Konvomep (Omeprazole and sodium bicarbonate): Uses, Dosage, Side Effects & Warnings

Uses

1 INDICATIONS AND USAGE 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 )

Dosage and administration

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 2.1 Important Administration Instructions
• 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. 2.2 Dosage Regimen 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 2.3 Preparation and Administration 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 46°F) for up to 30 days.

Dosage forms and strengths

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 )

Contraindications

4 CONTRAINDICATIONS 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 )

Warnings and precautions

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 ) 5.1 Presence of Gastric Malignancy 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. 5.2 Acute Tubulointerstitial Nephritis 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 )] . 5.3 Sodium Content 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. 5.4 Clostridium difficile -Associated Diarrhea 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. 5.5 Bone Fracture 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 )] . 5.6 Severe Cutaneous Adverse Reactions 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. 5.7 Cutaneous and Systemic Lupus Erythematosus 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.

Side effects

The following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial Nephritis [see Warnings and Precautions ( 5.2 )] . Clostridium difficile -Associated Diarrhea [see Warnings and Precautions ( 5.4 )] . Bone Fracture [see Warnings and Precautions ( 5.5 )] . Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.6 )] . Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions ( 5.7 )] . Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions ( 5.9 )] . Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions ( 5.10 )] . Fundic Gland Polyps [see Warnings and Precautions ( 5.14 )] . Most common adverse reactions (≥2%) are: headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of KONVOMEP has been established, in part, based on oral studies of an oral delayed-release omeprazole product and another oral omeprazole and sodium bicarbonate product. Clinical Trials with Omeprazole In the U.S. clinical trial population of 465 adult patients, the adverse reactions summarized in Table 2 were reported to occur in 1% or more of patients on therapy with omeprazole. Table 2: Adverse Reactions Occurring in 1% or More of Adult Patients in US Clinical Trials of Omeprazole Therapy Omeprazole % (n = 465) Placebo % (n = 64) Ranitidine % (n = 195) Headache 7 6 8 Diarrhea 3 3 2 Abdominal Pain 2 3 3 Nausea 2 3 4 Upper Respiratory Infection (URI) 2 2 3 Dizziness 2 0 3 Vomiting 2 5 2 Rash 2 0 0 Constipation 1 0 0 Cough 1 0 2 Asthenia 1 2 2 Back Pain 1 0 1 Table 3 summarizes the adverse reactions that occurred in 1% or more of omeprazole-treated patients from international double-blind and open-label clinical trials in which 2631 patients and subjects received omeprazole. Table 3: Adverse Reactions Occurring in 1% or More of Adult Patients in International Clinical Trials of Omeprazole Therapy Omeprazole % (n = 2631) Placebo % (n = 120) Abdominal Pain 5.2 3.3 Nausea 4.0 6.7 Diarrhea 3.7 2.5 Vomiting 3.2 10.0 Headache 2.9 2.5 Flatulence 2.7 5.8 Acid Regurgitation 1.9 3.3 Constipation 1.5 0.8 Asthenia 1.3 0.8 Clinical Trial of Another Omeprazole and Sodium Bicarbonate Product, 40 mg Adverse reactions reported in at least 3% of critically ill adult patients in a clinical trial of 40 mg omeprazole and sodium bicarbonate for oral suspension compared to intravenous cimetidine for up to 14 days are presented in Table 4 . Table 4: Common Adverse Reactions Reported in at least 3% of patients in either treatment group. by Body System and Preferred Term in a Randomized Controlled Trial of Critically Ill Adult Patients Treated up to 14 Days Body System Preferred Term Omeprazole and Sodium Bicarbonate for Oral Suspension, 40 mg (%) (n = 178) Intravenous Cimetidine 1,200 mg per day (%) (n = 181) NOS = Not otherwise specified. Blood and Lymphatic System Disorders Anemia NOS 7.9 7.7 Anemia NOS Aggravated 2.2 3.9 Thrombocytopenia 10.1 6.1 Cardiac Disorders Atrial Fibrillation 6.2 3.9 Bradycardia NOS 3.9 2.8 Supraventricular Tachycardia 3.4 1.1 Tachycardia NOS 3.4 3.3 Ventricular Tachycardia 4.5 3.3 Gastrointestinal Disorders In this trial, clinically significant upper gastrointestinal bleeding was considered a serious adverse reaction, but it is not included in this table. Constipation 4.5 4.4 Diarrhea NOS 3.9 8.3 Gastric Hypomotility 1.7 3.3 General Disorders and Administration Site Conditions Hyperpyrexia 4.5 1.7 Edema NOS 2.8 6.1 Pyrexia 20.2 16.0 Infections and Infestations Candidal Infection NOS 1.7 3.9 Oral Candidiasis 3.9 0.6 Sepsis NOS 5.1 5.0 Urinary Tract Infection 2.2 3.3 Investigations Liver Function Tests NOS Abnormal 1.7 3.3 Metabolism and Nutrition Disorders Fluid Overload 5.1 7.7 Hyperglycemia NOS 10.7 11.6 Hyperkalemia 2.2 3.3 Hypernatremia 1.7 5.0 Hypocalcemia 6.2 5.5 Hypoglycemia NOS 3.4 4.4 Hypokalemia 12.4 13.3 Hypomagnesemia 10.1 9.9 Hyponatremia 3.9 2.8 Hypophosphatemia 6.2 3.9 Psychiatric Disorders Agitation 3.4 8.8 Respiratory, Thoracic, and Mediastinal Disorders Acute Respiratory Distress Syndrome 3.4 3.9 Nosocomial Pneumonia 11.2 9.4 Pneumothorax NOS 0.6 4.4 Respiratory Failure 1.7 3.3 Skin and Subcutaneous Tissue Disorders Decubitus Ulcer 3.4 2.8 Rash NOS 5.6 6.1 Vascular Disorders Hypertension NOS 7.9 3.3 Hypotension NOS 9.6 6.6 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of omeprazole and sodium bicarbonate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Omeprazole Body as a Whole: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, urticaria (see also Skin below), fever, pain, fatigue, malaise, and systemic lupus erythematosus. Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitation, elevated blood pressure, and peripheral edema. Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, flatulence, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, dry mouth, stomatitis, abdominal swelling and fundic gland polyps. Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.

Drug interactions

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 )] .

Use in specific populations

8.1 Pregnancy Risk Summary 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. Data 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.

Pregnancy

8.1 Pregnancy Risk Summary 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. Data 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.

Pediatric use

8.4 Pediatric Use 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.

Geriatric use

8.5 Geriatric Use 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 )] .

Overdosage

If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage. Omeprazole Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth and other adverse reactions similar to those seen in normal clinical experience with the recommended dosage [see Adverse Reactions ( 6 )] . Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was taken alone. No specific antidote for omeprazole overdosage is known. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive. Sodium Bicarbonate Overdosage of sodium bicarbonate can cause electrolyte abnormalities (hypocalcemia, hypokalemia, hypernatremia), metabolic alkalosis and seizures. Institute supportive care and correct electrolyte abnormalities.

Description

(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

Mechanism of action

12.1 Mechanism of Action 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.

How supplied

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.

Patient information

Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Acute Tubulointerstitial Nephritis Advise the patient to call their healthcare provider immediately if they experience signs and/or symptoms associated with acute tubulointerstitial nephritis [see Warnings and Precautions ( 5.2 )] . Sodium Bicarbonate Buffer Content Inform patients on a sodium-restricted diet or patients at risk of developing congestive heart failure of the sodium content of KONVOMEP (526 mg or 22.8 mEq total sodium per 40 mg dose). Advise patients that: chronic use of bicarbonate with calcium or milk can cause milk-alkali syndrome chronic use of sodium bicarbonate may cause systemic alkalosis increased sodium intake can cause swelling and weight gain If any of these occur, instruct patients to contact their healthcare provider [see Warnings and Precautions ( 5.3 )] . Clostridium difficile- Associated Diarrhea Advise the patient to immediately call their healthcare provider if they experience diarrhea that does not improve [see Warnings and Precautions ( 5.4 )] . Bone Fracture Advise the patient to report any fractures, especially of the hip, wrist, or spine, to their healthcare provider [see Warnings and Precautions ( 5.5 )] . Severe Cutaneous Adverse Reactions Advise the patient to immediately call their healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus [see Warnings and Precautions ( 5.6 )] . Cutaneous and Systemic Lupus Erythematosus Advise the patient to immediately call their healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus [see Warnings and Precautions ( 5.7 )] . Cyanocobalamin (Vitamin B-12) Deficiency Advise the patient to report any clinical symptoms that may be associated with cyanocobalamin deficiency to their healthcare provider if they have been receiving KONVOMEP for longer than 3 years [see Warnings and Precautions ( 5.9 )] . Hypomagnesemia and Mineral Metabolism Advise the patient to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, and/or hypokalemia to their healthcare provider, if they have been receiving KONVOMEP for at least 3 months [see Warnings and Precautions ( 5.10 )] . Drug Interactions Advise patients to report to their healthcare provider if they start treatment with rilpivirine-containing products, clopidogrel, St. John’s wort or rifampin, or if they take high-dose methotrexate [see Contraindications ( 4 ) and Warnings and Precautions ( 5.8 , 5.11 and 5.13 )] . Administration Instruct the patient or caregiver to shake the reconstituted suspension well before each use. Advise patients that KONVOMEP may be administered orally, or via a nasogastric or orogastric tube. Instruct patients or caregivers to suspend enteral feeding approximately 3 hours before and 1 hour after administration of KONVOMEP by nasogastric or orogastric tube [see Dosage and Administration ( 2.3 )] . Store reconstituted KONVOMEP suspension in the refrigerator. Discard the reconstituted KONVOMEP suspension after 30 days.

Konvomep NDC products (1)

NDC	Strength & form	Labeler	Type
65628-272	Kit	Azurity Pharmaceuticals, Inc.	NDA

Frequently asked questions

What is Konvomep used for?

1 INDICATIONS AND USAGE 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…

What are the side effects of Konvomep?

The following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial Nephritis [see Warnings and Precautions ( 5.2 )] . Clostridium difficile -Associated Diarrhea [see Warnings and Precautions ( 5.4 )] . Bone Fracture [see Warnings and Precautions ( 5.5 )] . Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.6 )] . Cutaneous and… See the full label for the complete list.

Who makes Konvomep?

Konvomep is listed by 1 labeler in the FDA NDC directory, including Azurity Pharmaceuticals, Inc..