeprazole, a proton pump inhibitor (PPI) and sodium bicarbonate, indicated in adults for: • Treatment of active benign gastric ulcer ( 1 ) • Reduction of risk of upper gastrointestinal (GI) bleeding in critically ill patients ( 1 )

Recommended doses of KONVOMEP in the table below are based upon the omeprazole content. ( 2.2 ) Indication Recommended Adult Dosage ( 2.2 ) Active Benign Gastric Ulcer 40 mg once daily for 4 to 8 weeks Reduction of Risk of Upper GI Bleeding in Critically Ill Patients 40 mg initially followed by 40 mg 6 to 8 hours later and 40 mg once daily thereafter for 14 days • KONVOMEP is a kit of two bottles: one bottle containing omeprazole powder and one bottle of diluent containing sodium bicarbonate. • KONVOMEP is for reconstitution by a healthcare provider for use in adults. • After reconstitution, each mL of KONVOMEP contains 2 mg of omeprazole and 84 mg of sodium bicarbonate. • Take the sodium content of KONVOMEP into consideration when prescribing this product [see Warnings and Precautions ( 5.3 )] . • Recommended doses throughout the labeling are based upon the omeprazole component of KONVOMEP. The recommended dosage regimen in adults of KONVOMEP by indication is summarized in Table 1 . Recommended dosage is based upon the omeprazole content of KONVOMEP. Table 1: Recommended Dosage Regimen of KONVOMEP for Adults by Indication Indication Recommended Dosage Treatment Duration Treatment of Benign Gastric Ulcer 40 mg once daily 4 to 8 weeks Reduction of Risk of Upper GI Bleeding in Critically Ill Patients 40 mg initially; followed by 40 mg 6 to 8 hours later; and 40 mg once daily thereafter 14 days Preparation of Reconstituted Suspension by a Healthcare Provider Prior to Dispensing 1. Hold the neck of the bottle containing the omeprazole powder and tap all four of the bottom edges on a hard surface to loosen the powder. 2. Shake the diluent containing sodium bicarbonate for a few seconds. Open the diluent bottle and transfer about one-third of the contents into the bottle containing omeprazole powder, replace the omeprazole powder cap, and shake the bottle vertically for approximately 30 seconds. 3. Add a second one-third of the diluent into the omeprazole powder bottle and shake the bottle vigorously for approximately 30 seconds. 4. Add the remaining diluent into the omeprazole powder bottle. Allow diluent to drain into the omeprazole powder bottle for 10 seconds and shake the omeprazole bottle vigorously for approximately 30 seconds. 5. The reconstituted suspension contains 40 mg of omeprazole per 20 mL and should be pink to red and hazy. 6. Instruct the patient to shake the reconstituted suspension well before each use. Use an oral dosing device that measures the appropriate volume. Nasogastric or Orogastric Tube Administration (8 French or larger) If KONVOMEP is administered via nasogastric or orogastric tube, suspend enteral feeding approximately 3 hours before and 1 hour after administration of KONVOMEP. 1. Reconstitute KONVOMEP according to the steps for preparation provided above. 2. Use a catheter or oral tip syringe to administer KONVOMEP through the nasogastric or orogastric tube. 3. Shake the bottle well prior to dispensing 20 mL of KONVOMEP into the syringe. 4. Immediately inject the medication through the nasogastric or orogastric tube into the stomach. 5. Refill the syringe with 20 mL of water. 6. Flush any remaining medication from the nasogastric or orogastric tube into the stomach. Storage of Reconstituted Suspension Store the reconstituted KONVOMEP suspension under refrigerated conditions 2°C to 8°C (36°F to 45°F) for up to 30 days.

For Oral Suspension: 2 mg omeprazole and 84 mg sodium bicarbonate per mL of a pink to red hazy, strawberry-flavored liquid after reconstitution in 90 mL, 150 mL, or 300 mL bottles. Each kit contains a bottle of omeprazole as a white to off-white powder and a strawberry-flavored diluent containing sodium bicarbonate as a slightly hazy red liquid [see Description ( 11 ) and How Supplied/Storage and Handling ( 16 )] . For Oral Suspension: 2 mg omeprazole and 84 mg sodium bicarbonate per mL after reconstitution in 90 mL, 150 mL, or 300 mL bottles. ( 3 )

KONVOMEP is contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any components of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.2 )] . Proton pump inhibitors (PPIs), including KONVOMEP, are contraindicated in patients receiving rilpivirine containing products [see Drug Interactions ( 7 )] . • Known hypersensitivity to any components of the formulation ( 4 ) • Patients receiving rilpivirine‑containing products ( 4 , 7 )

• Gastric Malignancy : In adults, symptomatic response does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. ( 5.1 ) • Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients. ( 5.2 ) • Sodium Content : Take sodium content into consideration in patients on a sodium-restricted diet. Avoid in patients with Bartter’s syndrome, hypokalemia, hypocalcemia, and problems with acid-base balance. ( 5.3 ) • Clostridium difficile -Associated Diarrhea : PPI therapy may be associated with increased risk. ( 5.4 ) • Bone Fracture : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. ( 5.5 ) • Severe Cutaneous Adverse Reactions : Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.6 ) • Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue KONVOMEP and refer to specialist for evaluation. ( 5.7 ) • Interaction with Clopidogrel : Avoid concomitant use of KONVOMEP. ( 5.8 ) • Cyanocobalamin (Vitamin B-12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.9 ) • Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs. ( 5.10 ) • Interaction with St. John’s Wort or Rifampin : Avoid concomitant use of KONVOMEP. ( 5.11 , 7 ) • Interactions with Diagnostic Investigations for Neuroendocrine Tumors : Increased Chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors; temporarily stop KONVOMEP at least 14 days before assessing CgA levels. ( 5.12 ) • Interaction with Methotrexate : Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate administration, consider a temporary withdrawal of KONVOMEP. ( 5.13 , 7 ) • Fundic Gland Polyps : Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.14 ) In adults, symptomatic response to therapy with KONVOMEP does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a proton pump inhibitor (PPI). In older patients, also consider an endoscopy. Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue KONVOMEP and evaluate patients with suspected acute TIN [see Contraindications ( 4 )] . Each mL of reconstituted KONVOMEP contains 84 mg of sodium bicarbonate (equivalent to 1 mEq/mL of sodium). The total content of sodium, from active and inactive ingredients per mL of reconstituted KONVOMEP is 26.3 mg (1.14 mEq). Total sodium content per 40 mg dose (volume of 20 mL) of KONVOMEP is 526 mg (22.8 mEq). Chronic administration of bicarbonate with calcium or milk can cause milk-alkali syndrome. Chronic use of sodium bicarbonate may lead to systemic alkalosis, and increased sodium intake can produce edema and weight gain. The sodium content of KONVOMEP should be taken into consideration when administering to patients on a sodium-restricted diet or those at risk for developing congestive heart failure. Avoid KONVOMEP in patients with Bartter’s syndrome, hypokalemia, hypocalcemia, and problems with acid‑base balance. Published observational studies suggest that PPI therapy like KONVOMEP may be associated with an increased risk of Clostridium difficile -associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions ( 6.2 )] . Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines [see Dosage and Administration ( 2.2 ) and Adverse Reactions ( 6.2 )] . Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions ( 6.2 )] . Discontinue KONVOMEP at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematous cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving KONVOMEP, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations. Avoid concomitant use of KONVOMEP with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that interfere with CYP2C19 activity. Concomitant use of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using KONVOMEP, consider alternative antiplatelet therapy [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )] . Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with KONVOMEP. Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions ( 6.2 )] . Consider monitoring magnesium and calcium levels prior to initiation of KONVOMEP and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI. Drugs which induce CYP2C19 or CYP3A4 (such as St. John’s wort or rifampin) can substantially decrease omeprazole concentrations [see Drug Interactions ( 7 )] . Avoid concomitant use of KONVOMEP with St. John’s wort or rifampin. Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop KONVOMEP treatment for at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Drug Interactions ( 7 )] . Literature suggests that concomitant use of PPIs with methotrexate (primarily at high-dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high‑dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions ( 7 )] . PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

The following serious adverse reactions are described below and elsewhere in labeling:

Table 5 and Table 6 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with omeprazole and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 5: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics Antiretrovirals    Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3 )] . • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology ( 12.3 )] . • There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.    Intervention: Rilpivirine-containing products : Concomitant use with KONVOMEP is contraindicated [see Contraindications ( 4 )] . Atazanavir : Avoid concomitant use with KONVOMEP. See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with KONVOMEP. See prescribing information for nelfinavir. Saquinavir : See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals : See prescribing information for specific antiretroviral drugs. Warfarin    Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.    Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. Methotrexate    Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.13 )] .    Intervention: A temporary withdrawal of KONVOMEP may be considered in some patients receiving high‑dose methotrexate. CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam) Clopidogrel    Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3 )] . There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.    Intervention: Avoid concomitant use with KONVOMEP. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.8 )] . Citalopram    Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3 )] .    Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. Cilostazol    Clinical Impact: Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3 )] .    Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. Phenytoin    Clinical Impact: Potential for increased exposure of phenytoin.    Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. Diazepam    Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology ( 12.3 )] .    Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed. Digoxin    Clinical Impact: Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3 )] .    Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)    Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.    Intervention: Mycophenolate mofetil (MMF) : Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving KONVOMEP and MMF. Use KONVOMEP with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3 )] . See the prescribing information for other drugs dependent on gastric pH for absorption. Tacrolimus    Clinical Impact: Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.    Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. Interactions with Investigations of Neuroendocrine Tumors    Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.12 ) and Clinical Pharmacology ( 12.2 )] .    Intervention: Temporarily stop KONVOMEP treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. Interaction with Secretin Stimulation Test    Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.    Intervention: Temporarily stop KONVOMEP treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2 )] . False Positive Urine Tests for THC    Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.    Intervention: An alternative confirmatory method should be considered to verify positive results. Other    Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).    Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with KONVOMEP. Table 6: Clinically Relevant Interactions Affecting Omeprazole when Co-Administered with Other Drugs CYP2C19 or CYP3A4 Inducers    Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3 )] .    Intervention: St. John’s Wort, rifampin : Avoid concomitant use with KONVOMEP [see Warnings and Precautions ( 5.11 )] . Ritonavir-containing products : see prescribing information for specific drugs. CYP2C19 or CYP3A4 Inhibitors    Clinical Impact: Increased exposure of omeprazole  [see Clinical Pharmacology ( 12.3 )] .    Intervention: Voriconazole : Dosage adjustment of KONVOMEP is not usually required. See full prescribing information for voriconazole. See Full Prescribing Information for a list of clinically important drug interactions. ( 7 )

There are no adequate and well-controlled studies with KONVOMEP in pregnant women. KONVOMEP contains omeprazole and sodium bicarbonate. Omeprazole There are no adequate and well-controlled studies with omeprazole in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use ( see Data ). Reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 3.4 to 34 times an oral human dose of 40-mg (based on a body surface area for a 60‑kg person). Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole (an enantiomer of omeprazole) magnesium in rats and rabbits during organogenesis with doses about 68‑times and 42‑times, respectively, an oral human dose of 40‑mg esomeprazole or 40 mg omeprazole (based on body surface area for a 60‑kg person). Changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34-times an oral human dose of 40‑mg esomeprazole or 40‑mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age ( see Data ). Sodium Bicarbonate Available data with sodium bicarbonate use in pregnant women have not identified a drug associated risk of major birth defects or miscarriage. Published animal studies report that sodium bicarbonate administered to rats, mice or rabbits during pregnancy did not cause adverse developmental effects in offspring. The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Human Data There are no adequate and well-controlled studies with KONVOMEP in pregnant women. Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H 2 ‑receptor antagonists or other controls. A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Register, covering approximately 99% of pregnancies, from 1995 to 99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in‑utero to omeprazole that had any malformation, low birth weight, low Apgar score or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole‑exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 1996 to 2009 reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837,317 live births whose mothers did not use any PPI. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any PPI during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H 2 ‑blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H 2 ‑blocker, or were unexposed was 3.6%, 5.5%, and 4.1%, respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single-dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data Omeprazole Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) during organogenesis did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis), administered prior to mating through the lactation period. Esomeprazole The data described below was generated from studies using esomeprazole, an enantiomer of omeprazole. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole. No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg of esomeprazole or 40 mg omeprazole on a body surface area basis) administered during organogenesis. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development were performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg of esomeprazole or 40 mg omeprazole on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg/kg/day (about 17 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses of esomeprazole magnesium equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). Effects on maternal bone were observed in pregnant and lactating rats in a pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). When rats were dosed from gestational Day 7 through weaning on postnatal Day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses of esomeprazole magnesium equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal Day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational Day 7 or gestational Day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age. Available data from the published literature suggest both components of KONVOMEP, omeprazole and sodium bicarbonate, are present in human milk. There are no clinical data on the effects of omeprazole or sodium bicarbonate on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KONVOMEP and any potential adverse effects on the breastfed infant from KONVOMEP or from the underlying maternal condition. Safety and effectiveness of KONVOMEP have not been established in pediatric patients. Juvenile Animal Data Esomeprazole, an enantiomer of omeprazole, was shown to decrease body weight, body weight gain, femur weight, femur length, and overall growth at oral doses about 34 to 68 times a daily human dose of 40 mg esomeprazole or 40 mg omeprazole based on body surface area in a juvenile rat toxicity study. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole. A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about 17 to 68 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal Day 7 through postnatal Day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole. Omeprazole was administered to over 2000 elderly individuals (65 years of age or older) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies with buffered omeprazole have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young subjects). The plasma half-life averaged one hour, about twice that in nonelderly, healthy subjects taking omeprazole. However, no dosage adjustment is necessary in the elderly [see Clinical Pharmacology ( 12.3 )] .

How Supplied KONVOMEP (omeprazole and sodium bicarbonate for oral suspension) 2 mg/84 mg per mL is supplied as: A kit containing two bottles: • one bottle with child resistant closure of omeprazole USP, a white to off-white powder and • one bottle of pre‑measured strawberry‑flavored slightly hazy red diluent containing sodium bicarbonate (see table below). Prior to dispensing, reconstitute KONVOMEP for oral suspension [see Dosage and Administration ( 2.3 )] . Final Volume of KONVOMEP after reconstitution Kit Contents NDC Numbers 90 mL Bottle of 0.18 g omeprazole powder 65628-270-03 Bottle of diluent containing sodium bicarbonate 7.56 g per 90 mL 65628-271-03 Konvomep Kit 65628-272-03 150 mL Bottle of 0.3 g omeprazole powder 65628-270-05 Bottle of diluent containing sodium bicarbonate 12.6 g per 150 mL 65628-271-05 Konvomep Kit 65628-272-05 300 mL Bottle of 0.6 g omeprazole powder 65628-270-10 Bottle of diluent containing sodium bicarbonate 25.2 g per 300 mL 65628-271-10 Konvomep Kit 65628-272-10 Storage • Store KONVOMEP kit in the refrigerator, 2°C to 8°C (36°F to 46°F). • Store reconstituted suspension of KONVOMEP in the refrigerator, 2°C to 8°C (36°F to 46°F); discard unused reconstituted suspension after 30 days. • Keep containers tightly closed. • Protect containers from light. • Protect containers from freezing.

Omeprazole 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 gastric mucosa, omeprazole 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 acid secretion irrespective of the stimulus. Antisecretory Activity Results from a pharmacokinetic/pharmacodynamic (PK/PD) study of the antisecretory effect of repeated once‑daily dosing of 40 mg omeprazole and 1,680 mg sodium bicarbonate for oral suspension in healthy subjects are shown in Table 7 . Table 7: Effect of Omeprazole and Sodium Bicarbonate on Intragastric pH, Day 7 Parameter Once Daily Dosage of Omeprazole and Sodium Bicarbonate 40 mg Omeprazole and 1680 mg Sodium Bicarbonate (n = 24) Note: Values represent medians. All parameters were measured over a 24-hour period. % Decrease from Baseline for Integrated Gastric Acidity (mmol•hr/L) 84%    Coefficient of Variation 20% % Time Gastric pH > 4 (Hours) 77% (18.6 hours)    Coefficient of Variation 27% Median pH 5.2    Coefficient of Variation 17% The antisecretory effect lasts longer than would be expected from the very short (1 hour) plasma half-life, apparently due to irreversible binding to the parietal H+/K+ ATPase enzyme. Enterochromaffin-like (ECL) Cell Effects Human gastric biopsy specimens have been obtained from more than 3000 patients treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients. These studies are of insufficient duration and size to rule out the possible influence of long-term administration of omeprazole on the development of any premalignant or malignant conditions. Serum Gastrin Effects In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once‑daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy. Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.12 )] . Other Effects Systemic effects of omeprazole in the Central Nervous System (CNS), cardiovascular, and respiratory systems have not been found to date. Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of omeprazole 90 mg. In healthy subjects, a single intravenous dose of omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans. However, when intragastric pH is maintained at 4.0 or above, basal pepsin output is low, and pepsin activity is decreased. As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment. The course of Barrett’s esophagus in 106 patients was evaluated in a U.S. double-blind controlled study of omeprazole 40 mg twice daily for 12 months followed by 20 mg twice daily for 12 months or ranitidine 300 mg twice daily for 24 months. No clinically significant impact on Barrett’s mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during antisecretory therapy, complete elimination of Barrett’s mucosa was not achieved. No significant difference was observed between treatment groups in development of dysplasia in Barrett’s mucosa, and no patient developed esophageal carcinoma during treatment. No significant differences between treatment groups were observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm in diameter. Absorption The bioavailability and pharmacokinetics of KONVOMEP was assessed in 57 healthy male and female volunteers following a 40 mg dose under fasted conditions.  The absorption of omeprazole was rapid with a median time to peak plasma concentration of 0.33 hour (range 0.17 to 1.3 hr.).  The mean peak plasma concentration (SD) was 1250 ng/mL (470) and the AUC (0-inf) (SD) was 1640 h*ng/mL (1050). Omeprazole is a time-dependent autoinhibitor of CYP2C19. The bioavailability of omeprazole from omeprazole and sodium bicarbonate for oral suspension increases upon repeated administration. Following repeated once-daily dosing of omeprazole at a dose of 40 mg with sodium bicarbonate, a higher omeprazole mean C max (1.4-fold on Day 7) and increased AUC (2-fold on Day 7) were observed. The increase in mean steady-state AUC (on Day 7) for omeprazole at a dose of 40 mg was greater than dose proportional relative to a lower dose. When omeprazole and sodium bicarbonate for oral suspension 40 mg was administered in a two-dose loading regimen, the omeprazole AUC 0-inf (ng•hr/mL) was 1665 after Dose 1 and 3356 after Dose 2, while T max was approximately 30 minutes for both Dose 1 and Dose 2. When omeprazole and sodium bicarbonate for oral suspension 40 mg is administered one hour after a meal, the omeprazole AUC is reduced by approximately 27% and 22%, respectively, relative to administration one hour prior to a meal [see Dosage and Administration ( 2.3 )] . Distribution Omeprazole is bound to plasma proteins. Protein binding is approximately 95%. Elimination Metabolism Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system. The major part of its metabolism is dependent on the polymorphically expressed CYP2C19 [see Clinical Pharmacology ( 12.5 )] , responsible for the formation of hydroxyomeprazole, the major metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone. The mean plasma omeprazole half-life following administration of omeprazole/sodium bicarbonate oral suspension in healthy subjects is approximately 1 hour (range 0.4 to 4.2 hours), and the total body clearance is 500 to 600 mL/min. Excretion Following single-dose oral administration of a buffered solution of omeprazole, the majority of the dose (about 77%) is eliminated in urine as at least six metabolites. Two metabolites have been identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma – the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity. Special Populations Geriatric Patients The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered solution) was administered to healthy elderly subjects versus 58% in young subjects given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole, and no unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min (about half that of young subjects), and its plasma half-life averaged one hour, similar to that of young healthy subjects. Male and Female Patients There are no known differences in the absorption or excretion of omeprazole between males and females. Racial or Ethnic Groups [see Clinical Pharmacology ( 12.5 )] . Patients with Renal Impairment In patients with chronic renal impairment (creatinine clearance ranged between 10 and 62 mL/min/1.73 m 2 ), the disposition of omeprazole was very similar to that in healthy subjects, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. This increase in bioavailability is not considered to be clinically meaningful. Patients with Hepatic Impairment In patients with chronic hepatic disease classified as Child-Pugh Class A (n=3), B (n=4) and C (n=1), the bioavailability of omeprazole increased to approximately 100% compared to healthy subjects, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared to the mean half-life of 0.5 to 1 hour in healthy subjects. Plasma clearance averaged 70 mL/min, compared to a value of 500 to 600 mL/min in healthy subjects. Drug Interactions Studies Effect of Omeprazole on Other Drugs Omeprazole is a time-dependent inhibitor of CYP2C19 and can increase the systemic exposure of co‑administered drugs that are CYP2C19 substrates. In addition, administration of omeprazole increases intragastric pH and can alter the systemic exposure of certain drugs that exhibit pH-dependent solubility [see Drug Interactions ( 7 )] . Antiretrovirals For some antiretroviral drugs, such as rilpivirine, atazanavir and nelfinavir, decreased serum concentrations have been reported when given together with omeprazole [see Drug Interactions ( 7 )] . Rilpivirine: Following multiple doses of rilpivirine (150 mg, daily) and omeprazole (20 mg, daily), AUC was decreased by 40%, C max by 40%, and C min by 33% for rilpivirine. Nelfinavir: Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, C max by 37% and 89% and C min by 39% and 75% respectively for nelfinavir and M8. Atazanavir: Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, C max by 96%, and C min by 95%. Saquinavir: Following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. AUC was increased by 82%, C max by 75%, and C min by 106%. The mechanism behind this interaction is not fully elucidated. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with omeprazole. Clopidogrel In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when coadministered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period. In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole, but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction [see Warnings and Precautions ( 5.8 ), Drug Interactions ( 7 )] . Mycophenolate Mofetil Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a crossover study resulted in a 52% reduction in the C max and 23% reduction in the AUC of MPA [see Drug Interactions ( 7 )] . Cilostazol Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C max and AUC of cilostazol by 18% and 26% respectively. The C max and AUC of one of the active metabolites, 3,4-dihydro-cilostazol, which has 4 to 7 times the activity of cilostazol, were increased by 29% and 69%, respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and the above‑mentioned active metabolite [see Drug Interactions ( 7 )] . Diazepam Concomitant administration of omeprazole 20 mg once daily and diazepam 0.1 mg/kg given intravenously resulted in 27% decrease in clearance and 36% increase in diazepam half-life [see Drug Interactions ( 7 )] . Digoxin Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects) [see Drug Interactions ( 7 )] . Effect of Other Drugs on Omeprazole Voriconazole Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by 200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state C max and AUC 0-24 of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole [see Drug Interactions ( 7 )] . CYP2C19, a polymorphic enzyme, is involved in the metabolism of omeprazole. The CYP2C19*1 allele is fully functional while the CYP2C19*2 and *3 alleles are nonfunctional. There are other alleles associated with no or reduced enzymatic function. Patients carrying two fully functional alleles are extensive metabolizers and those carrying two loss-of-function alleles are poor metabolizers. In extensive metabolizers, omeprazole is primarily metabolized by CYP2C19. The systemic exposure to omeprazole varies with a patient’s metabolism status: poor metabolizers > intermediate metabolizers > extensive metabolizers. Approximately 3% of Caucasians and 15 to 20% of Asians are CYP2C19 poor metabolizers. In pharmacokinetic studies of single 20 mg omeprazole dose, the AUC of omeprazole in Asian subjects was approximately four-fold of that in Caucasians.

In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (approximately 0.4 to 34.2 times the human dose of 40 mg/day on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (approximately 3.36 times the human dose of 40 mg/day on a body surface area basis) for one year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment‑related ECL cell hyperplasia was observed at the end of one year (94% treated versus 10% controls). By the second year the difference between treated and control rats was much smaller (46% versus 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat, no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2 and 16 mg/kg/day (about 0.1 to 3.9 times the human dose of 40 mg/day on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague Dawley rats, no astrocytomas were found in males and females at the high dose of 140.8 mg/kg/day (about 34 times the human dose of 40 mg/day on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive. Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay and an in vivo rat liver DNA damage assay. In a 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H 2 -receptor antagonists. Omeprazole at oral doses up to 138 mg/kg/day (about 33.6 times the human dose of 40 mg/day on a body surface area basis) was found to have no effect on the fertility and general reproductive performance in rats.

The effectiveness of KONVOMEP has been established, in part, based on studies of an oral delayed-release omeprazole product for the treatment of active benign gastric ulcer. In a U.S. multicenter, double-blind study of two doses of omeprazole and placebo in 520 patients with endoscopically diagnosed gastric ulcer, the following results were obtained with 40 mg omeprazole and placebo. (see Table 8 .) Table 8: Treatment of Gastric Ulcer % of Patients Healed % of Patients Healed Omeprazole 40 mg once daily (n = 214) Placebo (n = 104) Week 4 55.6 p < 0.01 omeprazole 40 mg versus placebo 30.8 Week 8 82.7 48.1 For the stratified groups of patients with ulcer size less than or equal to 1 cm, no difference in healing rates between 40 mg and the lower omeprazole dosage was detected at either 4 or 8 weeks. For patients with ulcer size greater than 1 cm, 40 mg omeprazole was significantly more effective than the lower omeprazole dosage at 8 weeks. In a foreign, multinational, double-blind study of 602 patients with endoscopically diagnosed gastric ulcer, two doses of omeprazole and ranitidine 150 mg twice a day were evaluated. The following results were obtained with 40 mg omeprazole and ranitidine (see Table 9 ). Table 9: Treatment of Gastric Ulcer % of Patients Healed % of Patients Healed Omeprazole 40 mg once daily (n = 187) Ranitidine 150 mg twice daily (n = 199) Week 4 78.1 p < 0.01 omeprazole 40 mg versus ranitidine 56.3 Week 8 91.4 78.4 The effectiveness of KONVOMEP has been established, in part, based on studies of another omeprazole and sodium bicarbonate oral suspension product for the reduction of risk of upper GI bleeding in critically ill adult patients. A double-blind, multicenter, randomized, non-inferiority clinical trial was conducted to compare omeprazole and sodium bicarbonate oral suspension 40 mg/1680 mg and intravenous cimetidine for the reduction of risk of upper gastrointestinal (GI) bleeding in critically ill patients (mean APACHE II score = 23.7). The primary endpoint was significant upper GI bleeding defined as bright red blood which did not clear after adjustment of the nasogastric tube and a 5 to 10 minutes lavage, or persistent Gastroccult positive coffee grounds for 8 consecutive hours which did not clear with 100 mL lavage. Omeprazole and sodium bicarbonate oral suspension was administered as two doses of 40 mg omeprazole and 1680 mg sodium bicarbonate 6 to 8 hours apart on the first day via orogastric or nasogastric tube, followed by 40 mg omeprazole and 1680 mg sodium bicarbonate once daily thereafter. Cimetidine was administered intravenously as a 300 mg bolus, followed by 50 to 100 mg/hour continuously thereafter. Treatment was administered for up to 14 days (mean = 6.8 days). A total of 359 patients were studied, age range 16 to 91 years (mean age of 56 years), 58.5% were males, and 64% were Caucasians. The results of the study showed that omeprazole and sodium bicarbonate oral suspension was non-inferior to intravenous cimetidine, 7/178 (3.9%) patients in the omeprazole and sodium bicarbonate oral suspension group vs. 10/181 (5.5%) patients in the cimetidine group experienced clinically significant upper GI bleeding.

Carton Label NDC 65628-272-10 Rx Only KONVOMEP ® (omeprazole and sodium bicarbonate for oral suspension) 2 mg/84 mg per mL* *300 mL final volume. When reconstituted, each mL contains 2 mg omeprazole, USP, and 84 mg sodium bicarbonate, USP. EACH KIT INCLUDES: • One bottle containing 0.6 g omeprazole powder • One bottle containing 25.2 g sodium bicarbonate in 300 mL strawberry-flavored Diluent • One Full Prescribing Information • One Medication Guide Shake well before each use IMPORTANT NOTE TO PHARMACIST: Must Reconstitute before dispensing azurity ® pharmaceuticls Dispense Medication Guide to each patient. 300 mL final volume after reconstitution Principal Display Panel – Carton Label