grnb-61-01-03 5457-is not Impaired Among Older Adults

A10AB01 Regular Insulin 1000IU/10ml/vial A10AC01 Insulin(NPH) 1000IU/10 ml/vial 30% Reguler Insulin/ 70% Isophane insulin suspension 諾和密斯30諾易筆注射劑 A10AD30 /300IU/3ml/pen 蘭德仕注射劑 A10AE04 Insulin Glargine 300IU/3ml 複合維他命Ｂ注射液 氯化鉀注射液 美達加祿針 斷血炎注射液 嘉體民注射液 鐵補注射液 彌可保注射液 2000IU容可曼針筒注射劑 5000IU容可曼針筒注射劑 10000IU容可曼針筒注射 美血樂 人體血清白蛋白 10ml/vial，每1ml含Thiamine 100mg/Pantothenate 5mg/ Niacinamide 50mg/ Ribflavin 5mg/ Pyridoxine 5mg A12BA51 Potassium Chloride 20mEq/10ml A12AA07 Glucose 2000mg/Calcium Chloride 400mg/20ml/amp A11EA B02AA02 Tranexamic acid 250mg/5ml/amp B02BA01 Phytomenadione 10mg/ml/amp B03AB04 Ferric-hydroxide-sucrose complex 100mg/5ml/vial B03BA05 B03XA01 B03XA01 B03XA01 Mecobalamin 500mcg/ml/amp Epoetin beta 2000IU/0.3ml/syringe Epoetin beta 5000IU/0.3ml/syringe Epoetin beta 10000IU/0.6ml/syringe Methoxy polyethylene glycol-epoetin beta B03XA03 50mcg/0.3ml/syringe B05AA01 Normal Serum Albumin 20%/50ml/bot 500ml/bot，每100ml含 L-Isoleucine 288mg/ L-Leucine 327mg/ L-Lysine HCl 2H2O 432mg/ L-Methionine 288mg/ L-Phenylalanine B05BA01 192mg/ L-Threonine 96mg/ L-Valine 288mg/ LArginine HCl 300mg/ L-Histidine HCl 2H2O 150mg/ Glycine 447mg/ Sorbitol 5000mg B05BA03 Glucose 500mg/ml; 20ml/amp B05BA03 Glucose 100mg/ml; 500ml/bot B05BA03 Glucose 50mg/ml; 500ml/bot 每100ml含Sodium Chloride 0.6g/ Potassium Chloride B05BB01 0.03g/ Calcium Chloride 0.02g/ Sodium Lactate 0.31g; 500ml/bot B05BB02 5% Dextrose(25g)/Saline0.9%(4.5g)/500ml/bot B05BC01 B05XA02 B05XA03 B05XA03 B05XA03 B05XA03 B05XA03 D-Mannitol 200mg/ml; 100ml/bot Sodium bicarbonate 70mg/ml; 20ml/amp 0.45% NaCl 20ml/amp 0.9% NaCl 500ml/bag 0.9% NaCl 20ml/amp NaCl 500ml/bot/沖洗用 0.45% NaCl 500ml/bot

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ZEGERID safely and effectively. See full prescribing information for ZEGERID.ZEGERID (omeprazole/sodium bicarbonate) Powder for Oral Suspension ZEGERID (omeprazole/sodium bicarbonate) CapsulesInitial U.S. Approval: 2004----------------------------RECENT MAJOR CHANGES-------------------------­Warnings and Precautions, 11/2012 Clostridium difjicile associated diarrhea (5.4)Warnings and Precautions, 11/2012 Interaction with clopidogrel (5.5)Warnings and Precautions, 11/2012 Concomitant Use of ZEGERID with St. John’s Wort or Rifampin (5.8) Warnings and Precautions,Interactions with Diagnostic 11/2012 Investigations for Neuroendocrine Tumors (5.9)Warnings and Precautions, 04/2012 Concomitant Use of Zegerid with Methotrexate (5.10)------------------------INDICATIONS AND USAGE-------------------­ZEGERID is a proton pump inhibitor indicated for:• Short-term treatment of active duodenal ulcer (1.1)• Short-term treatment of active benign gastric ulcer (1.2)• Treatment of gastroesophageal reflux disease (GERD) (1.3)• Maintenance of healing of erosive esophagitis (1.4)• Reduction of risk of upper GI bleeding in critically ill patients (1.5) The safety and effectiveness of ZEGERID in pediatric patients (<18 years of age) have not been established. (8.4)----------------------DOSAGE AND ADMINISTRATION----------------------­• Short-Term Treatment of Active DuodenalUlcer: 20 mg oncedaily for 4 weeks (some patients may requirean additional 4 weeks of therapy (14.1)) (2)• Gastric Ulcer: 40 mg once daily for 4-8 weeks (2)• Gastroesophageal Reflux Disease (GERD) (2)-Symptomatic GERD (with no esophageal erosions): 20 mg once daily for up to 4 weeks-Erosive Esophagitis: 20 mg once daily for 4-8 weeks• Maintenance of Healing of Erosive Esophagitis: 20 mg once daily (2) • Reduction of Risk of Upper Gastrointestinal Bleeding in Critically Ill Patients: (40mg oral suspension only) 40 mg initially followed by 40 mg 6-8 hours later and 40 mg daily thereafter for 14 days (2)---------------------DOSAGE FORMS AND STRENGTHS---------------------­• ZEGERID is available as a capsule and as a powder for oral suspension in 20 mg and 40 mg strengths (3)-------------------------------CONTRAINDICATIONS----------------------------­• Known hypersensitivity to any components of the formulation (4)-----------------------WARNINGS AND PRECAUTIONS-----------------------­• Concomitant Gastric Malignancy: Symptomatic response to therapy with ZEGERID does not preclude the presence of gastric malignancy(5.1)• Atrophic Gastritis: Has been observed in gastric corpus biopsies from patients treated long-term with omeprazole (5.2) • Buffer Content: contains sodium bicarbonate (5.3)• PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. (5.4)• Avoid concomitant use of Zegerid with clopidogrel (5.5)• Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures ofthe hip, wrist, or spine. (5.6)• Hypomagnesemia has been reported rarely with prolonged treatment with PPIs (5.7)• Avoid concomitant use of Zegerid with St John’s Wort or rifampin due to the potential reduction in omeprazole concentrations (5.8, 7.2)• Interactions with diagnostic investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia andenterochromaffin-like cell hyperplasia and increased Choromogranin A levels which may interfere with diagnostic investigations forneuroendocrine tumors. (5.9, 12.2)------------------------------ADVERSE REACTIONS------------------------------­Most common adverse reactions (incidence ≥ 2%) are:Headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence (6)To report SUSPECTED ADVERSE REACTIONS, contact Santarus Ienc. at 1-888-778-0887 or FDA at 1-800-FDA-1088 or/medwatch.------------------------------DRUG INTERACTIONS------------------------------­• Drugs for which gastric pH can affect bioavailability (e.g., ketoconazole, ampicillin esters, iron salts, and digoxin): ZEGERID may interfere with absorption due to inhibition of gastric acid secretion (7.1) • Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin, phenytoin, cyclosporine, disulfiram, benzodiazepines): ZEGERID can prolong their elimination. Monitor to determine the need for possibledose adjustments when taken with ZEGERID (7.2)• Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time(7.2)• Voriconazole: May increase plasma levels of omeprazole (7.2)• Saquinavir: ZEGERID increases plasma levels of saquinavir (7.3)• ZEGERID may reduce plasma levels of atazanavir and nelfinavir (7.3) • Clopidogrel: Zegerid decreases exposure to the active metabolite of clopidogrel (7.5)• Tacrolimus: ZEGERID may increase serum levels of tacrolimus (7.6) • Methotrexate: Zegerid may increase serum level of methotrexate (7.8) -----------------------USE IN SPECIFIC POPULATIONS----------------------­• Pregnancy: Based upon animal data, may cause fetal harm (8.1)• The safety and effectiveness of ZEGERID in pediatric patients less than18 years of age have not been established. (8.4)• Hepatic Impairment: Consider dose reduction, particularly for maintenance of healing of erosive esophagitis (12.3)See 17 for PATIENT COUNSELING INFORMATION and Medication GuideRevised: 11/2012__________________________________________________________________________________________________________________________________FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE1.1 Duodenal Ulcer1.2 Gastric Ulcer1.3 Treatment of Gastroesophageal Reflux Disease (GERD)1.4 Maintenance of Healing of Erosive Esophagitis1.5 Reduction of Risk of Upper Gastrointestinal Bleeding in CriticallyIll Patients (40mg suspension only)2 DOSAGE AND ADMINISTRATION3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Concomitant Gastric Malignancy5.2 Atrophic Gastritis5.3 Buffer Content5.4 Clostridium Difficile associated diarrhea5.5 Interaction with clopidogrel5.6 Bone Fracture5.7 Hypomagnesemia5.8 Concomitant use of ZEGERID with St John’s Wort or rifampin5.9 Interactions with Investigations for Neuroendocrine Tumors5.10 Concomitant use Zegerid with Methotrexate6 ADVERSE REACTIONS6.1 Clinical Trials Experience6.2 Postmarketing Experience7 DRUG INTERACTIONS7.1 Drugs for which gastric pH can affect bioavailability7.2 Drugs metabolized by cytochrome P450 (CYP)7.3 Antiretroviral Agents7.4 Combination Therapy with Clarithromycin7.5 Clopidogrel7.6 Tacrolimus7.7 Interactions With Investigations of Neuroendocrine Tumors7.8 Methotrexate8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Hepatic Impairment8.7 Renal Impairment8.8 Asian Population10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES14.1 Duodenal Ulcer Disease14.2 Gastric Ulcer14.3 Gastroesophageal Reflux Disease GERD14.4 Long Term Maintenance Treatment of Erosive Esophagitis14.5 Reduction of Risk of Upper Gastrointestinal Bleeding in Critically Ill Patients15 REFERENCES16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are not listed.__________________________________________________________________________________________________________________________________FULL PRESCRIBING INFORMATION:1 INDICATIONS AND USAGE1.1 Duodenal UlcerZEGERID (omeprazole/sodium bicarbonate) is indicated for short-term treatment of active duodenal ulcer. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. [See Clinical Studies (14.1)]1.2 Gastric UlcerZEGERID is indicated for short-term treatment (4-8 weeks) of active benign gastric ulcer. [See Clinical Studies (14.2)]1.3 Treatment of Gastroesophageal Reflux Disease (GERD) Symptomatic GERDZEGERID is indicated for the treatment of heartburn and other symptoms associated with GERD. [See Clinical Studies (14.3)]Erosive EsophagitisZEGERID is indicated for the short-term treatment (4-8 weeks) of erosive esophagitis which has been diagnosed by endoscopy.The efficacy of ZEGERID used for longer than 8 weeks in these patients has not been established. If a patient does not respond to 8 weeks of treatment, it may be helpful to give up to an additional 4 weeks of treatment. If there is recurrence of erosive esophagitis or GERD symptoms (e.g., heartburn), additional 4-8 week courses of ZEGERID may be considered. [See Clinical Studies (14.3)]1.4 Maintenance of Healing of Erosive EsophagitisZEGERID is indicated to maintain healing of erosive esophagitis. Controlled studies do not extend beyond 12 months. [See Clinical Studies (14.4)]1.5 Reduction of Risk of Upper Gastrointestinal Bleeding in CriticallyIll Patients (40mg oral suspension only)ZEGERID Powder for Oral Suspension 40 mg/1680 mg is indicated for the reduction of risk of upper GI bleeding in critically ill patients. [See CLINICAL STUDIES, Reduction of Risk of Upper Gastrointestinal Bleeding in Critically Ill Patients (14.5)]2 DOSAGE AND ADMINISTRATIONZEGERID (omeprazole/sodium bicarbonate) is available as a capsule and as a powder for oral suspension in 20 mg and 40 mg strengths of omeprazole for adult use. Directions for use for each indication are summarized in Table 1. All recommended doses throughout the labeling are based upon omeprazole Since both the 20 mg and 40 mg oral suspension packets contain the same amount of sodium bicarbonate (1680 mg), two packets of 20 mg are not equivalent to one packet of ZEGERID 40 mg; therefore, two 20 mg packets of ZEGERID should not be substituted for one packet of ZEGERID 40 mg. Since both the 20 mg and 40 mg capsules contain the same amount of sodium bicarbonate (1100 mg), two capsules of 20 mg are not equivalent to one capsule of ZEGERID 40 mg; therefore, two 20 mg capsules of ZEGERID should not be substituted for one capsule of ZEGERID 40 mg.ZEGERID should be taken on an empty stomach at least one hour before a meal.For patients receiving continuous Nasogastric (NG)/ Orogastric (OG) tube feeding, enteral feeding should be suspended approximately 3 hours before and 1 hour after administration of ZEGERID Powder for Oral Suspension.Table 1: Recommended Doses of ZEGERID by Indication for Adults18 Years and OlderRecommendedIndication FrequencyDoseShort-Term Treatment of20 mg Once daily for 4 weeks*,+ Active Duodenal UlcerOnce daily for 4-8 Benign Gastric Ulcer 40 mgweeks **,+Gastroesophageal RefluxDisease (GERD)Symptomatic GERD (with Once daily for up to 420 mgno esophageal erosions) weeks+Erosive Esophagitis 20 mg Once daily for 4-8 weeks+Maintenance of Healing of20 mg Once daily** Erosive EsophagitisReduction of Risk of Upper 40 mg initially followed byGastrointestinal Bleeding in 40 mg 6-8 hours later and40 mgCritically Ill Patients 40 mg daily thereafter for (40 mg oral suspension only) 14 days*** Most patients heal within 4 weeks. Some patients may require an additional 4 weeks of therapy. [See Clinical Studies (14.1)]** For additional information, [See Clinical Studies (14)]+ For additional information, [See Indications and Usage (1)]Special PopulationsHepatic InsufficiencyConsider dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3)]Administration of CapsulesZEGERID Capsules should be swallowed intact with water. DO NOT USE OTHER LIQUIDS. DO NOT OPEN CAPSULE AND SPRINKLE CONTENTS INTO FOOD.Preparation and Administration of SuspensionDirections for use: Empty packet contents into a small cup containing 1-2 tablespoons of water. DO NOT USE OTHER LIQUIDS OR FOODS. Stir well and drink immediately. Refill cup with water and drink.If ZEGERID is to be administered through a nasogastric (NG) or orogastric (OG) tube, the suspension should be constituted with approximately 20 mL of water. DO NOT USE OTHER LIQUIDS OR FOODS. Stir well and administer immediately. An appropriately-sized syringe should be used to instill the suspension in the tube. The suspension should be washed through the tube with 20 mL of water.3 DOSAGE FORMS AND STRENGTHSZEGERID 20-mg Capsules: Each opaque, hard gelatin, white capsule, imprinted with the Santarus logo and “20”, contains 20 mg omeprazole and 1100 mg sodium bicarbonate.ZEGERID 40-mg Capsules: Each opaque, hard gelatin, colored dark blue and white capsule, imprinted with the Santarus logo and “40”, contains 40 mg omeprazole and 1100 mg sodium bicarbonate.ZEGERID Powder for Oral Suspension is a white, flavored powder packaged in unit-dose packets. Each packet contains either 20 mg or 40 mg omeprazole and 1680 mg sodium bicarbonate.4 CONTRAINDICATIONSZEGERID is contraindicated in patients with known hypersensitivity to any components of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, and urticaria.5 WARNINGS AND PRECAUTIONS 5.1 Concomitant Gastric Malignancy Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy. 5.2 Atrophic gastritis Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole. 5.3 Buffer Content 5.4 Clostridium difficile associated diarrhea Published observational studies suggest that PPI therapy like Zegerid may beassociated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered fordiarrhea that does not improve. [See Adverse Reactions (6.2)] Patients should use the lowest dose and shortest duration of PPI therapyappropriate to the condition being treated. 5.5Interaction with clopidogrel Avoid concomitant use of Zegerid with clopidogrel. Clopidogrel is a prodrug.Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that interfere with CYP2C19 activity. Concomitant use of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using Zegerid, consider alternative anti-platelet therapy [see Drug Interactions (7.5) and Pharmacokinetics (12.3)]. 5.6 Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines. [See Dosage and Administration (2) and Adverse Reactions (6.2)] 5.7 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. [See Adverse Reactions (6.2)] 5.8 Concomitant use of Zegerid with St John’s Wort or rifampin Drugs which induce CYP2C19 OR CYP34A (such as St John’s Wort or rifampin) can substantially decrease omeprazole concentrations. [See Drug Interactions (7.2)]. Avoid concomitant use of ZEGERD with St John’s Wort or rifampin. 5.9 Interactions with Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop omeprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary . [SeePharmacodynamics (12.2)]5.10Concomitant use of Zegerid with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients. [See Drug Interactions (7.7) 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in 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 Omeprazole Placebo Ranitidine (n = 465) (n = 64) (n = 195) Omeprazole Placebo (n = 2631) (n = 120) Body as a Whole, site unspecified Abdominal pain 5.2 3.3 Asthenia 1.3 0.8 Digestive System Constipation 1.5 0.8 Diarrhea 3.7 2.5 Flatulence 2.7 5.8 Nausea 4.0 6.7 Vomiting 3.2 10.0 Acid regurgitation 1.9 3.3 Nervous System/Psychiatric Headache 2.9 2.5 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) URI 1.9 1.6 2.6 Dizziness 1.5 (0.6) 0.0 2.6 (1.0) Vomiting 1.5 (0.4) 4.7 1.5 (0.5) Rash 1.5 (1.1) 0.0 0.0 Constipation 1.1 (0.9) 0.0 0.0 Cough 1.1 0.0 1.5 Asthenia 1.1 (0.2) 1.6 (1.6) 1.5 (1.0) Back Pain 1.1 0.0 0.5 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 AssessedA 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 4by body system and preferred term.Table 4: Number (%) of Critically Ill Patients withFrequently Occurring (≥ 3%) Adverse Events by BodySystem and Preferred Term(N=178) (N=181) MedDRABody System All AEs All AEs Preferred Term n (%) n (%) BLOOD AND LYMPHATIC SYSTEMDISORDERSAnemia 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)ADMINISTRATION SITE CONDITIONSHyperpyrexia 8 (4.5) 3 (1.7) Edema NOS 5 (2.8) 11 (6.1) Pyrexia 36 (20.2) 29 (16.0) INFECTIONS AND INFESTATIONSCandidal 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) INVESTIGATIONSLiver Function Tests NOS Abnormal 3 (1.7) 6 (3.3) METABOLISM AND NUTRITIONDISORDERSFluid 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) Hypophosphataemia 11 (6.2) 7 (3.9) PSYCHIATRIC DISORDERSAgitation 6 (3.4) 16 (8.8) RESPIRATORY, THORACIC ANDMEDIASTINAL DISORDERSAcute 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 TISSUEDISORDERSDecubitus Ulcer 6 (3.4) 5 (2.8) Rash NOS 10 (5.6) 11 (6.1) VASCULAR DISORDERSHypertension 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.6.2 Postmarketing ExperienceThe 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 Body as a Whole: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria (see also Skin below), fever, pain, fatigue, malaise. Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitation, elevated blood pressure, and peripheral edema.Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, flatulence, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, dry mouth, stomatitis 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. Metabolism and Nutritional Disorders: Hyponatremia, hypoglycemia, hypomagnesemia, and weight gain.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.Respiratory: Epistaxis, pharyngeal pain.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.Ocular: Blurred vision, ocular irritation, dry eye syndrome, optic atrophy, anterior ischemic optic neuropathy, optic neuritis and double vision. Urogenital: Interstitial nephritis (some with positive rechallenge), urinary tract infection, microscopic pyuria, urinary frequency, elevated serum creatinine, proteinuria, hematuria, glycosuria, testicular pain, and gynecomastia.Hematologic: Rare instances of pancytopenia, agranulocytosis (some fatal), thrombocytopenia, neutropenia, leukopenia, anemia, leucocytosis, and hemolytic anemia have been reported.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.Additional adverse reactions that could be caused by sodium bicarbonate include metabolic alkalosis, seizures, and tetany.7 DRUG INTERACTIONS7.1 Drugs for which gastric pH can affect bioavailabilityBecause 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.7.2 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 propranololmetabolized via the cytochrome P-450 system (e.g., cyclosporine, disulfiram,benzodiazepines). Patients should be monitored to determine if it is necessaryto adjust the dosage of these drugs when taken concomitantly withZEGERID.omeprazole exposure. Dose adjustment of omeprazole is not normallyrequired.. When voriconazole (400 mg every 12 hours for one day, then 200mg for 6 days) was given with omeprazole (40 mg once daily for 7 days) tohealthy 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 withoutvoriconazole.subjects, St John’s wort (300 mg three times daily for 14 days), an inducer ofCYP3A4, decreased the systemic exposure of omeprazole in CYP2C19 poormetabolisers (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 withomeprazole.Concomitant administration of atazanavir and proton pump inhibitors is notrecommended. Co-administration of atazanavir with proton pump inhibitorsis expected to substantially decrease atazanavir plasma concentrations andthereby reduce its therapeutic effect.Omeprazole has been reported to interact with some antiretroviral drugs. Theclinical importance and the mechanisms behind these interactions are notalways known. Increased gastric pH during omeprazole treatment maychange the absorption of the antiretroviral drug. Other possible interactionmechanisms are via CYP2C19. For some antiretroviral drugs, such asatazanavir and nelfinavir, decreased serum levels have been reported whengiven together with omeprazole. Following multiple doses of nelfinavir (1250mg, 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% respectivelyfor nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily)and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC wasdecreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitantadministration with omeprazole and drugs such as atazanavir and nelfinavir istherefore not recommended.Increased concentration of saquinavirFor other antiretroviral drugs, such as saquinavir, elevated serum levels havebeen reported with an increase in AUC by 82%, in Cmax by 75% and inCmin by 106% following multiple dosing of saquinavir/ritonavir (1000/100mg) twice daily for 15 days with omeprazole 40 mg daily co-administereddays 11 to 15. Dose reduction of saquinavir should be considered from thesafety perspective for individual patients. There are also some antiretroviraldrugs of which unchanged serum levels have been reported when given withomeprazole.Concomitant administration of clarithromycin with other drugs can lead toserious adverse reactions due to drug interaction [See Warnings andPrecautions in prescribing information for clarithromycin]. Because of thesedrug interactions, clarithromycin is contraindicated for co-administration withcertain drugs [See Contraindication in prescribing information forclarithromycin].Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is metabolizedto its active metabolite in part by CYP2C19. Concomitant use of omeprazole80 mg results in reduced plasma concentrations of the active metabolite ofclopidogrel and a reduction in platelet inhibition. Avoid concomitantadministration of Zegerid with clopidogrel. When using Zegerid, consider useof alternative anti-platelet therapy [see Pharmacokinetics (12.3)].Concomitant administration of omeprazole and tacrolimus may increase theserum levels of tacrolimus.Drug-induced decrease in gastric acidity results in enterochromaffin-like cellhyperplasia and increased Chromogranin A levels which may interfere withinvestigations for neuroendocrine tumors. [see Clinical Pharmacology (12)].Case reports, published population pharmacokinetic studies, and retrospectiveanalyses suggest that concomitant administration of PPIs and methotrexate(primarily at high dose; see methotrexate prescribing information) mayelevate and prolong serum levels of methotrexate and/or its metabolitehydroxymethotrexate. However, no formal drug interaction studies ofmethotrexate with PPIs have been conducted. [see Warnings and Precautions(5.10)].8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no adequate and well-controlled studies on the use of omeprazole inpregnant women. The vast majority of reported experience with omeprazoleduring human pregnancy is first trimester exposure and the duration of use israrely specified, eg, intermittent versus chronic. An expert review ofpublished data on experiences with omeprazole use during pregnancy byTERIS – the Teratogen Information System – concluded that therapeuticdoses during pregnancy are unlikely to pose a substantial teratogenic risk (thequantity and quality of data were assessed as fair).1Three epidemiological studies compared the frequency of congenitalabnormalities among infants born to women who used omeprazole duringpregnancy to the frequency of abnormalities among infants of womenexposed to H2-receptor antagonists or other controls. A population-basedprospective cohort epidemiological study from the Swedish Medical BirthRegistry, covering approximately 99% of pregnancies, reported on 955infants (824 exposed during the first trimester with 39 of these exposedbeyond first trimester, and 131 exposed after the first trimester) whosemothers used omeprazole during pregnancy.2 In utero exposure to omeprazolewas not associated with increased risk of any malformation (odds ratio 0.82,95% CI 0.50-1.34), low birth weight or low Apgar score. The number ofinfants born with ventricular septal defects and the number of stillborn infantswas slightly higher in the omeprazole exposed infants than the expectednumber in the normal population. The author concluded that both effects maybe random.A retrospective cohort study reported on 689 pregnant women exposed toeither H2-blockers or omeprazole in the first trimester (134 exposed toomeprazole).3 The overall malformation rate was 4.4% (95% CI 3.6-5.3) andthe malformation rate for first trimester exposure to omeprazole was 3.6%(95% CI 1.5-8.1). The relative risk of malformations associated with firsttrimester exposure to omeprazole compared with nonexposed women was 0.9(95% CI 0.3-2.2). The study could effectively rule out a relative risk greaterthan 2.5 for all malformations. Rates of preterm delivery or growthretardation did not differ between the groups.A controlled prospective observational study followed 113 women exposed toomeprazole during pregnancy (89% first trimester exposures).4 The reportedrates of major congenital malformations was 4% for the omeprazole group,2% for controls exposed to nonteratogens, and 2.8% in disease-pairedcontrols (background incidence of major malformations 1-5%). Rates ofspontaneous and elective abortions, preterm deliveries, gestational age atdelivery, and mean birth weight did not differ between the groups. Thesample size in this study has 80% power to detect a 5-fold increase in the rateof major malformation.Several studies have reported no apparent adverse short term effects on theinfant when single dose oral or intravenous omeprazole was administered toover 200 pregnant women as premedication for cesarean section undergeneral anesthesia.Reproduction studies conducted with omeprazole in rats at oral doses up to 28times the human dose of 40 mg/day (based on body surface area) and inrabbits at doses up to 28 times the human dose (based on body surface area)did not show any evidence of teratogenicity. In pregnant rabbits, omeprazoleat doses about 2.8 to 28 times the human dose of 40 mg/day, (based on bodysurface area) produced dose-related increases in embryo-lethality, fetalresorptions, and pregnancy loss. In rats treated with omeprazole at dosesabout 2.8 to 28 times the human dose (based on body surface area), dose-related embryo/fetal toxicity and postnatal developmental toxicity occurred inoffspring. [See Animal Toxicology and/or Pharmacology (13.2)].There are no adequate and well-controlled studies in pregnant women.。

Zmax TM(azithromycin extended release) for oral suspensionTo reduce the development of drug-resistant bacteria and maintain the effectiveness of Zmax TM and other antibacterial drugs, Zmax should be used only to treat infections that are proven or strongly suspected to be caused by bacteria.DESCRIPTIONZmax (azithromycin extended release) for oral suspension contains the active ingredient azithromycin (as azithromycin dihydrate), an azalide, a subclass of macrolide antibiotics. Azithromycin has the chemical name (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3- (dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring. Its molecular formula is C38H72N2O12, and its molecular weight is 749.0. Azithromycin has the following structural formula:33Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula ofC38H72N2O12•2H2O and a molecular weight of 785.0.Zmax is a single-dose, extended release formulation of microspheres for oral suspension containing azithromycin (as azithromycin dihydrate) and the following excipients: glyceryl behenate, poloxamer 407, sucrose, sodium phosphate tribasic anhydrous, magnesium hydroxide, hydroxypropyl cellulose, xanthan gum, colloidal silicon dioxide, titanium dioxide, artificial cherry flavor, and artificial banana flavor.Each bottle contains azithromycin dihydrate equivalent to 2.0 g of azithromycin. It is constituted with 60 mL of water and the entire contents are administered orally as a single dose.CLINICAL PHARMACOLOGYPharmacokineticsZmax is an extended release microsphere formulation. Based on data obtained from studies evaluatingthe pharmacokinetics (PK) of azithromycin in healthy adult subjects a higher peak serum concentration(C max) and greater systemic exposure (AUC0-24) of azithromycin are achieved on the day of dosingfollowing a single 2.0 g dose of Zmax versus 1.5 g of azithromycin tablets administered over 3 days (500 mg/day) or 5 days (500 mg on day 1, 250 mg/day on days 2-5) [Table 1]. Consequently, due to thesedifferent PK profiles, Zmax is not interchangeable with azithromycin tablet 3-day and 5-day dosingregimens.Table 1. Mean (SD) Pharmacokinetic Parameters for Azithromycin on Day 1 Following theAdministration of a Single Dose of 2.0 g Zmax or 1.5 g of Azithromycin Tablets Given over 3 Days(500 mg/day) or 5 Days (500 mg on Day 1 and 250 mg on Days 2-5) to Healthy Adult SubjectsAzithromycin RegimenPharmacokineticParameter*Zmax[n=41]†3-day ‡[n=12]5-day ‡[n=12]C max (µg/mL)0.821(0.281)0.441(0.223)0.434(0.202)T max§ (hr)5.0(2.0-8.0)2.5(1.0-4.0)2.5(1.0-6.0)AUC0-24 (µg·hr/mL)8.62(2.34)2.58(0.84)2.60(0.71)AUC0-8¶(µg·hr/mL)20.0(6.66)17.4(6.2)14.9(3.1)t1/2 (hr)58.8(6.91)71.8(14.7)68.9(13.8)* Zmax, 3-day and 5-day regimen parameters obtained from separate PK studies † n = 21 for AUC0-8 and t1/2‡ C max, T max and AUC0-24 values for Day 1 only§Median (range)¶ Total AUC for the 1-day, 3-day and 5-day regimensSD = standard deviationC max = maximum serum concentrationT max = time to C maxAUC = area under concentration vs. time curvet1/2 = terminal serum half-lifeAbsorptionIn a two-way crossover study, sixteen healthy adult subjects were administered single doses of 2.0 g Zmax and azithromycin powder for oral suspension (POS) (2 × 1.0 g sachets). The mean C max and AUC0-t of azithromycin were lower by 57% and 17%, respectively with Zmax compared to azithromycin POS. The bioavailability of Zmax relative to azithromycin POS was 83%. On average, peak serum concentrations were achieved approximately 2.5 hours later following Zmax administration compared to azithromycin POS. Thus, single 2.0 g doses of Zmax and azithromycin POS are not bioequivalent and are not interchangeable.When a 2.0 g dose of Zmax was administered to 15 healthy adult subjects following a high-fat meal (150 kcal from proteins, 250 kcal from carbohydrates and 500-600 kcal from fats) the mean azithromycin C max increased by 115% and the mean AUC0-t increased by 23% as compared to administration in a fasted state. When a 2.0 g dose of Zmax was administered to 88 adult subjects following a standard meal (56 kcal from proteins, 316 kcal from carbohydrates, and 207 kcal from fats) the mean azithromycin C max increased by 119% and the mean AUC0-72 increased 12% as compared to administration in the fasted state. (See DOSAGE AND ADMINISTRATION.)In a two-way crossover study, 39 healthy adult subjects were administered 2.0 g dose of Zmax alone and with 20 mL of regular strength aluminum and magnesium hydroxide antacid. Following the administration of Zmax with an aluminum and magnesium hydroxide antacid, the rate and extent of azithromycin absorption were not altered.DistributionThe serum protein binding of azithromycin is concentration dependent, decreasing from 51% at0.02 µg/mL to 7% at 2.0 µg/mL.Following oral administration, azithromycin is widely distributed throughout the body with an apparent steady-state volume of distribution of 31.1 L/kg.Higher azithromycin concentrations in tissues than in plasma or serum have been observed. The extensive distribution of drug to tissues may be relevant to clinical activity. The antimicrobial activity of azithromycin is pH related and appears to be reduced with decreasing pH. Hence, high tissue concentrations should not be interpreted as being quantitatively related to clinical efficacy. Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios are shown in Table 2.Table 2. Azithromycin Concentrations Following a 500 mg Dose in Adults*TISSUE OR FLUID TIME AFTERDOSE (hr) TISSUE OR FLUIDCONCENTRATION(µg/g or µg/mL)CORRESPONDINGPLASMA OR SERUMCONCENTRATION(µg/mL)TISSUE (FLUID)PLASMA (SERUM)RATIOSKIN 72-96 0.4 0.012 35LUNG 72-96 4.0 0.012 >100 SPUTUM†2-4 1.0 0.64 2 SPUTUM‡10-12 2.9 0.1 30 TONSIL§9-18 4.5 0.03 >100 TONSIL§180 0.9 0.006 >100 CERVIX¶19 2.8 0.04 70 * Azithromycin tissue concentrations were originally determined using 250 mg capsules.† Sample was obtained 2-4 hours after the first dose.‡ Sample was obtained 10-12 hours after the first dose.§ Dosing regimen of two doses of 250 mg each, separated by 12 hours.¶Sample was obtained 19 hours after a single 500 mg dose.The extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder). However, the clinical significance of these tissue concentration data is unclear as clinical data from adequate andwell-controlled studies of azithromycin treatment of infections in these additional body sites are not available.Following a regimen of 500 mg of azithromycin tablets on the first day and 250 mg daily for 4 days, only very low concentrations were noted in cerebrospinal fluid (less than 0.01 µg/mL) in the presence ofnon-inflamed meninges.MetabolismIn vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.EliminationSerum azithromycin concentrations following a single 2.0 g dose of Zmax declined in a polyphasic pattern with a terminal elimination half-life of 59 hours. The prolonged terminal half-life is thought to be due to a large apparent volume of distribution.Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.Special PopulationsRenal InsufficiencyAzithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of azithromycin (4 ×250 mg capsules), the mean C max and AUC0-120 increased by 5.1% and 4.2%, respectively in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function (GFR >80 mL/min). The meanC max and AUC0-120 increased 61% and 35%, respectively in subjects with end-stage renal disease (GFR<10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). Based upon the pharmacokinetic data for azithromycin in subjects with renal impairment, no dose adjustment for Zmax is recommended in patients with GFR >10 mL/min. (See DOSAGE AND ADMINISTRATION.)Hepatic InsufficiencyThe pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.GenderThe impact of gender on the pharmacokinetics of azithromycin has not been evaluated for Zmax. However,previous studies have demonstrated no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment of Zmax is recommended based on gender.Geriatric PatientsThe pharmacokinetics of azithromycin following administration of Zmax has not been evaluated in geriatric patients.Pediatric PatientsZmax is not approved for pediatric patients.Drug-Drug InteractionsDrug interaction studies were performed with azithromycin capsules and tablets (doses ranged from 500 to 1200 mg) and drugs likely to be co-administered. The effects of co-administration of azithromycin on the pharmacokinetics of other drugs are shown in Table 3 and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 4.Co-administration of azithromycin capsules and tablets at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 3. Although the drug interaction studies were not conducted with Zmax , no potential drug interactions are expected since the total exposure to azithromycin is comparable for Zmax and the other azithromycin regimens. Therefore, no dosage adjustment of drugs listed in Table 3 is recommended when co-administered with Zmax. (See PRECAUTIONS - Drug Interactions.)Co-administration of azithromycin tablets with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C max and AUC of azithromycin. Similar results are expected with Zmax . Although no dosage adjustment of Zmax is recommended when administered with drugs listed in Table 4, close monitoring for known side effects of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted when co-administered with nelfinavir. (See PRECAUTIONS - Drug Interactions.)Table 3. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of AzithromycinRatio (with/without Azithromycin) ofCo-administered DrugPharmacokinetic Parameters (90%CI); No Effect = 1.00 Co-administeredDrugDose of Co-administeredDrugDose of Azithromycin*nMean C max Mean AUC Atorvastatin 10 mg/day × 8 days500 mg/day PO on days 6-812 0.83 (0.63 to 1.08)1.01 (0.81 to 1.25)Carbamazepine200 mg/day × 2 days, then 200 mg BID × 18 days 500 mg/day PO for days 16-1870.97 (0.88 to 1.06) 0.96 (0.88 to 1.06) Cetirizine20 mg/day × 11 days500 mg PO on day 7, then 250 mg/day on days 8-11141.03 (0.93 to 1.14) 1.02 (0.92 to 1.13) Didanosine 200 mg PO BID × 21 days1,200 mg/day POon days 8-21 6 1.44 (0.85 to 2.43)1.14 (0.83 to 1.57)Efavirenz 400 mg/day × 7days600 mg PO on day 7 14 1.04† 0.95† Fluconazole 200 mg PO single dose 1,200 mg POsingle dose18 1.04 (0.98 to 1.11)1.01 (0.97 to 1.05)Indinavir 800 mg TID × 5days1,200 mg PO on day 5 18 0.96 (0.86 to 1.08)0.90 (0.81 to 1.00)Midazolam 15 mg PO on day 3 500 mg/day PO × 3days12 1.27 (0.89 to 1.81)1.26 (1.01 to 1.56)Nelfinavir 750 mg TID × 11 days1,200 mg PO onday 9 14 0.90 (0.81 to 1.01)0.85 (0.78 to 0.93)Rifabutin 300 mg/day × 10days500 mg PO on day 1, then 250 mg/day on days 2-106‡NASildenafil 100 mg on days 1 and 4 500 mg/day PO × 3days12 1.16 (0.86 to 1.57)0.92 (0.75 to 1.12)Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg PO on day7, then 250 mg/dayon days 8-11101.19 (1.02 to 1.40) 1.02 (0.86 to 1.22) Theophylline 300 mg PO BID × 15 days500 mg PO on day6, then 250 mg/day on days 7-108 1.09 (0.92 to 1.29)1.08 (0.89 to 1.31)Triazolam 0.125 mg on day 2 500 mg PO on day1, then 250 mg/day on day 2121.06†1.02†Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day PO × 7 days 1,200 mg PO on day 7120.85(0.75 to 0.97)/0.90 (0.78 to 1.03)0.87(0.80 to 0.95)/0.96 (0.88 to 1.03)Zidovudine 500 mg/day PO × 21 days600 mg/day PO × 14 days5 1.12 (0.42 to 3.02)0.94 (0.52 to 1.70)Zidovudine500 mg/day PO × 21 days1,200 mg/day PO × 14 days41.31 (0.43 to 3.97) 1.30 (0.69 to2.43)NA = not available* Refers to azithromycin capsules and tablets unless specified † 90% confidence interval not reported‡ Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when co-administered with azithromycin and 71 ng/mL when co-administered with placebo.Table 4. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs (See PRECAUTIONS - Drug Interactions )Ratio (with/without co-administereddrug) of AzithromycinPharmacokinetic Parameters (90%CI); No Effect = 1.00 Co-administeredDrugDose of Co-administeredDrugDose of Azithromycin*nMean C max Mean AUC Efavirenz 400 mg/day × 7 days600 mg PO on day 714 1.22 (1.04 to 1.42)0.92† Fluconazole 200 mg PO single dose1,200 mg PO single dose18 0.82 (0.66 to 1.02)1.07 (0.94 to 1.22)Nelfinavir 750 mg TID × 11 days1,200 mg PO on day 914 2.36 (1.77 to 3.15)2.12 (1.80 to 2.50)Rifabutin300 mg/day × 10 days500 mg PO on day 1, then 250 mg/day on days 2-106‡NAAl and Mg hydroxide20 mL regular strength, single dose2.0 g Zmax, single dose390.99 (0.93 to 1.06) 0.99 (0.92 to 1.08)NA = not available* Refers to azithromycin capsules and tablets unless specified † 90% confidence interval not reported‡ Mean azithromycin concentrations one day after the last dose were 53 ng/mL when co-administered with 300 mg daily rifabutin and 49 ng/mL when co-administered with placebo.Microbiology Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms, thus interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.Azithromycin concentrates in fibroblasts, epithelial cells, macrophages, and circulating neutrophils and monocytes. In vitro incubation techniques have shown that the ratio of intracellular to extracellular concentration was >30 after one hour incubation. In vivo studies suggest that concentration inmacrophages and circulating white blood cells may contribute to drug distribution to inflamed tissues.Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.Aerobic and facultative Gram-positive microorganisms Streptococcus pneumoniaeNOTE: Erythromycin- and penicillin-resistant Gram-positive isolates may demonstrate cross-resistance to azithromycin.Aerobic and facultative Gram-negative microorganisms Haemophilus influenzae Moraxella catarrhalis“Other” microorganisms Chlamydophila pneumoniae Mycoplasma pneumoniaeBeta-lactamase production should not affect azithromycin activity.The following in vitro data are available, but their clinical si gnificance is unknown.At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for azithromycin. However, the safety and effectiveness of azithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.Aerobic and facultative Gram-positive microorganismsStaphylococcus aureusStreptococcus pyogenesStreptococcus agalactiaeStreptococci (Groups C, F, G)Viridans group streptococciAerobic and facultative Gram-negative microorganismsBordetella pertussisLegionella pneumophilaAnaerobic microorganismsPeptostreptococcus speciesPrevotella bivia“Other” microorganismsUreaplasma urealyticumSusceptibility Testing Methods:in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.Dilution techniques:Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of azithromycin powder. The MIC values should be interpreted according to criteria provided in Table 5.Diffusion techniques:Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-µg azithromycin to test the susceptibility of microorganisms to azithromycin. The disk diffusion interpretive criteria are provided in Table 5.Table 5. Susceptibility Test Result Interpretive Criteria for AzithromycinMinimum Inhibitory Concentrations (µg/mL)Disk Diffusion (zone diameters in mm)PathogenS I R* S I R* Haemophilus spp. ≤ 4 -- -- ≥ 12 -- -- Streptococci includingS. pneumoniae< 0.5 1 > 2 ≥ 18 14-17 ≤ 13* The current absence of data on resistant strains precludes defining any category other than “susceptible.” If strains yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.No interpretive criteria have been established for testing Moraxella catarrhalis. This species is not usually tested.A report of “susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. A report of “intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; other therapy should be selected.QUALITY CONTROLStandardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard azithromycin powder should provide the range of values noted in Table 6. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains, which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant.Table 6. Acceptable Quality Control Ranges for AzithromycinQC Strain Minimum InhibitoryConcentrations (µg/mL)Disk Diffusion (zone diameters in mm)Haemophilus influenzaeATCC 49247 1.0-4.0 13-21 Streptococcus pneumoniaeATCC 49619 0.06-0.25 19-25INDICATIONS AND USAGEZmax is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Please see DOSAGE AND ADMINISTRATION for specific dosing recommendations.AdultsAcute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae, in patients appropriate for oral therapy. (See CLINICAL STUDIES.)To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zmax and other antibacterial drugs, Zmax should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to Zmax. Therapy with Zmax may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.CONTRAINDICATIONSZmax is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or any macrolide or ketolide antibiotic.WARNINGSSerious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely in patients on azithromycin therapy using other formulations. Although rare, fatalities have been reported. (See CONTRAINDICATIONS.) Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent exposure to antigen has not been determined.If an allergic reaction occurs, appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in 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.PRECAUTIONSGeneralBecause azithromycin is principally excreted via the liver, caution should be exercised when azithromycin is administered to patients with impaired hepatic function. Due to the limited data in subjects with GFR <10 mL/min, caution should be exercised when prescribing azithromycin in these patients. (See CLINICAL PHARMACOLOGY - Special Populations - Renal Insu fficiency.)Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out i n patients at increased risk for prolonged cardiac repolarization.Prescribing Zmax in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for PatientsPatients should be instructed to take Zmax on an empty stomach (at least 1 hour before or 2 hours following a meal).Patients should be instructed to immediately contact a physician if any signs of an allergic reaction occur. Patients who vomit within the first hour should contact their health care provider about further treatment. Keep bottle tightly closed. Store at room temperature. Use within 12 hours of constitution. Shake bottle well before use. The entire contents of the bottle should be consumed.Patients should be advised that Zmax may be taken without regard to antacids containing magnesium hydroxide and/or aluminum hydroxide.Patients should be counseled that antibacterial drugs including Zmax should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). Not taking the complete prescribed dose may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Zmax or other antibacterial drugs in the future.Drug InteractionsCo-administration of nelfinavir at steady-state with a single dose of azithromycin (2 × 600 mg tablets) results in increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known side effects of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. (See ADVERSE REACTIONS.)Azithromycin did not affect the prothrombin time response to a single dose of warfarin. However, prudent medical practice dictates careful monitoring of prothrombin time in all patients treated with azithromycin and warfarin concomitantly. Concurrent use of macrolides and warfarin in clinical practice has been associated with increased anticoagulant effects.Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. (See CLINICAL PHARMACOLOGY - Drug-Drug Interactions.) When used in therapeutic doses, azithromycin had a modest effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (intravenous and oral), triazolam, trimethoprim/sulfamethoxazole or zidovudine. Co-administration with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. No dosage adjustment of either drug is recommended when azithromycin is co-administered with any of the above agents.Interactions with the drugs listed below have not been reported in clinical trials with azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interaction. Nonetheless, they have been observed with macrolide products. Until further data are developed regarding drug interactions when azithromycin and these drugs are used concomitantly, careful monitoring of patients is advised:Digoxin–elevated digoxin concentrations.Ergotamine or dihydroergotamine–acute ergot toxicity characterized by severe peripheralvasospasm and dysesthesia.Cyclosporine, hexobarbital and phenytoin concentrations.Laboratory Test InteractionsThere are no reported laboratory test interactions.Repeat TreatmentStudies evaluating the use of repeated courses of Zmax have not been conducted.Carcinogenesis, Mutagenesis, Impairment of FertilityLong-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay. No evidence of impaired fertility due to azithromycin was found in rats given daily doses up to 10 mg/kg (approximately 0.05 times the single 2.0 g oral adult human dose on a mg/m2 basis).PregnancyTeratogenic Effects. Pregnancy Category B: Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose concentrations (i.e., 200 mg/kg/day). These daily doses in rats and mice, based on mg/m2, are estimated to be approximately equivalent to one or one-half of, respectively, the single adult oral dose of 2.0 g. In the animal studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.。

see commentary on page 1089Patients with IgA nephropathy have increased serum galactose-deficient IgA1levelsZ Moldoveanu 1,RJ Wyatt 2,JY Lee 3,M Tomana 3,BA Julian 1,3,J Mestecky 1,3,W-Q Huang 1,SR Anreddy 1,5,S Hall 1,MC Hastings 2,KK Lau 2,6,WJ Cook 4and J Novak 11Department of Microbiology,University of Alabama at Birmingham,Birmingham,Alabama,USA;2Department of Pediatrics,University of Tennessee Health Sciences Center and Children’s Foundation Research Center,Memphis,Tennessee,USA;3Department of Medicine,University of Alabama at Birmingham,Birmingham,Alabama,USA and 4Department of Pathology,University of Alabama at Birmingham,Birmingham,Alabama,USAImmunoglobulin A (IgA)nephropathy is the most prevalent form of glomerulonephritis worldwide.A renal biopsy is required for an accurate diagnosis,as no convenientbiomarker is currently available.We developed a serological test based upon the observation that this nephropathy is characterized by undergalactosylated IgA1in the circulation and in mesangial immune deposits.In the absence ofgalactose,the terminal saccharide of O -linked chains in the hinge region of IgA1is terminal or sialylatedN -acetylgalactosamine.A lectin from Helix aspersa ,recognizing N -acetylgalactosamine,was used to develop an enzyme-linked immunosorbent assay that measures galactose-deficient IgA1in serum.The median serum lectin-binding IgA1level was significantly higher for 153Caucasian adult patients with IgA nephropathy without progression to end-stage renal disease as compared with that for 150healthy Caucasian adult controls.As thelectin-binding IgA1levels for the controls were not normally distributed,the 90th percentile was used for determination of significant ing a value of 1076U/ml as the upper limit of normal,117of the 153patients with IgA nephropathy had an elevated serum lectin-binding IgA1level.The sensitivity as a diagnostic test was 76.5%,with specificity 94%;the positive predictive value was 88.6%and the negative predictive value was 78.9%.We conclude that this lectin-binding assay may have potential as a noninvasive diagnostic test for IgA nephropathy.Kidney International (2007)71,1148–1154;doi:10.1038/sj.ki.5002185;published online 7March 2007KEYWORDS:IgA nephropathy;lectin;ELISA;IgA1;O -glycosylation;galactose deficiencySince its initial description in 1968,1immunoglobulin A (IgA)nephropathy (IgAN)has become recognized as the most common primary glomerulonephritis worldwide.2IgAN is characterized by mesangial deposits of IgA1with co-deposits of C3,and often also IgG or IgM or both.1,3–6Over 50%of IgAN patients exhibit increased serum levels of IgA and IgA-containing circulating immune complexes (CIC).7–9The mesangial immune deposits likely originate from these CIC.We have found that these complexes contain aberrantly glycosylated polymeric IgA1(galactose (Gal)-deficient in O -linked glycans).10–13In vitro studies have demonstrated that these CIC readily bind to mesangial cells and induce their proliferation.12–16Thus,aberrantly glyco-sylated polymeric IgA1may be involved in the pathogenesis of the glomerular injury in IgAN.Indeed,elution of glomerular immune deposits from renal tissue of patients with IgAN has demonstrated substantial quantities of Gal-deficient IgA1.17,18Several laboratories have localized the aberrant glycosyla-tion to the O -linked glycans in the hinge region of some IgA1molecules.5,15,19–21In the absence of Gal,the terminal N -acetylgalactosamine (GalNAc)residues,sialylated GalNAc,or the hinge-region glycopeptides are recognized by naturally occurring IgG or IgA1antibodies with anti-glycan or anti-hinge region peptide specificities,thus generating CIC.10Some of the resultant CIC escape normal clearance and deposit in the mesangium.These observations support the postulate that O -glycosylation abnormalities of IgA1predis-pose to mesangial IgA deposition.5,12,14,15,21,22For the diagnosis of IgAN,a renal biopsy is required because there is no established serological marker.To avoid this invasive procedure,particularly in individuals with mild disease,we sought to develop a noninvasive test to support the diagnosis of IgAN using a GalNAc-specific lectin.Based on previous work by our group and others,the lectin from Helix aspersa (HAA)is well suited for detecting Gal-deficient IgA1O -linked glycans.10,11,15–17,23–26In this study,we show that a quantitative lectin-based enzyme-linked immunosor-bent assay (ELISA)can be successfully used to measure serum levels of Gal-deficient IgA in sera of patients with IgAN.o r i g i n a l a r t i c l e &2007International Society of NephrologyReceived 12April 2006;revised 14January 2007;accepted 23January 2007;published online 7March 2007Correspondence:J Novak,Department of Microbiology,University of Alabama at Birmingham,84519th Street South,Room 734,Birmingham,AL 35294,USA.E-mail:jannovak@5Current address:Department of Internal Medicine,Thomas Jefferson University,Philadelphia,Pennsylvania,USA.6Current address:Department of Pediatrics,University of California,Davis,Sacramento,California,USA.RESULTSSerum IgA concentrationMedian serum IgA concentration was3943m g/ml(range 1171–11713m g/ml)for153Caucasian IgAN patients who had not progressed to end-stage renal disease as compared with2843m g/ml(range886–8185m g/ml)for150healthy controls(P o0.0001)(Table1).Fifty patients had a serum IgA concentration higher than4761m g/ml(90th percentile for controls).These data indicate a sensitivity of32.7%and specificity of90%with a positive predictive value of76.9% and a negative predictive value of56.7%(Table2).In agreement with a previous publication,22the diagnostic utility of total levels of serum IgA was not satisfactory. Serum HAA-IgA levelsSerum HAA-IgA levels for the patient and healthy control groups are shown in Figure1a.The individual levels for the control group were not distributed normally with a marked skewing towards elevated levels.The median serum HAA-IgA level for the patients of1731U/ml(range320–8317U/ml) was significantly higher than the median of615U/ml(range 264–1807U/ml)for the control group(P o0.0001).The serum HAA-IgA level was higher than1076U/ml(90th percentile for controls)for117of the153patients.These data indicate a sensitivity of76.5%and a specificity of90%with a positive predictive value of88.6%and a negative predictive value of78.9%.To illustrate the potential of this assay,the results are also presented as a receiver operating characteristic curve in Figure1b.The area under the curve is0.9021with a standard error0.0178,indicating that the true-positive rate was high and the false-positive rate was low.The95% confidence interval was0.8672–0.9370(P o0.0001).Reproducibility of the HAA-IgA ELISA was high(repeated the assays had an r¼0.970;P o0.0001).The serum HAA-IgA and IgA levels correlated significantly in IgAN patients(r2¼0.571, P o0.0001)and healthy controls(r2¼0.392,P o0.0001).The median value of the HAA-binding fraction of IgA was 445U/mg IgA(range129–879)for153Caucasian IgAN patients who had not progressed to end-stage renal disease as compared with248U/mg IgA(range56–666)for150healthy controls(P o0.0001).Ninety-four patients had a HAA-binding fraction of IgA higher than394U/mg IgA(90th percentile for controls).These data indicate a sensitivity of 61.4%and specificity of90%with a positive predictive value of86.2%and a negative predictive value of69.6%.Seven of 36patients with normal HAA-IgA levels had an HAA-binding fraction of IgA above the90th percentile for controls; among the135healthy controls with a HAA-IgA level belowTable1|Clinical features and levels of serum IgA and HAA-IgA for subgroups of patients with IgA nephropathyGroup N Genderratio(M/F)Age atdiagnosis(years)mean7SDInterval tostudy(years)mean7SDHAA-IgA(U/ml)median(range)IgA(l g/ml)median(range)HAA-IgA(U/mg IgA)median(range)UP/Crratiomedian(range)GFR a(ml/min/1.73m2)mean7SDAll patients153 1.6837.0714.5 4.976.91731(320–8317)3943(1171–11713)445(129–879)0.60(0.06–19.3)57.0731.4Male patients9639.8715.0 3.975.61731(373–8317)3846(1171–11713)455(129–834)0.65(0.06–5.35)53.3730.8Female patients5732.2727.8 6.578.41707(320–4366)4213(1409–7283)428(129–879)0.54(0.06–19.3)63.1732.0o8weeks after biopsy34 1.6237.5714.10.0670.041800(508–4366)3956(1418–6327)451(160–879)0.81(0.07–4.36)61.0739.045years after biopsy46 1.0930.2711.913.377.01974(504–4391)4440(2037–9148)425(129–812)0.19(0.06–19.3)60.7738.5GFR o30ml/min/1.73m235 3.3842.0715.5 4.577.21856(391–4391)3584(1418–8887)525(141–879)1.25(0.07–7.46)17.976.8GFR490ml/min/1.73m226 1.1727.579.5 3.274.91466(320–3579)3299(1409–7422)373(170–710)0.38(0.06–2.53)105.0716.3Normal urinalysis26 1.3630.0710.311.878.92030(504–3901)4571(2037–7350)417(208–820)0.09(0.06–0.19)45.5716.2GFR,glomerular filtration rate;HAA,lectin from Helix aspersa;IgA,immunoglobulin A;UP/Cr ratio,urinary protein/creatinine ratio.a Estimated GFR was calculated using the MDRD formula(53).Table2|Diagnostic utility of serum IgA and HAA-IgA assaysControl PatientsYes No Yes No Sensitivity Specificity Positive predictive Negative predictive IgA44761m g/ml151********.327(0.258,0.405)0.900(0.842,0.938)0.769(0.654,0.855)0.567(0.504,0.629) HAA-IgA41076U/ml151********.758(0.685,0.819)0.900(0.842,0.938)0.885(0.820,0.929)0.785(0.718,0.840) HAA-IgA4394U/mg IgA1513594590.614(0.535,0.685)0.900(0.842,0.938)0.785(0.628,0.756)0.696(0.628,0.756) HAA,lectin from Helix aspersa;IgA,immunoglobulin A.The numbers in the brackets are the95%confidence intervals.Z Moldoveanu et al.:Galactose-deficient IgA in IgA nephropathy o r i g i n a l a r t i c l ethe cutoff point,11had a similarly increased value for HAA-binding fraction of IgA.Western blot analysisTo verify the ELISA data,selected serum samples from four IgAN patients and two healthy controls representing a wide range of HAA-IgA values were analyzed by Western blotting for total and Gal-deficient IgA (see Materials and methods).The band intensity was measured by densitometry and the ratio of HAA-IgA to IgA heavy chain was calculated.This value was plotted against HAA-binding fraction of IgA1(U/mg IgA)determined by ELISA in the same sample.The data in Figure 2are representative for the IgAN patients and healthy controls over the wide range of HAA-IgA values.The results from the two assays showed good correlation (r 2¼0.818,P ¼0.046).Clinical and pathological associationsSerum HAA-IgA and IgA concentrations as well as values for the HAA-binding fraction of IgA (U/mg IgA)are shown for subgroups of patients in Table 2.There was no significant difference based upon gender.The median level for 26patients with a normal urinalysis at the time of study was 2030Units/ml (88%with an elevated level).Levels of HAA-IgA for subjects with an estimated glomerular filtration rate (GFR)X 90ml/min/1.73m 2were similar to those of patients with an estimated GFR o 30ml/min/1.73m 2.Furthermore,the HAA-IgA levels did not significantly differ between patients who had undergone renal biopsy within eight weeks of the blood sampling and patients whose blood was obtained more than five years after biopsy.Serum HAA-IgA levels did not significantly correlate with urinary protein/creatinine (UP/Cr)ratio (r ¼À0.128,P ¼0.211),estimated GFR (r ¼À0.147,P ¼0.069),or interval since biopsy (r ¼0.0844,P ¼0.300).Thus,the serum HAA-IgA level did not appear to be an indicator of disease activity in our cohort of Caucasian adults with IgAN.Renal biopsies from 34patients,who had blood obtained within eight weeks of diagnostic biopsy,were graded according to the Haas system 27by two investigators (WJC and BAJ)blinded to the clinical and laboratory data.Levels of HAA-IgA were above the cutoff value of healthy controls in five of eight (63%)patients with subclass 1,2,and 3histological features and in 20of 26(77%)patients with subclass 4and 5disease.DISCUSSIONIn this study,wedeveloped a quantitative assay to measure serum Gal-deficient IgA (HAA-IgA).Although the total IgA correlated with the HAA-IgA levels,only the serum HAA-IgA level differentiated IgAN patients from the healthy controls with high sensitivity (Table 2).This finding may be explained by a greater amount of Gal-deficient IgA recognized by naturally occurring anti-glycan antibodies,resulting in formation of CIC.10In our ELISA,serum IgA was captured by a polyclonal IgA heavy chain-specific antibody.As a result,both subclasses,IgA1that accounts for about 84%of serum IgA 28,29andControlsPatients10002000300040005000600070008000900090thpercentileU n i t s /m l1-SpecificityS e n s i t i v i t yabFigure 1|Serum levels of Gal-deficient IgA in IgAN patients and healthy controls.(a )HAA-IgA level (U/ml,see Materials and methods)in sera from IgAN patients and healthy controls.(b )Receiver operating characteristic curve for HAA-IgA levels.Area under the curve is 0.902.The arrows with numbers indicate key points:(1)HAA-IgA serum level 1076U/ml;sensitivity 0.765,specificity 0.900;(2)HAA-IgA serum level 1702U/ml;sensitivity 0.503,specificity 0.993;and (3)HAA-IgA serum level 1810U/ml;sensitivity 0.444,specificity 1.000.0.00.20.40.60.8HAA-IgA (ELISA; U/mg IgA)H A A -b i n d i n g f r a c t i o n o f I g A (W e s t e r n b l o t )Figure 2|Reactivity of HAA with serum IgA in ELISA and Western blot assays.ELISA data are expressed as HAA-IgA (U/mg IgA);Western blot data are the ratios of heavy-chain band densities for HAA-binding IgA and total IgA.Six samples with wide range of HAA-IgA reactivities were used.The inset shows the two extremes:a highly reactive sample and a modestly reactive sample.o r i g i n a l a r t i c l eZ Moldoveanu et al.:Galactose-deficient IgA in IgA nephropathyIgA2,are captured.However,only IgA1has O-linked glycans and,therefore,is the only IgA subclass that can bind to HAA, a GalNAc-specific lectin.Consequently,the HAA-IgA assay is a measure of serum Gal-deficient IgA1.Mesangial IgA deposition is incidentally encountered in asymptomatic individuals in frequencies that vary among studies,ranging from2to16%.30–34For example,in a study in Japan,biopsies from510newly procured living-donor renal allografts taken at the time of transplantation showed mesangial IgA deposition in82(16.1%)of them.33By contrast,in a study of necropsy examinations of756Finish adults who had committed suicide or met with a violent death,mesangial IgA deposits were found in18(2.4%)of the individuals.32However,these renal biopsies with IgA deposits rarely showed any significant pathological changes by light microscopy.Consequently,the clinical significance of these observations is not clear,but many otherwise normal healthy individuals may have mesangial deposits of IgA without clinical manifestation of nephritis or pathological changes of the glomeruli.It would have been interesting to have renal biopsy data on our cohort of healthy controls and to assess the frequency of IgA deposits with and without concurrent renal pathology by light microscopy.However,this could not have been carried out for ethical reasons.Several groups of investigators have shown significantly increased binding of GalNAc-specific lectins to serum IgA1 from patients with IgAN or Henoch–Scho¨nlein purpura nephritis.10,11,23,35–40Using HAA,Linossier et al.39showed increased binding for IgAN patients with normal thickness of the glomerular basement membrane on electron microscopy. Studies with other GalNAc-specific lectins,Vicia villosa lectin23,38and Glycine max lectin,40showed increased serum Gal-deficient IgA1in patients with Henoch–Scho¨nlein purpura nephritis and IgAN,respectively.However,these results did not distinguish the patients from healthy controls; thus,the test would not be adequate to diagnose either disorder.Several candidates for a serological diagnostic marker of IgAN,such as increased levels of serum IgA or of IgA-containing complexes withfibronectin,IgG,or C3,have been previously examined.7–9,39–45Although the serum IgA con-centration is significantly elevated in about half of the patients with IgAN,46,47this parameter is not satisfactory as a diagnostic test,as confirmed by our study(Table2).Jennette et al.42found that93%of30patients with IgAN or Henoch–Scho¨nlein purpura nephritis had serum IgA-fibro-nectin aggregates,compared with7%ter, the same group performed a larger study with63adult and 25pediatric subjects and found IgA-fibronectin aggregates in only40%of samples.43Furthermore,just48%of the patients ever showed IgA-fibronectin aggregates,despite sampling on more than one occasion.43Czerkinsky et al.7reported the presence of IgA1-and IgG-containing CIC in40%of30 patients with IgAN and none in the14normal subjects. Coppo et al.8,41found IgA-CIC in65%of IgAN patients using a conglutinin-binding assay.The levels of IgA-CIC correlated with clinical activity,as denoted by the magnitude of microscopic hematuria or a history of macroscopic hematuria.Mixed IgA1-IgG CICs were detected in68%of patients as reported by Schena et al.9Activated C3was detected in30–57%of patients with IgAN.44,45To date,none of these assays has been introduced as a diagnostic test.Using a panel of15lectins,our group has examined the reactivity of de-sialylated serum IgA1from10patients with IgAN and10healthy controls.11All of the GalNAc-specific lectins demonstrated higher reactivity with serum IgA1from the IgAN patients than with IgA1from healthy controls; however,the highest specificity was obtained with HAA.11 The specificity of many lectins(including those specific for hinge-region O-linked glycans)may vary by the geographical location of the source(animal or plant)and by the method of preparation.It is thus possible that the HAA from the source we chose had selectivity properties that were superior to those of the other GalNAc-specific lectins we tested.11,26 These results prompted us to select HAA to use in our lectin ELISA to measure the levels of Gal-deficient IgA1.Gal-deficient IgA1likely conveys nephritogenic properties to the IgA1-CIC.Gal-deficient IgA1has been isolated from the immune deposits in the renal mesangium of patients with IgAN.17,18Furthermore,immune complexes with Gal-deficient IgA1stimulate mesangial cells in culture to proliferate5,13,15,16,48and secrete components of the extra-cellular matrix and cytokines.49–51Although the size and biological activity of these CIC may be determined by various factors,including the antigen to antibody ratio,13the aberrant glycosylation seems to play a central role in inducing glomerular injury.52Thus,measurement of Gal-deficient IgA1in serum samples may be of diagnostic significance, despite the lack of an association between the serum HAA-IgA level and disease severity,as assessed by histological features,magnitude of proteinuria,or interval since diag-nosis.The elevated serum HAA-IgA levels in patients during a clinically quiescent phase many years after clinical onset suggest that defective galactosylation may serve as a biomarker for the disease.Although Gal-deficiency of IgA1O-linked glycans can be analyzed by Western blotting,gas-liquid chromatography, and mass spectrometry,these procedures are expensive and cumbersome.In contrast,an ELISA is a relatively rapid, inexpensive,and high-throughput assay with excellent reproducibility.We anticipate that the HAA-IgA ELISA could be easily adapted for the clinical laboratory.If the sensitivity of this assay can be improved while maintaining its high specificity,it may be developed into a noninvasive diagnostic test for IgAN.MATERIALS AND METHODSPatients and healthy controlsThe study included153Caucasian patients with IgAN who had undergone biopsy for the evaluation of proteinuria,hematuria,or renal dysfunction.Thirteen patients were younger than age18years at the time of biopsy.All patients were older than age18at time ofZ Moldoveanu et al.:Galactose-deficient IgA in IgA nephropathy o r i g i n a l a r t i c l eblood sampling for the study.Ninety-three were male,yielding a male to female ratio of1.68.Blood and urine samples were obtained on one occasion.Mean age at biopsy was37.0years(range10–75 years).The mean interval between the date of diagnosis by biopsy and the date of blood sampling for this study was4.9years(range 0–29years).Thirty-four(22%)patients were studied within eight weeks of biopsy and47(31%)had blood drawn more thanfive years after biopsy.Serum creatinine concentration,urinalysis and random spot UP/Cr ratio were obtained at the time of study.Estimated GFR was calculated using the Modification of Diet in Renal Disease formula.53Estimated GFR was X90ml/min/1.73m2for26(17%) patients,X60but o90ml/min/1.73m2for40(26%)patients,X30 but o60ml/min/1.73m2for52(34%)patients,and o30ml/min/ 1.73m2for35(23%)patients.The biopsy-proven diagnosis of IgAN was based upon the demonstration by direct immunofluorescence of IgA as the dominant or co-dominant Ig in a predominantly mesangial distribution and the lack of clinical or serological evidence for systemic lupus erythematosus,vasculitis,or Henoch–Scho¨nlein purpura3and the absence of X2þmesangial C1q deposition.54 The healthy controls consisted of153Caucasian residents of Alabama,Kentucky,or Tennessee.All were at least18years of age (range18–80years).The mean age was27.071.9years.The group consisted of74males and76females.Serum creatinine,UP/Cr ratio and blood pressure were measured for each healthy control. Individuals with UP/Cr ratio40.20or estimated GFR o60ml/ min/1.73m2were excluded.Estimated GFR was o90ml/min/ 1.73m2for78(50.9%)of the healthy controls.The Institutional Review Boards at the University of Alabama at Birmingham and the University of Tennessee Health Sciences Center approved this study.Written informed consent was obtained from all subjects.Determination of serum IgA and Gal-deficient IgA by ELISA For measurement of serum total and Gal-deficient IgA,high-adsorption polystyrene96-microwell plates(Nalge Nunc Interna-tional,Rochester,NY,USA)were coated overnight with3m g/ml F(ab0)2fragment of goat IgG anti-human IgA(Jackson Immuno-Research Labs.,West Grove,PA,USA)in phosphate-buffered saline. Coated plates were blocked with1%bovine serum albumin(Sigma Chemical Company,St Louis,MO,USA)in phosphate-buffered saline-0.05%-Tween20,and serial twofold dilutions of samples and standards in blocking solution(in duplicate)were incubated overnight at room temperature.The standard for IgA consisted of a pool of normal human sera(Binding Site,Birmingham,UK), previously calibrated for Ig isotype concentration by ELISA and radial immunodiffusion.The bound IgA was detected by incubation with biotin-labeled F(ab0)2fragment of goat IgG anti-human IgA (BioSource,Camarillo,CA,USA)for3h at371C followed by1h incubation with horseradish peroxidase-conjugated ExtrAvidin (Sigma).For quantitation of Gal-deficient IgA,the standard consisted of a polymeric Gal-deficient IgA1isolated from serum of a patient with IgA1myeloma.This Ig has been previously shown to mimic the aberrantly glycosylated IgA1from IgAN patients.10To remove terminal sialic acid from O-linked GalNAc on IgA,the samples and the IgA1myeloma protein standard were incubated with100m l(1mU)/well neuraminidase(Roche Diagnostic Corp., Indianapolis,IN,USA)in0.01M acetate buffer pH5for3h at 371C.11After washing,100m l biotin-labeled HAA,a GalNAc-specific lectin,(1:500dilution;Sigma)was added to each well.Following3h incubation at371C,the plates were washed and horseradish peroxidase-ExtrAvidin(Sigma)was added and incubated for1h at 371C.For both IgA and Gal-deficient IgA,the wells were developed with the peroxidase chromogenic substrate O-phenylenediamine-H2O2(Sigma).The color reaction was stopped with1M sulfuric acid and the absorbance was measured at490nm with an EL312Bio-Kinetics microplate reader(Bio-Tek Instruments Inc.,Winooski,VT, USA).The amounts of total IgA and Gal-deficient IgA in the tested samples were calculated with the DeltaSoft II program(BioMettalics Inc.,Princeton,NJ,USA)by interpolating the optical densities on calibration curves,constructed using serum IgA and a Gal-deficient IgA1myeloma protein.As the standard IgA1myeloma protein is not entirely devoid of galactose,the expression of results in m g/ml does not precisely reflect the concentration of Gal-deficient IgA1in the sera.Therefore,we expressed the results in U/ml.One unit of HAA-IgA was defined as1m g of this standard.The results were also normalized to total IgA and expressed in U/mg IgA.Duplicate serum samples from21healthy controls were analyzed to assess the degree of intra-assay variation.The results showed excellent reproducibility(r¼0.970;P o0.0001).To verify the accuracy of the ELISA measurements of total IgA level in serum,five serum samples and the calibration serum were analyzed in the clinical laboratory of the University of Alabama Hospital.The differences in the measurements by ELISA and nephelometry ranged between2and17%,the mean difference was975%.Western blot analysisSerum samples from six individuals(four IgAN patients and two controls)representing a wide range of HAA-IgA values were normalized for IgA content(1.0or0.1m g IgA/well for blots to be developed with HAA or anti-IgA,respectively),then reduced with 5%b-mercaptoethanol,and electrophoreticaly separated on a 4–15%gradient sodium dodecyl sulfate-polyacrylamide gel(Bio-Rad,Hercules,CA,USA).The gels were then electroblotted to polyvinylidine difluoride membrane(0.45m m,Millipore,Billerica, MA,USA).After the transfer,polyvinylidine difluoride membranes were blocked with SuperBlock buffer(Pierce,Rockford,IL,USA) containing0.05%Tween20,washed and treated for3h at371C with 10mU/ml neuraminidase(Roche).Membranes were then washed and incubated overnight at41C with1:500dilution biotin-labeled HAA(Sigma)in blocking buffer.To detect the heavy chain of IgA,a duplicate membrane was incubated overnight at41C with biotinylated goat F(ab’)2IgG anti-human IgA(Biosource).The biotin-labeled probes bound to IgA were detected,after addition of streptavidin-horseradish peroxidase conjugate,with SuperSignal West Pico Solution(Pierce).The positive bands were visualized using X-rayfilm(Kodak,Rochester,NY,USA)and thefilms were analyzed by densitometry to calculate the ratios of HAA-IgA to a-chain.Statistical analysisWilcoxon rank sum test was used to compare subject and control groups for serum concentrations of IgA,HAA-IgA levels,and relative HAA-binding to IgA.The90th percentile for healthy controls was the cutoff point for calculation of sensitivity and specificity.The receiver operating characteristic curve for HAA-IgA levels in patients and controls was constructed using GraphPad Prism version4.00for Windows(GraphPad Software,San Diego,CA,USA).The Spearman correlation coefficients were used to assess the relationship between HAA-IgA levels and UP/Cr ratio,estimated GFR and the interval since diagnosis by biopsy.SAS9.1(SAS Institute,Cary,NC,USA)was used for descriptive statistics and calculation of correlation coefficients.o r i g i n a l a r t i c l e Z Moldoveanu et al.:Galactose-deficient IgA in IgA nephropathyACKNOWLEDGMENTSThis work was supported by National Institutes of Health grants DK57750and DK61525and by the General Clinical Research Centers of the University of Alabama at Birmingham M01RR00032and the University of Tennessee Health Sciences Center M01RR00211.JN was also supported by NIH Grants DK71802and DK64400.We express our appreciation to Catherine Barker and Sue Woodford(University of Alabama at Birmingham)and Dr Kimberly Fisher and Sandra Grimes (University of Tennessee)for help with collecting clinical samples and to Rose Kulhavy(University of Alabama at Birmingham)for providing the IgA1myeloma protein.We appreciate the technical assistance of Rhubell Brown,Candace Kirksey,and Claretha Nichols in the processing of the serum samples.REFERENCES1.Berger J,Hinglais N.Les depots intercapillaires d’IgA-IgG(Intercapillarydeposits of IgA-IgG).J Urol Nephrol1968;74:694–695.2.Julian BA,Waldo FB,Rifai A et al.IgA nephropathy,the most commonglomerulonephritis worldwide.A 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