Side Effects of Prilosec (omeprazole)

奥美拉唑(omeprazole) is a proton pump inhibitor (PPI) that blocks the production of acid by the stomach and is used to treat conditions such as ulcers,gastroesophageal reflux disease(GERD), and Zollinger-Ellison syndrome, which are caused by stomach acid.

奥美拉唑, like other proton-pump inhibitors, blocks the enzyme in the wall of the stomach that produces acid. By blocking the enzyme, the production of acid is decreased, and this allows the stomach andesophagusto heal.

Common side effects of Prilosec include

• diarrhea,
• nausea,
• vomiting,
• headaches,
• rash,
• dizziness,
• nervousness,
• abnormal heartbeats,
• muscle pain,
• weakness, and infrequently,
• leg crampsand water retention.

Serious side effects of Prilosec includeClostridium difficileinfection. Long-term use of Prilosec can result in serious side effects such as increased risk ofosteoporosis-relatedfractureswith high doses, reduced absorption of vitamin B12 (cyanocobalamin), low levels of magnesium (hypomagnesemia), and an increased risk ofheart attacks.

Drug interactionsof Prilosec includediazepam,warfarin, andphenytoin, because Prilosec potentially can increase the concentrations in blood of thesedrugsby decreasing their elimination by theliver.

• The absorption of certain drugs may be affected by stomach acidity.
• 奥美拉唑as well as otherPPIsreduce the absorption and concentration in blood ofketoconazoleand increase the absorption and concentration in blood ofdigoxin. This may reduce the effectiveness of ketoconazole or increase digoxin toxicity.
• 奥美拉唑may increase blood levels ofsaquinavirand reduce blood levels ofnelfinavirandatazanavir, drugs used to treathuman immunodeficiency virus(HIV).
• Clopidogrel is converted to its active form by enzymes in the liver. Prilosec reduces the activity of these enzymes and potentially can reduce the activity of clopidogrel.
• 奥美拉唑should not be used with clopidogrel.
• 奥美拉唑increases the concentration ofcilostazoland the dose of cilostazol should be reduced when given with Prilosec.
• 奥美拉唑may increase blood levels ofmethotrexateand他克莫司.

Use of Prilosec inpregnant女性没有充分评估。奥美拉唑should be used duringpregnancyonly if the benefits justify the unknown risks.

奥美拉唑is excreted inbreast milkand potentially could cause adverse effects in the infant. Consult your doctor beforebreastfeeding.

Omeprazole like other PPIs is well-tolerated. The most common side effects are:

• diarrhea,
• nausea,
• vomiting,
• headaches,
• rashand
• dizziness.

Other important side effects include:

• Nervousness,
• abnormal heartbeat,
• musclepain,
• weakness,
• legcrampsand water retention occur infrequently.

Each packet ofZegeridpowder for oral suspension contains 460 mg of sodium and each capsule contains 304 mg of sodium. This should be taken into consideration in patients who need a sodium-restricteddiet.

Proton pump inhibitorsmay increase the risk ofClostridium difficileinfection. High doses and long-term use (1 year or longer) may increase the risk ofosteoporosis-related fractures of the hip, wrist, or spine. Prolonged use also reduces absorption of vitamin B12 (cyanocobalamin).

Long-term use of PPIs has also been associated with low levels of magnesium (hypomagnesemia). Analysis of patients taking PPIs for long periods of time showed an increased risk ofheart attacks.

Therefore, it is important to use the lowest doses and shortest duration of treatment necessary for the condition being treated.

Clinical Trials Experience With Prilosec Monotherapy

Becauseclinical trialsare 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 data described below reflects exposure to Prilosec Delayed-Release Capsules in 3096 patients from worldwide clinical trials (465 patients from US studies and 2,631 patients from international studies).

Indications clinically studied in US trials included

• duodenal ulcer,
• resistant ulcer, and
• Zollinger-Ellison syndrome.

The international clinical trials were double blind and open-label in design. The most common adverse reactions reported (i.e., with an incidence rate ≥ 2%) from Prilosec-treated patients enrolled in these studies included

• headache(6.9%),
• abdominal pain(5.2%),
• nausea (4.0%),
• diarrhea(3.7%),
• vomiting (3.2%), and
• flatulence(2.7%).

Additional adverse reactions that were reported with an incidence ≥ 1% included

• acid regurgitation (1.9%),
• upper respiratory infection(1.9%),
• constipation(1.5%),
• dizziness (1.5%),
• rash (1.5%),
• asthenia (1.3%),
• back pain(1.1%), and
• cough(1.1%).

The clinical trial safety profile in patients greater than 65 years of age was similar to that in patients 65 years of age or less.

The clinical trial safety profile in pediatric patients who received Prilosec Delayed-Release Capsules was similar to that in adult patients.

• Unique to the pediatric population, however, adverse reactions of the respiratory system were most frequently reported in both the 1 to < 2 and 2 to 16 year age groups (75.0% and 18.5%, respectively).
• Similarly,feverwas frequently reported in the 1 to 2 year age group (33.0%), and accidental injuries were reported frequently in the 2 to 16 year age group (3.8%).

Clinical Trials Experience With Prilosec In Combination Therapy ForH. pyloriEradication

In clinical trials using either dual therapy with Prilosec andclarithromycin, or triple therapy with Prilosec, clarithromycin, andamoxicillin, no adverse reactions unique to these drug combinations were observed. Adverse reactions observed were limited to those previously reported with omeprazole, clarithromycin, oramoxicillinalone.

Dual Therapy (Prilosec/clarithromycin)

Adverse reactions observed in controlled clinical trials using combination therapy with Prilosec and clarithromycin (n = 346) that differed from those previously described for Prilosec alone were

• taste perversion (15%),
• 舌变色(2%),
• rhinitis(2%),
• pharyngitis(1%) and
• flu-syndrome (1%).

For more information on clarithromycin, refer to the clarithromycin prescribing information, Adverse Reactions section.

Triple Therapy (Prilosec/clarithromycin/amoxicillin)

The most frequent adverse reactions observed in clinical trials using combination therapy with Prilosec, clarithromycin, and amoxicillin (n = 274) were

• diarrhea (14%),
• taste perversion (10%), and
• headache(7%).

None of these occurred at a higher frequency than that reported by patients taking antimicrobial agents alone. For more information on clarithromycin or amoxicillin, refer to the respective prescribing information, Adverse Reactions sections.

Post-marketing Experience

The following adverse reactions have been identified during post-approval use of Prilosec Delayed-Release Capsules. 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 includinganaphylaxis,anaphylactic shock,angioedema, bronchospasm, interstitial nephritis,urticaria, (seealsoSkinbelow);fever;pain;fatigue; malaise;

Cardiovascular:Chest painorangina, tachycardia, bradycardia,palpitations, elevated官网地址bwin, peripheraledema

Endocrine:Gynecomastia

Gastrointestinal:Pancreatitis(some fatal),anorexia, irritable colon, fecal discoloration, esophagealcandidiasis, mucosal atrophy of the tongue, stomatitis,abdominal swelling,dry mouth,microscopic colitis. 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 ZE syndrome on long-term treatment with Prilosec. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.

Hepatic:Liver diseaseincluding hepatic failure (some fatal), liver necrosis (some fatal),hepatic encephalopathyhepatocellular disease, cholestatic disease, mixedhepatitis,黄疸, and elevations ofliver functiontests [ALT, AST, GGT,alkaline phosphatase, andbilirubin]

Infections and Infestations:Clostridium difficileassociated diarrhea

Metabolism and Nutritional disorders:Hypoglycemia, hypomagnesemia, with or without hypocalcemia and/orhypokalemia,hyponatremia,weight gain

Musculoskeletal:Muscle weakness,myalgia,muscle cramps,joint pain,leg pain, bonefracture

Nervous System/Psychiatric:Psychiatric andsleepdisturbances includingdepression, agitation, aggression,hallucinations,confusion,insomnia, nervousness, apathy, somnolence,anxiety, and dream abnormalities;tremors, paresthesia;vertigo

Respiratory:Epistaxis, pharyngeal pain

Skin:Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and非常thema multiforme;photosensitivity;urticaria; rash;skin inflammation; pruritus;petechiae; purpura;alopecia;dry skin;hyperhidrosis

Special Senses:Tinnitus, taste perversion

Ocular:Optic atrophy, anterior ischemicoptic neuropathy,optic neuritis,dry eye syndrome, ocular irritation,blurred vision,double vision

Urogenital:Interstitial nephritis,hematuria,proteinuria, elevated serumcreatinine, microscopic pyuria,urinary tract infection, glycosuria, urinary frequency,testicular pain

Hematologic:Agranulocytosis (some fatal), hemolyticanemia, pancytopenia,neutropenia,anemia,thrombocytopenia, leukopenia, leucocytosis

Interference With Antiretroviral Therapy

• 伴随atazanavir和奈非那韦的使用proton pump inhibitors is not recommended.
• Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development ofdrug resistance.
• Co-administration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction.
• 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.

Reduced Concentrations Of Atazanavir And Nelfinavir

• 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 hr before atazanavir),
• AUC was decreased by 94%,
• C max by 96%, and Cmin by 95%.
• Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended.

Increased Concentrations 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.

Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with Prilosec. 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.

Drugs For Which Gastric pH Can Affect Bioavailability

Due to its effects on gastric acid secretion, omeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability.

Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts,erlotinib, andmycophenolate mofetil(MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with omeprazole.

• 伴随的奥美拉唑治疗(每天20毫克) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects).
• Co-administration of digoxin with Prilosec is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with Prilosec.
• 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 Prilosec and MMF.
• Use Prilosec with caution in transplant patients receiving MMF.

Effects On Hepatic Metabolism/Cytochrome P-450 Pathways

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 withtheophyllineorpropranololwas found, there have been clinical reports of interaction with other drugs metabolized via the cytochrome P450 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 Prilosec.
• Concomitant administration of omeprazole andvoriconazole(a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure.
• Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered.
• When voriconazole (400 mg Q12h x 1 day, then 200 mg x 6 days) was given with omeprazole (40 mg once daily x 7 days) to healthy subjects, it significantly increased the steady-state C max and AUC0-24 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.
• Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased Cmax and AUC of cilostazol by 18% and 26% respectively.
• C max and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively.
• Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered.
• 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 ofSt. John's Wortor rifampin with omeprazole.

Clopidogrel

• 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 Prilosec with clopidogrel.
• When using Prilosec, consider use of alternative anti-platelet therapy.
• 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.

Tacrolimus

• 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.

Combination Therapy With Clarithromycin

• Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions.
• Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs.

Methotrexate

• Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; seemethotrexate 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.