NEXIUM - A Staggering
Number of Side Effects
By Ted Twietmeyer
So, your physician gave you or someone you know some Nexium pills for acid reflux problems?
The doctor didn't say anything about any bad side effects?
Did the physician pull the bottles from the boxes, and then put the bottles in a bag first without the side effect sheets? Many doctors often tell patients "Oh, don't worry about the side effects. It's nothing."
Want to know what information you're REALLY missing and need to know?
SPECIAL NOTE FOR CARDIAC PATIENTS:
Down near the end of this lengthy insane list, is a comment that this drug can interefere with Digoxin. This is a very popular heart drug used for years to treat high blood pressure and other cardiac problems. (But be sure to read all of the other text.)
How long it will be before this drug is pulled from the market?
The safety of NEXIUM was evaluated in over 15,000 patients (aged 18-84 years) in clinical trials worldwide including over 8,500 patients in the United States and over 6,500 patients in Europe and Canada. Over 2,900 patients were treated in long-term studies for up to 6-12 months. In general, NEXIUM was well tolerated in both short and long-term clinical trials.
A study was performed evaluating the safety of NEXIUM in pediatric patients aged 12-17 for the treatment of symptomatic gerd The safety in the treatment of healing of erosive esophagitis was assessed in four randomized comparative clinical trials, which included 1,240 patients on NEXIUM 20 mg, 2,434 patients on NEXIUM 40 mg, and 3,008 patients on omeprazole 20 mg daily. The most frequently occurring adverse events (>1%) in all three groups was headache (5.5, 5.0, and 3.8, respectively) and diarrhea (no difference among the three groups). Nausea, flatulence, abdominal pain, constipation, and dry mouth occurred at similar rates among patients taking NEXIUM or omeprazole.
Additional adverse events that were reported as possibly or probably related to NEXIUM with an incidence < 1% are listed below by body system:
Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, chest pain substernal, facial edema, peripheral edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, leg edema, malaise, pain, rigors; Cardiovascular: flushing, hypertension, tachycardia; Endocrine: goiter; Gastrointestinal: bowel irregularity, constipation aggravated, dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, frequent stools, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting; Hearing: earache, tinnitus; Hematologic: anemia, anemia hypochromic, cervical lymphoadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia; Hepatic: bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased; Metabolic/Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease; Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica; Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, dizziness, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect; Reproductive: dysmenorrhea, menstrual disorder, vaginitis; Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis; Skin and Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria; Special Senses: otitis media, parosmia, taste loss, taste perversion; Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria; Visual: conjunctivitis, vision abnormal.
Endoscopic findings that were reported as adverse events include: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, gastritis, hernia, benign polyps or nodules, Barrett's esophagus, and mucosal discoloration.
The incidence of treatment-related adverse events during 6-month maintenance treatment was similar to placebo. There were no differences in types of related adverse events seen during maintenance treatment up to 12 months compared to short-term treatment.
Two placebo-controlled studies were conducted in 710 patients for the treatment of symptomatic gastroesophageal reflux disease. The most common adverse events that were reported as possibly or probably related to NEXIUM were diarrhea (4.3%), headache (3.8%), and abdominal pain (3.8%).
Postmarketing Reports There have been spontaneous reports of adverse events with postmarketing use of esomeprazole. These reports occurred rarely and are listed below by body system: Blood And Lymphatic System Disorders: agranulocytosis, pancytopenia; Eye Disorders: blurred vision; Gastrointestinal Disorders: pancreatitis; stomatitis1; Hepatobiliary Disorders: hepatic failure2; hepatitis with or without jaundice; Immune System Disorders: anaphylactic reaction/shock; Infections and Infestations: GI candidiasis3; Musculoskeletal And Connective Tissue Disorders: muscular weakness4, myalgia; Nervous System Disorders: hepatic encephalopathy5, taste disturbance 6; Psychiatric Disorders; aggression7, agitation 8, depression, hallucination9, Renal and Urinary Disorders: interstitial nephritis 10; Reproductive System and Breast Disorders: gynecomastia11; Respiratory, Thoracic and Mediastinal Disorders: bronchospasm12; Skin and Subcutaneous Tissue Disorders: alopecia, erythema multiforme, hyperhidrosis13, photosensitivity14, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN, some fatal).
Other adverse events not observed with NEXIUM, but occurring with omeprazole can be found in the omeprazole package insert, ADVERSE REACTIONS section.
Combination Treatment with Amoxicillin and Clarithromycin
In clinical trials using combination therapy with NEXIUM plus amoxicillin and clarithromycin, no adverse events peculiar to these drug combinations were observed. Adverse events that occurred have been limited to those that had been observed with either NEXIUM, amoxicillin, or clarithromycin alone.
The most frequently reported drug-related adverse events for patients who received triple therapy for 10 days were diarrhea (9.2%), taste perversion (6.6%), and abdominal pain (3.7%). No treatment-emergent adverse events were observed at higher rates with triple therapy than were observed with NEXIUM alone.
For more information on adverse events with amoxicillin or clarithromycin, refer to their package inserts, ADVERSE REACTIONS sections.
The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to NEXIUM, were reported in <1% of patients: increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid stimulating hormone (see CLINICAL PHARMACOLOGY, Endocrine Effects for further information on thyroid effects). Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine.
In clinical trials using combination therapy with NEXIUM plus amoxicillin and clarithromycin, no additional increased laboratory abnormalities particular to these drug combinations were observed.
For more information on laboratory changes with amoxicillin or clarithromycin, refer to their package inserts, ADVERSE REACTIONS section.
Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.
In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin. Post-marketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
Esomeprazole may potentially interfere with CYP2C19, the major esomeprazole metabolizing enzyme. Coadministration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam. Increased plasma levels of diazepam were observed 12 hours after dosing and onwards. However, at that time, the plasma levels of diazepam were below the therapeutic interval, and thus this interaction is unlikely to be of clinical relevance.
Coadministration of oral contraceptives, diazepam, phenytoin, or quinidine did not seem to change the pharmacokinetic profile of esomeprazole.
Concomitant administration of esomeprazole may reduce the plasma levels of atazanavir, thus appropriate clinical monitoring is recommended.
Studies evaluating concomitant administration of esomeprazole and either naproxen (non-selective NSAID) or rofecoxib (COX-2 selective NSAID) did not identify any clinically relevant changes in the pharmacokinetic profiles of esomeprazole or these NSAIDs.
Esomeprazole inhibits gastric acid secretion. Therefore, esomeprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, iron salts and digoxin).
Combination Therapy with Clarithromycin
Co-administration of esomeprazole, clarithromycin, and amoxicillin has resulted in increases in the plasma levels of esomeprazole and 14-hydroxyclarithromycin. (See CLINICAL PHARMACOLOGY, Pharmacokinetics: Combination Therapy with Antimicrobials.)
Concomitant administration of clarithromycin with pimozide is contraindicated. (See clarithromycin package insert.)
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING CLARITHROMYCIN, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS. (See WARNINGS in prescribing information for clarithromycin.)
Amoxicillin: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. These reactions are more apt to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.
There have been well documented reports of individuals with a history of penicillin hypersensitivity reactions who have experienced severe hypersensitivity reactions when treated with a cephalosporin. Before initiating therapy with any penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and the appropriate therapy instituted.
SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
PSEUDOMEMBRANOUS COLITIS HAS BEEN REPORTED WITH NEARLY ALL ANTIBACTERIAL AGENTS, INCLUDING CLARITHROMYCIN AND AMOXICILLIN, AND MAY RANGE IN SEVERITY FROM MILD TO LIFE THREATENING. THEREFORE, IT IS IMPORTANT TO CONSIDER THIS DIAGNOSISIN PATIENTS WHO PRESENT WITH DIARRHEA SUBSEQUENT TO THE ADMINISTRATION OF ANTIBACTERIAL AGENTS.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis".
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
Symptomatic response to therapy with NEXIUM does not preclude the presence of gastric malignancy.
Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which NEXIUM is an enantiomer.
Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of esomeprazole was assessed using omeprazole studies. In two 24-month oral carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.7 to 57 times the human dose of 20 mg/day expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 5.6 times the human dose on a body surface area basis) for 1 year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of 1 year (94% treated vs 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for 2 years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive.
Esomeprazole was negative in the Ames mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. Esomeprazole, however, was positive in the in vitro human lymphocyte chromosome aberration test. Omeprazole was positive in the in vitro human lymphocyte chromosome aberration test, the in vivo mouse bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test.
The potential effects of esomeprazole on fertility and reproductive performance were assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 56 times the human dose on a body surface area basis) was found to have no effect on reproductive performance of parental animals.
Teratogenic Effects. Pregnancy Category B
Teratology studies have been performed in rats at oral doses up to 280 mg/kg/day (about 57 times the human dose on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 35 times the human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Teratology studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 56 times the human dose on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 56 times the human dose on a body surface area basis) 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 5.5 to 56 times the human dose on a body surface area basis) 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 5.6 to 56 times the human doses on a body surface area basis). There are no adequate and well-controlled studies in pregnant women. Sporadic reports have been received of congenital abnormalities occurring in infants born to women who have received omeprazole during pregnancy.
Pregnancy Category B. See full prescribing information for amoxicillin before using in pregnant women.
Pregnancy Category C. See WARNINGS (above) and full prescribing information for clarithromycin before using in pregnant women.
The excretion of esomeprazole in milk has not been studied. However, omeprazole concentrations have been measured in breast milk of a woman following oral administration of 20 mg. Because esomeprazole is likely to be excreted in human milk, because of the potential for serious adverse reactions in nursing infants from esomeprazole, and because of the potential for tumorigenicity shown for omeprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Use of NEXIUM in adolescent patients 12 to 17 years of age for short-term treatment of GERD is supported by a) extrapolation of results, already included in the currently approved labeling, from adequate and well-controlled studies that supported the approval of NEXIUM for adults, and b) safety and pharmacokinetic studies performed in adolescent patients.
(See CLINICAL PHARMACOLOGY, Pharmacokinetics, Pediatric for pharmacokinetic information.) The safety and effectiveness of NEXIUM for the treatment of symptomatic GERD in patients <12 years of age have not been established. The safety and effectiveness of NEXIUM for other pediatric uses have not been established.
12 to 17 Years of Age
In a multicenter, randomized, double-blind, parallel-group study, 149 adolescent patients (12 to 17 years of age; 89 female; 124 Caucasian, 15 Black, 10 Other) with clinically diagnosed GERD were treated with either NEXIUM 20 mg or NEXIUM 40 mg once daily for up to 8 weeks to evaluate safety and tolerability. Patients were not endoscopically characterized as to the presence or absence of erosive esophagitis.
The most frequently reported (at least 2%) treatment related adverse events in these patients were headache (8.1%), abdominal pain (2.7%), diarrhea (2%) and nausea (2%). No new safety concerns were identified.
Of the total number of patients who received NEXIUM in clinical trials, 1459 were 65 to 74 years of age and 354 patients were >75 years of age.
No overall differences in safety and efficacy were observed between the elderly and younger individuals, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
A single oral dose of esomeprazole at 510 mg/kg (about 103 times the human dose on a body surface area basis), was lethal to rats. The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia, and intermittent clonic convulsions.
There have been some reports of overdosage with esomeprazole. Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2,400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience (see omeprazole package insert - ADVERSE REACTIONS). No specific antidote for esomeprazole is known. Since esomeprazole is extensively protein bound, it is not expected to be removed by dialysis. In the event of overdosage, treatment should be symptomatic and supportive.
As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose, a certified Regional Poison Control Center should be contacted. Telephone numbers are listed in the Physicians' Desk Reference (PDR) or local telephone book.
NEXIUM is contraindicated in patients with known hypersensitivity to any component of the formulation or to substituted benzimidazoles.
Clarithromycin is contraindicated in patients with a known hypersensitivity to any macrolide antibiotic.
Concomitant administration of clarithromycin with pimozide is contraindicated. There have been post-marketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered with pimozide resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsade de pointes) most likely due to inhibition of hepatic metabolism of pimozide by erythromycin and clarithromycin. Fatalities have been reported. (Please refer to full prescribing information for clarithromycin.)
Amoxicillin is contraindicated in patients with a known hypersensitivity to any penicillin. (Please refer to full prescribing information for amoxicillin.)
Patients should be informed of the following:
NEXIUM Delayed-Release Capsules should be taken at least one hour before meals.
For patients who have difficulty swallowing capsules, one tablespoon of applesauce can be added to an empty bowl and the NEXIUM Delayed-Release Capsule can be opened, and the pellets inside the capsule carefully emptied onto the applesauce. The pellets should be mixed with the applesauce and then swallowed immediately. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The pellets should not be chewed or crushed. The pellet/applesauce mixture should not be stored for future use.
Antacids may be used while taking NEXIUM.