"The U.S. Food and Drug Administration today approved the first generic versions of Aciphex (rabeprazole sodium) delayed-release tablets, used to treat gastroesophageal reflux disease (GERD) in adults and adolescents (ages 12 and up).
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 clinical practice.
In the U.S. clinical trial population of 465 patients, the adverse reactions summarized in Table 2 were reported to occur in 1% or more of patients on therapy with omeprazole. Numbers in parentheses indicate percentages of the adverse reactions considered by investigators as possibly, probably or definitely related to the drug.
Table 2: Adverse Reactions Occurring In 1% or More of
Patients on Omeprazole Therapy
(n = 465)
(n = 64)
(n = 195)
|Headache||6.9 (2.4)||6.3||7.7 (2.6)|
|Diarrhea||3.0 (1.9)||3.1 (1.6)||2.1 (0.5)|
|Abdominal Pain||2.4 (0.4)||3.1||2.1|
|Nausea||2.2 (0.9)||3.1||4.1 (0.5)|
|Dizziness||1.5 (0.6)||0.0||2.6 (1.0)|
|Vomiting||1.5 (0.4)||4.7||1.5 (0.5)|
|Asthenia||1.1 (0.2)||1.6 (1.6)||1.5 (1.0)|
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 2,631 patients and subjects received omeprazole.
Table 3: Incidence of
Adverse Reactions ≥ 1% Causal Relationship not Assessed
(n = 2631)
(n = 120)
|Body as a Whole, site unspecified|
A controlled clinical trial was conducted in 359 critically ill patients, comparing ZEGERID 40 mg/1680 mg suspension once daily to I.V. cimetidine 1200 mg/day for up to 14 days. The incidence and total number of AEs experienced by ≥ 3% of patients in either group are presented in Table 4 by body system and preferred term.
Table 4: Number (%) of Critically Ill Patients with Frequently
Occurring ( ≥ 3%) Adverse Events by Body System and Preferred Term
|MedDRA Body System Preferred Term||All AEs n (%)||All AEs n (%)|
|BLOOD AND LYMPHATIC SYSTEM DISORDERS|
|Anemia NOS||14 (7.9)||14 (7.7)|
|Anemia NOS Aggravated||4 (2.2)||7(3.9)|
|Thrombocytopenia||18 (10.1)||11 (6.1)|
|Atrial Fibrillation||11 (6.2)||7(3.9)|
|Bradycardia NOS||7 (3.9)||5 (2.8)|
|Supraventricular Tachycardia||6 (3.4)||2 (1.1)|
|Tachycardia NOS||6 (3.4)||6 (3.3)|
|Ventricular Tachycardia||8 (4.5)||6 (3.3)|
|GASTROINTESTINAL DISORDERS *|
|Constipation||8 (4.5)||8 (4.4)|
|Diarrhea NOS||7 (3.9)||15 (8.3)|
|Gastric Hypomotility||3 (1.7)||6 (3.3)|
|GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS|
|Hyperpyrexia||8 (4.5)||3 (1.7)|
|Edema NOS||5 (2.8)||11 (6.1)|
|Pyrexia||36 (20.2)||29 (16.0)|
|INFECTIONS AND INFESTATIONS|
|Candidal Infection NOS||3 (1.7)||7(3.9)|
|Oral Candidiasis||7(3.9)||1 (0.6)|
|Sepsis NOS||9 (5.1)||9 (5.0)|
|Urinary Tract Infection NOS||4 (2.2)||6 (3.3)|
|Liver Function Tests NOS Abnormal||3 (1.7)||6 (3.3)|
|METABOLISM AND NUTRITION DISORDERS|
|Fluid Overload||9 (5.1)||14 (7.7)|
|Hyperglycaemia NOS||19 (10.7)||21 (11.6)|
|Hyperkalaemia||4 (2.2)||6 (3.3)|
|Hypernatraemia||3 (1.7)||9 (5.0)|
|Hypocalcaemia||11 (6.2)||10 (5.5)|
|Hypoglycaemia NOS||6 (3.4)||8 (4.4)|
|Hypokalaemia||22 (12.4)||24 (13.3)|
|Hypomagnesaemia||18 (10.1)||18 (9.9)|
|Hyponatraemia||7 (3.9)||5 (2.8)|
|Agitation||6 (3.4)||16 (8.8)|
|RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS|
|Acute Respiratory Distress Syndrome||6 (3.4)||7(3.9)|
|Nosocomial Pneumonia||20 (11.2)||17 (9.4)|
|Pneumothorax NOS||1 (0.6)||8 (4.4)|
|Respiratory Failure||3 (1.7)||6 (3.3)|
|SKIN AND SUBCUTANEOUS TISSUE DISORDERS|
|Decubitus Ulcer||6 (3.4)||5 (2.8)|
|Rash NOS||10 (5.6)||11 (6.1)|
|Hypertension NOS||14 (7.9)||6 (3.3)|
|Hypotension NOS||17 (9.6)||12 (6.6)|
|* Clinically significant upper gastrointestinal bleeding was considered a serious adverse event but it is not included in this table. NOS = Not otherwise specified.|
The following adverse reactions have been identified during post-approval use of omeprazole. Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure.
Body as a Whole: Hypersensitivity reactions, including anaphylaxis anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria (see also Skin below), fever, pain, fatigue, malaise.
Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, flatulence, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, dry mouth, stomatitis and abdominal swelling. During treatment with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued. 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.
Hepatic: Mild and, rarely, marked elevations of liver function tests [ALT (SGPT), AST (SGOT), γ-glutamyl transpeptidase, alkaline phosphatase, and bilirubin (jaundice)]. In rare instances, overt liver disease has occurred, including hepatocellular, cholestatic, or mixed hepatitis, liver necrosis (some fatal), hepatic failure (some fatal), and hepatic encephalopathy.
Infections and Infestations: Clostridium difficile associated diarrhea.
Musculoskeletal: Muscle cramps, myalgia, muscle weakness, joint pain, bone fracture, and leg pain.
Nervous System/Psychiatric: Psychic disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, tremors, apathy, somnolence, anxiety, dream abnormalities; vertigo; paresthesia; and hemifacial dysesthesia.
Skin: Severe generalized skin reactions including toxic epidermal necrolysis (TEN; some fatal), Stevens-Johnson syndrome, and erythema multiforme (some severe); purpura and/or petechiae (some with rechallenge); skin inflammation, urticaria, angioedema, pruritus, photosensitivity, alopecia, dry skin, and hyperhidrosis.
Special Senses: Tinnitus, taste perversion.
Urogenital: Interstitial nephritis (some with positive rechallenge), urinary tract infection, microscopic pyuria, urinary frequency, elevated serum creatinine, proteinuria, hematuria, glycosuria, testicular pain, and gynecomastia.
The incidence of clinical adverse experiences in patients greater than 65 years of age was similar to that in patients 65 years of age or less.
Read the Zegerid (omeprazole, sodium bicarbonate) Side Effects Center for a complete guide to possible side effects
Drugs For Which Gastric pH Can Affect Bioavailability
Because of its inhibition of gastric acid secretion, it is theoretically possible that omeprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (e.g., ketoconazole, ampicillin esters, iron salts, and digoxin). In the clinical efficacy trials, antacids were used concomitantly with the administration of omeprazole.
Drugs Metabolized By Cytochrome P450 (CYP)
Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are metabolized by oxidation in the liver. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time.
Although in normal subjects no interaction with theophylline or propranolol was found, there have been clinical reports of interaction with other drugs metabolized via the cytochrome P-450 system (e.g., cyclosporine, disulfiram, benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with ZEGERID.
Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. Dose adjustment of omeprazole is not normally required. When voriconazole (400 mg every 12 hours for one day, then 200 mg for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, it significantly increased the steady-state Cmax and AUC024 of omeprazole, 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.
Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin) may lead to decreased omeprazole serum levels. In a cross-over study in 12 healthy male subjects, St John's wort (300 mg three times daily for 14 days), an inducer of CYP3A4, decreased the systemic exposure of omeprazole in CYP2C19 poor metabolisers (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (Cmax and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St. John's Wort or rifampin with omeprazole.
Concomitant administration of atazanavir and proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect. Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg, daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended.
Increased Concentration of Saquinavir
For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported with an increase in AUC by 82%, in Cmax by 75% and in Cmin by 106% 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. Dose reduction of saquinavir should be considered from the safety perspective for individual patients. There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole.
Combination Therapy With Clarithromycin
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interaction [See WARNINGS AND PRECAUTIONS in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs [See Contraindication in prescribing information for clarithromycin].
Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of Zegerid with clopidogrel. When using Zegerid, consider use of alternative anti-platelet therapy [see Pharmacokinetics].
Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus.
Interactions With Investigations Of Neuroendocrine Tumors
Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors. [see CLINICAL PHARMACOLOGY].
Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted. [see WARNINGS AND PRECAUTIONS].
Read the Zegerid Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 3/11/2014
This monograph has been modified to include the generic and brand name in many instances.
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