a) Tachycardia has been observed following overdose of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).
b) OMEPRAZOLE: Mild and transient tachycardia (110 beats/minute) was reported in a 26-year-old pregnant woman following an overdose of 320 mg. Resolution of the tachycardia occurred within 24 hours (Ferner & Allison, 1993).

a) Elevated blood pressure has been reported postmarketing with the use of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).

a) OMEPRAZOLE: A 64-year-old man with a diagnosis of Barrett's esophagitis was started on omeprazole and developed lethargy and episodes of dizziness and headache. The medication was stopped and symptoms resolved; upon rechallenge the patient had progressive drowsiness along with periods of "absent mindedness" and incoherent speech; symptoms again improved with drug cessation (Meeuwisse et al, 1997).

a) SUMMARY: Drowsiness and confusion have been reported following overdose of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).
b) CASE SERIES
c) CASE REPORTS

a) Headache may occur with therapeutic use of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011; Ferner & Allison, 1993; Meeuwisse et al, 1997).

a) Headache has been reported following overdose of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).
b) OMEPRAZOLE: Headache and blurred vision was reported in a 40-year-old man following a 400 mg overdose. Headache was reported in a 26-year-old woman following a 320 mg overdose. Symptoms resolved within 24 to 32 hours in both cases (Ferner & Allison, 1993).

a) Dizziness has been reported following therapeutic use of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011; Meeuwisse et al, 1997).

a) Severe hypomagnesemia was reported in two patients following long term (9 and 5 years, respectively) use of omeprazole (20 mg and 40 mg daily, respectively). Both patients developed hypocalcemic-induced seizures secondary to hypomagnesemia. There was no clinical or laboratory evidence of generalized malabsorption, and both patients recovered with high dose magnesium therapy. However, symptoms did not completely resolve until omeprazole therapy was discontinued (Cundy & Dissanayake, 2008). The authors suggested that intermittent use of proton-pump inhibitors might prevent hypomagnesemia.

a) Nausea and vomiting have been reported (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011; Chernin, 2001).

a) Epigastric pain, flatulence, nausea, and vomiting, which persisted for up to 13 hours, were reported in a 28-year-old woman following an intentional overdose (Gallerani et al, 1996).
b) In a retrospective study of 1813 exposures (66% age 5 years and older; 7% age 6 to 19; 27% age 20 years and greater) to proton pump inhibitors, the most frequently reported adverse clinical effects were gastrointestinal (mainly vomiting which occurred in 1.7% of 1534 cases that reported adverse events, nausea (1.2%), abdominal pain (1%)) and neurological (mainly drowsiness) (Forrester, 2007).

a) Abdominal pain and flatulence have been reported (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011; Chernin, 2001).

a) OMEPRAZOLE: Epigastric pain has been reported following an overdose of 320 mg in a 26-year-old pregnant woman (Ferner & Allison, 1993).
b) Epigastric pain, flatulence, nausea, and vomiting, which persisted for up to 13 hours, were reported in a 28-year-old woman following an intentional overdose (Gallerani et al, 1996).

a) Dry mouth has been reported (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011; Chernin, 2001).

a) CASE REPORT: Dry mouth was reported in an overdose of 400 mg omeprazole in a 40-year-old man (Ferner & Allison, 1993).

a) Diarrhea is frequently reported with therapeutic use of proton pump inhibitors (ie, omeprazole, esomeprazole) (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011; Chernin, 2001).
b) Proton pump inhibitor (PPI) therapy may be associated with an increased risk of Clostridium difficile–associated diarrhea (CDAD). Adverse event reports submitted to the US Food and Drug Administration of patients experiencing CDAD in association with PPI treatment include several cases of CDAD in patients at increased risk (eg, elderly, chronic and/or concomitant underlying medical condition, or use of broad spectrum antibiotic); however, the role of PPI use could not be definitively eliminated. A review of medical literature found an increased risk of C difficile infection or disease, including CDAD, with PPI exposure when compared with no PPI exposure (range, 1.4 to 2.75 times higher), and clinical outcomes included colectomies and fatalities (rare). There were no clearly defined relationships between C difficile infection or CDAD and prior PPI use, dose, or duration of use, and there was very little information about use of nonprescription products (US Food and Drug Administration, 2012).
c) Use of proton pump inhibitors (PPIs) within 14 days of incident clostridium difficile infection diagnosis was associated with a 42% increased risk of recurrent clostridium (C.) difficile infection (CDI), according to a retrospective, cohort study (n=1166; median age 74 yr; interquartile range, 63 to 82 yr; 97.2% male). Inpatients and outpatients were identified for incident CDI diagnosis and categorized as PPI-exposed (n=527) or PPI-nonexposed (n=639) from Veterans Healthcare System databases over approximately a 5-year period. A positive finding of C. difficile toxin between 15 to 90 days after incident CDI diagnosis (follow-up) was considered recurrent infection. More PPI-exposed patients (within 14 days of incident CDI diagnosis) had a recurrent CDI compared with non-PPI exposed patients (25.2% vs 18.5%), with an associated adjusted hazard ratio (HR) of 1.42 (95% confidence interval (CI), 1.1 to 1.83, p=0.008). Among patients exposed to PPIs, the risk for recurrent CDI was highest among those 80 years of age and older (n=384) HR, 1.86 (95% CI, 1.15 to 3.01; p=0.01), and among those receiving non-CDI antibiotics (n=426) during follow-up HR, 1.71 (95% CI, 1.11 to 2.64; p=0.01) (Linsky et al, 2010).

a) OMEPRAZOLE: There is a significant rise in serum gastrin levels in both animals and humans tested with therapeutic administration (Ekland et al, 1985; Sharma et al, 1984).

a) Pancreatitis, some cases fatal, has been reported postmarketing with the use of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).

a) OMEPRAZOLE: Although slight rises have occurred in liver function tests such as gamma-glutamyltranspeptidase, serum alanine aminotransferase and bilirubin, the reactions were not considered clinically significant (Sharma et al, 1983; Loof et al, 1984).

a) CASE REPORTS

a) Hepatic encephalopathy has been reported postmarketing with the use of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).

a) Hepatic failure, some cases fatal, has been reported postmarketing with the use of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).
b) CASE REPORT: A case of fulminant hepatic failure and death was believed to be caused by omeprazole. The patient was being treated with omeprazole 20 mg/day for erosive esophagitis. After seventeen days of treatment, he presented to the hospital with worsening epigastric pain, anorexia, nausea, and vomiting. Liver function tests were markedly increased on presentation and had been normal before treatment started. The patient was given supportive care, but his condition worsened and he died. All serological tests for viruses were negative, and other causes of hepatic failure were ruled out (Jochem et al, 1992).

a) Although rare, acute interstitial nephritis (AIN) has been reported in association with all proton-pump inhibitors (PPIs). Association of PPIs to biopsy-proven AIN has been made based on 1) the temporal relationship of the use of the PPI to the diagnosis of AIN, 2) resolution of symptoms and improvement of renal function upon withdrawal of the PPI, and 3) several cases of positive rechallenge (Torpey et al, 2004; Harmark et al, 2007; Geevasinga et al, 2006; Simpson et al, 2006; Torpey et al, 2004; Myers et al, 2001). The mean duration of treatment prior to onset of symptoms is reported at 9 to 13 weeks (Brewster & Perazella, 2007). A decline in renal function is usually noted over a period of days to weeks (Geevasinga et al, 2006; Sierra et al, 2007). Fatigue, malaise, weakness, nausea, vomiting, anorexia, and weight loss are commonly reported symptoms (Brewster & Perazella, 2007; Sierra et al, 2007). Classic drug hypersensitivity signs and symptoms, such as the clinical triad of rash, fever and eosinophilia, are seen in less than 10% of patients (Brewster & Perazella, 2007). Abnormal urine analysis measurements have included hematuria, pyuria, proteinuria and eosinophiluria, although these findings may occur in less than half of patients. Normocytic normochromic anemia, elevated erythrocyte sedimentation rates, and elevated C-reactive protein levels are also reported (Brewster & Perazella, 2007; Sierra et al, 2007; Simpson et al, 2006; Geevasinga et al, 2006). Discontinuation of the PPI is the primary therapy, while corticosteroids are often used but efficacy has not been demonstrated in controlled clinical trials (Sierra et al, 2007; Simpson et al, 2006; Geevasinga et al, 2006; Torpey et al, 2004). The majority of patients regain renal function, although not always to pre-AIN levels (Simpson et al, 2006; Geevasinga et al, 2006; Torpey et al, 2004).
b) Acute interstitial nephritis (sterile pyuria along with a positive renal biopsy) was reported in two elderly patients following omeprazole therapy; symptoms recurred with rechallenge (Badov et al, 1997).

a) Elevated serum creatinine levels have been reported postmarketing with the use of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).
b) CASE REPORT: A case involved a 75-year-old man treated with omeprazole and metoclopramide for esophagitis who developed anemia, azotemia, and elevated creatinine (3.48 mg/dL). Omeprazole and metoclopramide were discontinued and prednisolone started. Renal function improved with creatinine decreasing to 2.2 mg/dL. Two years later, the patient was retreated with omeprazole for esophagitis. Upon the start of therapy, the patient developed dyspnea, wheezing, diminished urinary output, raised jugular venous pressure, bilateral rales, and distended abdomen. Serum creatinine was 15.65 mg/dL. Omeprazole was discontinued, dialysis treatment ensued, and the patient's symptoms quickly resolved (Assouad et al, 1994).

a) Neutropenia has been reported postmarketing with the use of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).
b) OMEPRAZOLE: Isolated cases of neutropenia and agranulocytosis have been reported following therapeutic use of omeprazole (Holt et al, 1999; Odou et al, 1999). It has been suggested that a hypersensitivity response may have been responsible for producing this adverse effect (Odou et al, 1999).
c) CASE REPORT: A 60-year old man experienced neutropenia after taking omeprazole for 3 days. The patient had been recently admitted for dehydration and malnutrition, with various vitamin supplements initiated including thiamine and pyridoxine. His medical history was significant for chronic alcohol abuse, hepatitis C infection (untreated), and stage 3 chronic kidney disease. One month after his hospitalization, he was started on omeprazole 20 mg daily for diffuse gastritis; pretreatment absolute neutrophil count (ANC) was 2.7 x 10(9)/L. Repeat laboratory analysis after 9 days of omeprazole revealed an ANC of 0.9 x 10(9)/L; omeprazole was discontinued. Five days later the ANC increased to 1.9 x 10(9)/L, and eventually it rose to 3.7 x 10(9)/L. Seven months later, a repeat endoscopy revealed Barrett's esophagus and hiatal hernia. After failing a trial of ranitidine and sucralfate, pantoprazole 40 mg per day was initiated. However after 2 days of pantoprazole therapy, the ANC decreased to 0.8 x 10(9)/L. Pantoprazole was discontinued. The patient's ANC increased to 2.4 x 10(9)/L four days later, and the next month it was 4.2 x 10(9)/L. Bone aspirations were not conducted at either time. The patient did not experience any infectious sequelae during either episode (Gouraud et al, 2010).
d) OMEPRAZOLE: Incidental neutropenia (WBC, 2.8 x 10(9)/L; neutrophils, 0.67 x 10(9)/L) was reported in a 77-year-old woman following 3 weeks of therapy with omeprazole. Prior to omeprazole therapy this patient's full blood count was normal. Following discontinuation of omeprazole and a dose of granulocyte colony-stimulating factor, the neutrophil count returned to normal (Holt et al, 1999).

a) Agranulocytosis has been reported postmarketing with the use of omeprazole; some cases have been fatal (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).

a) Pancytopenia has been reported postmarketing with the use of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).

a) OMEPRAZOLE: A moderate leukocytosis (10,400 x 10(6)/L) with an increase of neutrophils has been reported in 28-year-old woman following ingestion of 560 mg of omeprazole (Gallerani et al, 1996).

a) OMEPRAZOLE
b) DEXLANSOPRAZOLE

a) CASE REPORT: A 51-year-old man who received long-term omeprazole treatment (3 years of 40 to 60 mg daily) for gastroesophageal reflux disease developed megaloblastic anemia secondary to cobalamin deficiency. A 9-day treatment of intramuscular hydroxocobalamin 1000 mcg/day corrected the anemia within 3 months. The cause of this complication was attributed to a lack of release of dietary cobalamine caused by omeprazole therapy. The transfer of protein-bound cobalamin to R binder and intrinsic factor requires a normal secretion of hydrochloric acid and pepsin; a process affected by omeprazole therapy (Bellou et al, 1996).

a) Thrombocytopenia has been reported postmarketing with the use of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).

a) OMEPRAZOLE: LICHEN SPINULOSUS was reported in a 33-year-old woman taking 40 mg omeprazole daily for hemorrhagic gastritis. Although gastrointestinal symptoms started to resolve, the patient complained of generalized pruritus. The following day, an eruption appeared on her lower limbs. A clinical diagnosis of lichen spinulosus was made, and was confirmed upon subsequent biopsy. Omeprazole was discontinued, and the rash resolved over the next seven days. Topical corticosteroids were used for symptomatic relief (Lee et al, 1989).

a) OMEPRAZOLE: Following a 3 month course of omeprazole, 20 mg twice daily, a 41-year-old man developed red, exfoliative scaling on his back, trunk, and legs, with extreme sloughing of the skin on his hands. The only concomitant medication taken was Mylanta(R). A diagnosis of drug-induced hypersensitivity was made and omeprazole was discontinued. Symptoms, mostly localized to his hands, continued to occur 18 months later despite therapy with local and systemic steroids (Rebuck et al, 1998).

a) OMEPRAZOLE: A 26-year-old pregnant woman presented to the ED with flushing following a 320 mg overdose. No other physical signs were present (Ferner & Allison, 1993).
b) Flushing has been reported following overdose of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).

a) Toxic epidermal necrolysis has been reported postmarketing with the use of omeprazole; some cases have been fatal (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).
b) CASE REPORT: A 43-year-old woman experienced toxic epidermal necrolysis (TEN) following 3 weeks of omeprazole for the treatment of chronic abdominal bloating. She presented to her physician with a 3-day history of erythematous rash over her face and chest, fatigue, pharyngitis, and dry eyes. Within 24 hours, the patient was admitted with shortness of breath, pyrexia, and rash, which had spread to her back, arms, and legs. Vesicles appeared within the erythematous regions on her upper body, and she developed extensive oral and genital mucosal ulceration, conjunctivitis and blepharitis. Blood test results showed an increase in C-reactive protein (CRP) of 122 mg/L. Otherwise, her liver and hematological function and chest radiography were unremarkable. The rash became desquamative and spread to her entire body. Supportive care included fentanyl and hydrocortisone 150 mg twice daily for 3 days. Over the next 48 hours, the patient's skin loss became more extensive, with 95% epidermal detachment. Her WBC count decreased from 7.3 x 10(9)/L to 1.3 x 10(9)/L, with neutropenia of 0.7 x 10(9)/L. A 3-day course of IV IG and subQ granulocyte stimulating factor (GSF) 500 mcg were initiated until her neutrophil count improved to greater than 2 x 10(9)/L. Although there was some improvement, the patient developed sepsis, pneumonia, and hypoxia requiring ventilatory and circulatory support. Her liver enzymes increased, as well as CRP (381 mg/L). Intravenous antibiotics were started and the patient transferred to a specialized intensive care and burns unit. She subsequently developed severe acute respiratory distress syndrome and acute renal failure requiring hemodialysis. Her skin gradually improved with the use of emollient creams and re-epithelialization of all areas. Although eventually weaned from ventilatory support, renal function remained impaired requiring intermittent hemodialysis(Thakor et al, 2009).

a) CASE REPORT: Cutaneous leukocytoclastic vasculitis occurred in a 71-year-old woman 4 weeks after initiation of omeprazole 20 mg/day for epigastric pain. The patient presented with pruritus and an erythematous macular, papular rash (1 to 10 mm in diameter) on her hands, thighs, and lower abdomen. A skin biopsy specimen revealed small vessel vasculitis with neutrophilic infiltration, nuclear dust, and focal fibrinoid deposits within the vessel walls. There was also evidence of complete fibrinoid necrosis of some blood vessels and erythrocyte extravasation in the adjacent dermis. Omeprazole was withdrawn from therapy and treatment with budesonide and amiodarone continued. Within a few days, all skin lesions resolved completely. No rechallenge was performed. Omeprazole was the causative agent of this patient's cutaneous vasculitis (Odeh et al, 2002).

a) Urticaria has been reported postmarketing with the use of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).
b) CASE REPORT: A case of urticaria with a positive rechallenge was reported in a 34-year-old woman receiving omeprazole therapy. Over a 5-day period, the patient developed a variety of symptoms following each omeprazole dose. Symptoms included shortness of breath, cough, and diffuse wheezing. Chest radiograph revealed a right pleural effusion, and laboratory findings were significant for eosinophilia. On the 4th day of therapy, she developed swollen, erythematous lips and eyelids consistent with mild angioedema and shortness of breath. On the 5th day, rechallenge with omeprazole resulted in generalized total body urticaria and pruritus that responded to diphenhydramine (Bowlby & Dickens, 1993).

a) ESOMEPRAZOLE: CASE REPORT: A 51-year-old woman who was taking esomeprazole magnesium for GERD and meloxicam and ibuprofen for osteoarthritis for more than 3 years, presented to the ED with a 5-day history of abdominal pain, fever, chills, severe bilateral leg pain, headache, earache, sore throat, and rapidly progressive spontaneous necrotizing fasciitis and gas gangrene. On presentation, she had a quarter-sized erythematous and tender lesion on the inner aspect of her right thigh. Laboratory results revealed leukopenia, slight thrombocytopenia, and decreased hemoglobin and hematocrit concentrations. Her condition rapidly worsened and she developed tachypnea, hypotension, and cardiopulmonary decompensation. Despite supportive care, she developed a cardiac arrest and died a few hours later. An autopsy revealed spreading tissue gas gangrene, myonecrosis, and multiple intestinal ulcers containing Clostridium septicum. It was hypothesized that the long-term use of esomeprazole may have exacerbated NSAID enteropathy by shifting the bacteria flora and promoted survival and germination of Clostridium spores in the GI. This caused the transfer of the C. septicum bacteria into the bloodstream, resulting in systemic infection and spontaneous gas gangrene (Wu et al, 2014).

a) Rhabdomyolysis has occurred with the use proton pump inhibitors (PPIs), such as omeprazole, pantoprazole, lansoprazole, esomeprazole, and rabeprazole. This is based on an analysis of spontaneous reports from the worldwide adverse drug reaction database (Vigibase) held by the World Health Organization (WHO) Collaborating Center, the Uppsala Monitoring Center. Of the 292 case reports indicative of myopathy, 35 cases were rhabdomyolysis, and 12 of these patients took concomitant statin therapy. Among 16 cases when time-to-onset was recorded, muscle symptoms developed during the first 7 days of treatment in 9 cases, between 14 days and 3 months in 4 cases, and between 1.5 years and 10 years in 3 cases (Clark & Strandell, 2006).
b) Rhabdomyolysis associated with intravenous administration of omeprazole was reported in a case report, involving a 56-year-old Japanese man treated for esophageal and gastric hemorrhage. He experienced elevated serum creatine phosphokinase at 3856 international unit per liter (/L) (normal range, 43 to 272 international units/L) and elevated serum myoglobin level at 467 nanograms/milliliter (ng/mL) (normal, less than or equal to 65 ng/mL) on the fifth day after receiving intravenous omeprazole 20 mg twice daily. Although the patient did not have any physical and neurological symptoms, the laboratory findings were indicative of skeletal muscle destruction secondary to rhabdomyolysis. Laboratory abnormalities improved within 5 days after withdrawal of omeprazole therapy (Nozaki et al, 2004).

a) The use of various proton pump inhibitors (PPIs) have been associated with myopathy. This is based on 292 spontaneous reports from the worldwide adverse drug reaction database (Vigibase) held by the World Health Organization (WHO) Collaborating Center, the Uppsala Monitoring Center. In the analysis, case reports of omeprazole, pantoprazole, lansoprazole, esomeprazole, and rabeprazole, with terms indicative of myopathy, were reviewed. There were 868 cases of 'myalgia' excluded due to its unspecificity associated with a variety of conditions. In one-third of the 292 myopathy cases, the PPI was the single drug administered; and in 57% of the cases when concomitant medication was used, PPI was the single reporter-suspected drug of being associated with myopathy. Sixty-nine patients recovered upon withdrawal of PPI (positive dechallenge), and muscular symptoms reoccurred among 15 patients when the PPI was reinstated (positive rechallenge). Other myopathies were reported, including 35 cases with rhabdomyolysis, and 27 cases with myositis or polymyositis. When time-to-onset was recorded, the majority of myopathy, including polymyositis, occurred within 10 days of PPI administration while a fair number of cases occurred between 50 days to several years following administration of a PPI. Furthermore, 3 index cases involving one or more PPIs were identified (Clark & Strandell, 2006):
b) CASE REPORT: The first case involved a 69-year-old male who developed myalgia and muscle weakness indicative of myopathy with lansoprazole, esomeprazole, and rabeprazole at different time periods. Muscular symptoms resolved 23 days following withdrawal of lansoprazole (30 to 60 mg per day). Subsequently, he developed myalgia and muscle weakness with the use of esomeprazole (20 to 40 mg per day), and recovered without sequelae following drug withdrawal. Rechallenge with rabeprazole led to development of muscular symptoms that again resolved after discontinuation of therapy. A second case involved a 22-year-old female who developed muscle weakness and paresthesia the day after administration of omeprazole 20 mg per day. Her symptoms subsided following omeprazole withdrawal but reoccurred upon rechallenge with omeprazole. The last case involved a 70-year-old male who developed muscle atrophy, myalgia and myopathy on the same day of esomeprazole administration. Similar to the 22-year-old female, he reported a positive dechallenge and a positive rechallenge (Clark & Strandell, 2006).
c) CASE REPORT: A suspected case of omeprazole-induced myopathy was described in a case report involving a 71-year-old man treated with omeprazole for severe epigastric pain. Within 12 hours after a single intravenous omeprazole dose of 40 mg, the patient experienced an increase in creatine kinase (CK), creatine kinase isoenzymes (MB fraction), and myoglobin levels. CK level peaked on day 2 of hospitalization at 1665 units/deciliter (dL) (normal range, 10 to 100 units/dL), CK-MB level at 18.5 units/dL (normal, less than 10 units/dL), and myoglobin level peaked at 22 hours at 1994 mcg/L (normal, less than 90 mcg/L). Although the patient did not experience any myalgia, weakness, or cramps, the laboratory findings allowed for exclusion of myocardial infraction and suspicion of musculoskeletal injury related to myopathy. Within a week upon discontinuation of omeprazole treatment, the patient recovered from epigastralgia with concomitant improvement and subsequent normalization of laboratory results (Tuccori et al, 2006).

a) Proton pump inhibitors may increase the risk of osteoporosis-related hip, wrist, or spine fractures, especially in patients on high-dose (eg, multiple daily doses) or long-term (eg, longer than one year) therapy (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).

a) CASE REPORTS

a) Anaphylaxis and anaphylactic shock have been reported postmarketing with the use of omeprazole (Prod Info PRILOSEC(R) delayed-release oral suspension, 2011).
b) CASE REPORT: A 35-year-old man with a history of hepatitis and pancreatitis from ethanol abuse experienced omeprazole-induced anaphylaxis demonstrated by skin tests and increased serum tryptase levels. The patient was administered intravenous (IV) omeprazole 40 mg diluted in 100 mL of saline solution twice daily and metamizole IV (an analgesic) for abdominal pain due to worsening pancreatitis. The patient had been previously hospitalized on multiple occasions for abdominal pain and was taking ranitidine, vitamin K, and metamizole at home. Omeprazole had been administered on other occasions. Following two days of therapy and within a few minutes after starting an omeprazole infusion, the patient experienced sweating, paleness, abdominal pain, itching on his legs, dyspnea, and hypotension (70/40 mmHg). No other medications had been administered during the previous 12 hours. Following supportive care, he recovered completely. Skin intradermal tests were performed two months later and were positive with omeprazole IV (4 mg/mL), omeprazole capsules diluted in saline solution (20 mg/mL), and lansoprazole capsules diluted in saline solution (30 mg/mL). The same intradermal skin tests were negative in six control subjects. Serum specific IgE anti-omeprazole was not detected by an radioimmunoassay (Galindo et al, 1999).
c) CASE REPORT: A 57-year-old man developed anaphylaxis after second exposure to omeprazole. Six weeks before the anaphylactic reaction, the patient was given omeprazole 20 mg orally. Treatment was discontinued due to urticaria. Upon second exposure to oral omeprazole (20 mg), the patient developed urticaria, angioedema, hypotension, became unconscious, then developed asystole. The patient later recovered without further complications. Skin tests, performed during a follow-up visit, confirmed that the patient was allergic to omeprazole (Ottervanger et al, 1996).

a) Four epidemiological studies failed to show an increased risk of congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. In the first population-based retrospective cohort study (including 955 infants exposed to omeprazole in utero; 824 exposed during the first trimester and 131 exposed after the first trimester), the number of infants with malformations, low birth weight, low Apgar score, or hospitalization were similar to those of control infants. However, in the omeprazole-exposed group, a slightly higher number of infants born with ventricular septal defects and stillborn infants was observed. In another study, the overall rate of birth defects was 2.9% in infants exposed to omeprazole (n=1800) during the first trimester compared with 2.6% of infants not exposed to proton pump inhibitors (n=837,317). In the third study, the overall malformation rate was 3.6% in infants exposed to omeprazole (n=134) during the first trimester compared with 5.5% and 4.1% of infants exposed to H2-blockers (n=555) or with no exposure (n=1572), respectively. Major congenital malformations were reported in 4% of omeprazole exposed infants compared with 2% and 2.8% of those exposed to non-teratogens or disease paired controls, respectively. Similar rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were observed. There were no short-term effects observed in infants whose mothers were administered a single oral or VI dose of omeprazole as premedication for cesarean sections (Prod Info PRILOSEC(R) oral delayed-release capsules, 2016; Prod Info PRILOSEC(R) oral delayed-release suspension, 2016).
b) In a multicenter, prospective, controlled trial of 113 pregnant women, there was no association between omeprazole exposure in the period of organogenesis and increased risk for major malformations. Women exposed to omeprazole were matched to controls exposed to non-teratogens and with disease-paired controls receiving histamine blockers for similar indications. No increased risk of spontaneous abortions, decreased birth weights, or perinatal complications were reported following omeprazole exposure throughout pregnancy (Lalkin et al, 1998).
c) A series of observational cohort studies suggested that omeprazole does not cause an increased rate of congenital anomalies when used during pregnancy. Of 17 pregnant women who took the drug, there were 18 resultant pregnancies. Thirteen discontinued the drug before the last menstrual period and five were exposed during the first trimester. Of the five exposed during the first trimester, there were four births without congenital anomalies, and one pregnancy intentionally terminated (Wilton et al, 1998).
d) In several studies, pregnant women were given omeprazole for prophylaxis against pulmonary aspiration for elective or emergency cesarean section (Stuart et al, 1996; Orr et al, 1993; Moore et al, 1989).
e) CASE REPORT: A 41-year-old pregnant woman refractory to ranitidine and cisapride therapy was given omeprazole from week 29 through 35 of pregnancy. A healthy child was delivered on week 35 of pregnancy without any apparent adverse effects secondary to omeprazole. The mother continued to take omeprazole for 3 months while breastfeeding the infant. The peak breast milk omeprazole concentration was 58 nanomoles which was about 7% of the highest serum concentration. No adverse effects were apparent in the infant (Marshall et al, 1998).
f) CASE REPORT: A woman with Zollinger-Ellison syndrome who was treated with omeprazole during two pregnancies delivered two healthy infants (Harper et al, 1995).
g) No ill effects were observed in 955 infants born to mothers who used omeprazole in early (n=863) and/or late (n=131) pregnancy, based on data from the Swedish Medical Birth Registry (Kallen, 2001).
h) In another study, delivery outcome was observed after maternal use of proton pump inhibitors (ie, omeprazole, lansoprazole) during early pregnancy in 275 women, NO increased risk on the rate of congenital malformations was observed (Kallen, 1998).
i) In a multicenter prospective controlled study comparing pregnancies exposed to proton pump inhibitors and those exposed to non-teratogens, there was no difference in the rate of major malformations among the omeprazole and control groups. There were 233 exposures to omeprazole (median daily dose of 20 mg) for 22 days (median duration of treatment) during the first trimester. Among the omeprazole exposures, there were 247 live births, 3 stillbirths, 24 spontaneous abortions, and 26 elective abortions. Two of the elective abortions were related to prenatal anomaly diagnoses. The major congenital anomaly rate was 3.6% in the omeprazole group and 3.8% in the control group (p=0.9). Similar results were reported for pantoprazole and lansoprazole (Diav-citrin et al, 2005).
j) A meta-analysis examining 593 infants exposed to proton pump inhibitors (PPI) found no significant correlation between first-trimester fetal exposure and teratogenicity. The combined relative risk of major fetal malformation with PPI exposure was 1.18 (95% confidence interval, 0.72 to 1.94, p=0.7). Five cohort studies were examined, and omeprazole was the most commonly prescribed PPI. The median omeprazole dose was 20 mg daily, while the mean duration of therapy was 15.3 weeks (range, 3 days to 42 weeks) (Nikfar et al, 2002).

a) No adverse effects were observed in the newborn infants. Delivery outcome was reported after maternal use of proton pump inhibitors (omeprazole, lansoprazole) during early pregnancy in 275 women; no increased risk on the rate of congenital malformations was observed (Kullen, 1998).

a) DEXLANSOPRAZOLE
b) ESOMEPRAZOLE
c) ESOMEPRAZOLE STRONTIUM
d) LANSOPRAZOLE
e) OMEPRAZOLE
f) PANTOPRAZOLE
g) RABEPRAZOLE

a) RATS, RABBITS: Abnormalities in bone morphology (ie, shortened femur, decreases in cortical bone width and thickness, decreases in tibial growth plate thickness, bone marrow hypocellularity) occurred in rat offspring exposed to about 3.4 times the human dose of esomeprazole magnesium clinical studies. In addition, femoral physeal dysplasia occurred in rat offspring exposed to esomeprazole magnesium at doses 33.6 times the human dose (Prod Info NEXIUM(R) I.V. intravenous injection, 2014).

a) RATS: In pre-and postnatal toxicity studies, maternal adverse effects on bone, including statistically significant decreased femur weight of up to 14% compared with placebo, occurred in pregnant and lactating rats administered esomeprazole strontium at an equimolar oral dose of 138 mg esomeprazole/kg/day from gestation day 7 through weaning on postnatal day 21 (Prod Info ESOMEPRAZOLE STRONTIUM oral delayed-release capsules, 2013).

a) RABBITS: When given to pregnant rabbits in doses of 80 mmol/day, maternal anorexia and weight loss were seen. However, no adverse effects on the fetus were observed (Hansson et al, 1986).
b) OVINE: In an ovine study, omeprazole was found to cross the placenta. Fetal plasma omeprazole concentrations were found to be about half those of unbound omeprazole in maternal plasma (Ching et al, 1986). Pantoprazole has been shown to cross the placenta in animals (Prod Info Pantoloc(TM), 2001).

a) It is likely that esomeprazole (the S-isomer of omeprazole) is excreted into human breast milk since limited data has shown daily maternal doses of omeprazole 20 mg produce low levels of omeprazole in human milk. Exercise caution when administering esomeprazole to a nursing woman (Prod Info NEXIUM(R) oral delayed-release capsules, suspension, 2014; Prod Info NEXIUM(R) I.V. intravenous injection, 2014a).

a) Esomeprazole and strontium are excreted into human breast milk; however, the effect on the nursing infant from exposure to esomeprazole strontium through breast milk is unknown. In animal studies, high doses of esomeprazole strontium had effects on developing bone in rats. Therefore, the manufacturer recommends to either discontinue nursing or esomeprazole strontium, considering the importance of the drug to the mother (Prod Info ESOMEPRAZOLE STRONTIUM oral delayed-release capsules, 2013).

a) Lactation studies with omeprazole have not been conducted. Limited data suggest that omeprazole may be excreted into human breast milk, but its effect on milk production or the breastfed infant remain unknown (Prod Info PRILOSEC(R) oral delayed-release capsules, 2016; Prod Info PRILOSEC(R) oral delayed-release suspension, 2016). Omeprazole was detected in breast milk, reaching a peak concentration of less than 7% of the peak serum concentration, following administration of 20 mg orally once daily (Marshall et al, 1998a). This correlates to 0.004 mg omeprazole/200 mL breast milk. Due to the potential for adverse effects in a nursing infant, the manufacturer recommends using caution when administering omeprazole to lactating women (Prod Info PRILOSEC(TM) oral delayed release capsules, 2013; Prod Info PRILOSEC(TM) oral delayed release suspension, 2013).
b) A 41-year-old woman nursed her infant for 3 months while taking omeprazole 20 mg once daily without any adverse effects to the infant. The breast milk omeprazole concentration began to increase at 90 minutes and peaked at 180 minutes following ingestion. The peak concentration was 58 nanomoles, approximately 7% of the highest serum omeprazole concentration, correlating to 0.004 mg omeprazole/200 mL breast milk (Marshall et al, 1998a).
c) Omeprazole concentrations were detected in the breast milk of a woman who was treated with 20 mg of oral omeprazole (Prod Info VIMOVO(TM) delayed release oral tablets, 2010; Prod Info NEXIUM(R) intravenous injection, 2008).

a) Lactation studies have not been conducted with rabeprazole and it is not known whether rabeprazole is excreted into human breast milk or it affects milk production or the breasted infant. Rabeprazole is present in the milk of lactating rats. The potential for adverse effects in a nursing infant from exposure to the drug are unknown (Prod Info ACIPHEX(R) oral delayed-release tablets, 2016; Prod Info ACIPHEX(R) SPRINKLE(TM) oral delayed-release capsules, 2016).

a) Excretion of pantoprazole into human milk was detected in a study of one nursing mother who was exposed to a single 40-mg dose of pantoprazole (Prod Info PROTONIX(R) delayed-release oral tablets, suspension, 2008).

a) RATS: Esomeprazole is an enantiomer of omeprazole, which was studied for carcinogenic potential. Gastric carcinoids were detected in rats, but not in mice, after exposure to omeprazole. The development of the carcinoids seemed to be related to prolonged exposure of the gastric enterochromaffin-like (ECL) cells to high plasma gastrin levels (Prod Info ESOMEPRAZOLE STRONTIUM oral delayed-release capsules, 2013).

a) RATS: Dose-related gastric enterochromaffin-like (ECL) cell carcinoids were demonstrated in male and female Sprague-Dawley rats after 24 months of oral lansoprazole doses of 5 to 150 mg/kg/day (approximately 1 to 40 times the recommended human dose of 30 mg/day based on body surface area). The incidence of intestinal metaplasia of the gastric epithelium was also increased in both sexes (Prod Info PREVACID(R) oral delayed-release capsules, 2011).

a) MICE: A dose-related increase in gastric enterochromaffin-like (ECL) cell hyperplasia was demonstrated in CD-1 mice who were treated for 24 months with oral lansoprazole doses of 15 to 600 mg/kg/day (2 to 80 times the recommended human dose based on body surface area) (Prod Info PREVACID(R) oral delayed-release capsules, 2011).
b) RATS: Dose-related gastric enterochromaffin-like (ECL) cell hyperplasia was demonstrated in male and female Sprague-Dawley rats after 24 months of oral lansoprazole doses of 5 to 150 mg/kg/day (approximately 1 to 40 times the recommended human dose of 30 mg/day based on body surface area). The incidence of intestinal metaplasia of the gastric epithelium was also increased in both sexes (Prod Info PREVACID(R) oral delayed-release capsules, 2011).

a) MICE: Lansoprazole caused an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma) in CD-1 male mice who were treated for 24 months with oral doses of 300 and 600 mg/kg/day (40 to 80 times the recommended human dose based on body surface area (BSA)) and female mice who received 150 to 600 mg/kg/day (20 to 80 times the recommended human dose based on BSA). The incidence of tumors exceeded the ranges of background incidences in historic controls for this strain of mice (Prod Info PREVACID(R) oral delayed-release capsules, 2011).

a) MICE: Lansoprazole produced adenoma of the rete testis in CD-1 male mice who were treated for 24 months with oral doses of 75 to 600 mg/kg/day (10 to 80 times the recommended human dose based on body surface area) (Prod Info PREVACID(R) oral delayed-release capsules, 2011).
b) RATS: A dose-related increase in testicular interstitial cell adenomas was demonstrated in male Sprague-Dawley rats after 24 months of oral lansoprazole doses of 15 to 150 mg/kg/day (4 to 40 times the recommended human dose based on body surface area). The incidence of adenomas exceeded the low background incidence (range, 1.4% to 10%) for this strain of rat (Prod Info PREVACID(R) oral delayed-release capsules, 2011).

a) RATS: Gastric carcinoids were detected in rats, but not in mice, after exposure to omeprazole. The development of the carcinoids seemed to be related to prolonged exposure of the gastric enterochromaffin-like (ECL) cells to high plasma gastrin levels (Ekland et al, 1985).

a) MICE: A 26-week p53 (+/-) transgenic mouse carcinogenicity study with lansoprazole was not positive (Prod Info PREVACID(R) oral delayed-release capsules, 2011).

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.

a) ALBUTEROL

a) Consider systemic corticosteroids in patients with significant bronchospasm.
b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).

a) DIPHENHYDRAMINE

a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).

a) EPINEPHRINE

a) OXYGEN: 5 to 10 liters/minute via high flow mask.
b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

a) CARDIAC MONITOR: All complicated cases.
b) IV ACCESS: Routine in all complicated cases.

a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.

a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).

a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.

a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

a) 30 mg orally once daily (Prod Info DEXILANT SoluTab(TM) oral delayed release disintegrating tablets, 2016)

a) Varies by indication; 30 mg or 60 mg orally once daily (Prod Info DEXILANT(R) oral delayed release capsules, 2016)

a) 12 YEARS OR OLDER: 30 mg orally once daily (Prod Info DEXILANT SoluTab(TM) oral delayed release disintegrating tablets, 2016)

a) 12 YEARS OR OLDER: Varies by indication; 30 mg or 60 mg orally once daily (Prod Info DEXILANT(R) oral delayed release capsules, 2016)

a) WEIGHT 3 TO 5 KG: 2.5 mg orally once daily for up to 6 weeks (Prod Info NEXIUM(R) oral delayed-release capsules, oral delayed-release suspension, 2014).
b) WEIGHT GREATER THAN 5 TO 7.5 KG: 5 mg orally once daily for up to 6 weeks (Prod Info NEXIUM(R) oral delayed-release capsules, oral delayed-release suspension, 2014).
c) WEIGHT GREATER THAN 7.5 TO 12 KG: 10 mg orally once daily for up to 6 weeks (Prod Info NEXIUM(R) oral delayed-release capsules, oral delayed-release suspension, 2014).

a) WEIGHT LESS THAN 20 KG: 10 mg orally once daily for 8 weeks (Prod Info NEXIUM(R) oral delayed-release capsules, oral delayed-release suspension, 2014).
b) WEIGHT 20 KG OR GREATER: 10 or 20 mg orally once daily for 8 weeks (Prod Info NEXIUM(R) oral delayed-release capsules, oral delayed-release suspension, 2014).

a) 20 or 40 mg orally once daily for 4 to 8 weeks (Prod Info NEXIUM(R) oral delayed-release capsules, oral delayed-release suspension, 2014).

a) WEIGHT LESS THAN 55 KG: The recommended dose is 10 mg IV infusion over 10 to 30 min once daily (Prod Info NEXIUM(R) I.V. intravenous injection, 2014).
b) WEIGHT 55 KG OR GREATER: The recommended dose is 20 mg IV infusion over 10 to 30 min once daily (Prod Info NEXIUM(R) I.V. intravenous injection, 2014).

a) The recommended dose is 0.5 mg/kg IV infusion over 10 to 30 min once daily (Prod Info NEXIUM(R) I.V. intravenous injection, 2014).

a) Safety and efficacy have not been established (Prod Info NEXIUM(R) I.V. intravenous injection, 2014).

a) Weight 30 kg or less: 15 mg orally once daily for up to 12 weeks (Prod Info PREVACID(R) delayed-release oral capsules, suspension, orally disintegrating tablets, 2008).
b) Weight more than 30 kg: 30 mg orally once daily for up to 12 weeks (Prod Info PREVACID(R) delayed-release oral capsules, suspension, orally disintegrating tablets, 2008).

a) NONEROSIVE GERD: 15 mg orally once daily for up to 8 weeks (Prod Info PREVACID(R) delayed-release oral capsules, suspension, orally disintegrating tablets, 2008).
b) EROSIVE ESOPHAGITIS: 30 mg orally once daily for up to 8 weeks (Prod Info PREVACID(R) delayed-release oral capsules, suspension, orally disintegrating tablets, 2008).

a) 15 mg orally once daily (Prod Info PREVACID(R) delayed-release oral capsules, suspension, orally disintegrating tablets, 2008).

a) 60 mg orally once daily; dose varies with individual patient (Prod Info PREVACID(R) delayed-release oral capsules, suspension, orally disintegrating tablets, 2008).

a) 3 TO LESS THAN 5 KG: 2.5 mg orally once daily for up to 6 weeks (Prod Info PRILOSEC(R) oral delayed-release capsules, 2016; Prod Info PRILOSEC(R) oral delayed-release suspension, 2016).
b) 5 TO LESS THAN 10 KG: 5 mg orally once daily (Prod Info PRILOSEC(R) oral delayed-release capsules, 2016; Prod Info PRILOSEC(R) oral delayed-release suspension, 2016).
c) 10 TO LESS THAN 20 KG: 10 mg orally once daily (Prod Info PRILOSEC(R) oral delayed-release capsules, 2016; Prod Info PRILOSEC(R) oral delayed-release suspension, 2016).
d) 20 KG OR GREATER: 20 mg orally once daily (Prod Info PRILOSEC(R) oral delayed-release capsules, 2016; Prod Info PRILOSEC(R) oral delayed-release suspension, 2016).

a) Weight less than 15 kg: 5 mg orally once daily for up to 12 weeks using the delayed-release capsule (Prod Info ACIPHEX(R) Sprinkle(TM) oral delayed-release capsules, 2013).
b) Weight 15 kg or more: 10 mg orally once daily for up to 12 weeks using the delayed-release capsule (Prod Info ACIPHEX(R) Sprinkle(TM) oral delayed-release capsules, 2013).

a) 20 mg orally once daily for up to 8 weeks using the delayed-release tablet (Prod Info ACIPHEX(R) delayed-release oral tablets, 2013).

a) Maximum plasma concentration of omeprazole at approximately 6 hours following an overdose of 320 milligrams was 2930 nanomoles/liter (or 1012 micrograms/liter) in a 26-year-old woman. Elimination half-life was measured at 52 minutes (Ferner & Allison, 1993).

a) Greater than 100 mg/kg (RTECS, 2006)

a) Greater than 4 g/kg (RTECS, 2006)

a) Greater than 100 mg/kg (RTECS, 2006)

a) Greater than 100 mg/kg (RTECS, 2006)

a) 2210 mg/kg (RTECS, 2006)

a) Greater than 100 mg/kg (RTECS, 2006)