ATryn

antithrombin (recombinant)

Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION

Indications and Usage for ATryn

ATryn® is a recombinant antithrombin indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients1.

It is not indicated for treatment of thromboembolic events in hereditary antithrombin deficient patients.

ATryn Dosage and Administration

For Intravenous Use Only after Reconstitution

Preparation for Administration

• Bring vials to room temperature no more than 3 hours prior to reconstitution.


• Reconstitute with 10 mL Sterile Water for Injection [(WFI) not supplied with ATryn] immediately prior to use. Do not shake.


• Do not use solution containing visible particulates or if it is discolored or cloudy.


• Draw solution from one or more vials into a sterile disposable syringe for intravenous administration or add solution to an infusion bag containing 0.9% sterile sodium chloride for injection (e.g., dilute solution to obtain a concentration of 100 IU/mL).


• Administer using an infusion set with a 0.22 micron pore-size, in-line filter.


• Administer contents of infusion syringes or diluted solution within 8 to 12 hours of preparation when stored at room temperature (68-77°F (20-25°C)).


• Discard unused product in accordance with local requirements.

Recommended Dose and Schedule

• The dosage of ATryn is to be individualized based on the patient's pre-treatment functional AT activity level (expressed in percent of normal) and body weight (expressed in kilograms) and using therapeutic drug monitoring (Table 1).


• The goal of treatment is to restore and maintain functional antithrombin (AT) activity levels between 80% - 120% of normal (0.8 - 1.2 IU/mL).


• Treatment should be initiated prior to delivery or approximately 24 hours prior to surgery to ensure that the plasma antithrombin level is in the target range at that time.


• Different dosing formulae are used for the treatment of surgical and pregnant patients. Pregnant women who need a surgical procedure other than Cesarean section should be treated according to the dosing formulae for pregnant patients.


• Administer loading dose as a 15-minute intravenous infusion, immediately followed by a continuous infusion of the maintenance dose.


• AT activity monitoring and dose adjustments should be made according to Table 2.


• Continue treatment until adequate follow-on anticoagulation is established.

Table 1: Dosing Formula for Surgical Patients and Pregnant Women

	Loading Dose (IU)	Maintenance Dose (IU/hour)
Surgical Patients	(100 - baseline AT activity level) x Body Weight (kg) / 2.3	(100 - baseline AT activity level) x Body Weight (kg) / 10.2
Pregnant Women	(100 - baseline AT activity level) x Body Weight (kg) / 1.3	(100 - baseline AT activity level) Body Weight (kg) / 5.4

AT Activity Monitoring and Dose Adjustment

AT activity monitoring is required for proper treatment. Check AT activity once or twice per day with dose adjustments made according to Table 2.

Table 2: AT Activity Monitoring and Dose Adjustment

Initial Monitor Time	AT Level	Dose Adjustment	Recheck AT Level
2 hours after initiation of treatment	< 80%	Increase 30%	2 hours after each dose adjustment
	80% to 120%	None	6 hours after initiation of treatment or dose adjustment
	> 120%	Decrease 30%	2 hours after each dose adjustment

As surgery or delivery may rapidly decrease the AT activity levels, check the AT level just after surgery or delivery. If AT activity level is below 80%, an additional bolus dose may be administered to rapidly restore decreased AT activity level. In such instances, the loading dose formulae in Table 1 should be used, utilizing in the calculation the last available AT activity result. Thereafter, restart the maintenance dose at the same rate of infusion as before the bolus.

Dosage Forms and Strengths

ATryn is a sterile lyophilized formulation. Each vial of ATryn contains the potency stated on the label, which is approximately 1750 IU.

Contraindications

ATryn is contraindicated in patients with known hypersensitivity to goat and goat milk proteins.

Warnings and Precautions

Hypersensitivity Reactions

Allergic-type hypersensitivity reactions are possible. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. If these symptoms occur during administration, treatment must be discontinued immediately and emergency treatment should be administered.

Coagulation Monitoring Tests

The anticoagulant effect of drugs that use antithrombin to exert their anticoagulation may be altered when ATryn is added or withdrawn. To avoid excessive or insufficient anticoagulation, coagulation tests suitable for the anticoagulant used (e.g., aPTT and anti-Factor Xa activity) are to be performed regularly, at close intervals, and in particular in the first hours following the start or withdrawal of ATryn. Additionally, monitor the patients for the occurrence of bleeding or thrombosis in such situation.

Adverse Reactions

The serious adverse reaction that has been reported in clinical studies is hemorrhage (intra-abdominal, hemarthrosis and post procedural). The most common adverse events reported in clinical trials at a frequency of ≥ 5% are hemorrhage and infusion site reaction.

Clinical Trial 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 practice.

Adverse reactions that occurred in clinical trials with hereditary AT deficient patients are shown in Table 3 by System Organ Class.

Table 3: Adverse Reactions in Hereditary AT Deficient Patients (one event per patient, 2% of total population, n=47)

Gastrointestinal Disorders

Intra-abdominal Hemorrhage

General Disorders and Administration Site Disorders

Application Site Pruritus

Feeling Hot

Non-cardiac Chest Pain

Investigations

Hepatic Enzyme Abnormal

Musculoskeletal and Connective Tissue Disorders

Hemarthrosis

Renal and Urinary Disorders

Hematuria

Vascular Disorders

Hematoma

Immunogenicity

For ATryn, a potential safety issue is the development of an immunological reaction to the recombinant protein or any of the potential contaminating proteins. Assays were developed and used to detect antibodies directed against antithrombin (Recombinant), goat AT, or goat-milk proteins. No confirmed specific immunological reaction was seen in any of the patients tested, nor were there any clinical adverse events that might indicate such a response.

A post-marketing patient registry has been established to collect additional data on the immunogenic potential of ATryn in patients treated with ATryn on more than one occasion. Physicians are encouraged to participate in the registry by collecting pre- and post-treatment serum samples from patients according to instructions provided by Lundbeck Inc. and submitting them to Lundbeck Inc. for analysis for the development of antibodies to antithrombin (Recombinant). Serum samples should be collected within one week before initiation of treatment and on days 1, 7 and 28 days from initiation of treatment. Physicians wanting to participate in this program are encouraged to contact Lundbeck Inc. at 1-800-455-1141. Lundbeck Inc. will provide detailed instructions for the collection, processing and shipping of samples, as well as all tubes and labels that are necessary for the collection and processing of samples.

Drug Interactions

The anticoagulant effect of heparin and low molecular weight heparin (LMWH) is enhanced by antithrombin. The half-life of antithrombin may be altered by concomitant treatment with these anticoagulants due to an altered antithrombin turnover. Thus, concurrent administration of antithrombin with heparin, low molecular weight heparin, or other anticoagulants that use antithrombin to exert their anticoagulant effect must be monitored clinically and biologically. To avoid excessive anticoagulation, regular coagulation tests (aPTT, and where appropriate, anti-Factor Xa activity) are to be performed at close intervals, with adjustment in dosage of the anticoagulant as necessary.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C: In rats, a dose of 210 mg/kg/day ATryn (5-6 times the human dose for pregnant women) administered during most of the pregnancy and entire lactation showed a slight but statistically significant increase in pup mortality in day one through day four when compared to concurrent control (90% compared to 94% viability index for 210 mg/kg/day versus control). This slight statistical difference does not reflect a true treatment-related effect. This same dose was shown to be safe in a second rat study when administered around parturition and during lactation where the no adverse effect level for dam and pups was 210 mg/kg/day.

There are no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Studies in pregnant women have not shown that ATryn increases the risk of fetal abnormalities if administered during the third trimester of pregnancy. In clinical trials in hereditary AT deficient patients, 22 pregnant women have been treated with ATryn around parturition.

No adverse reactions were reported in 22 neonates born from pregnant women treated with ATryn during clinical trials.

Labor and Delivery

ATryn is indicated for the treatment of pregnant women during the peri-partum period. Pregnant patients who need a surgical procedure other than Cesarean section are to be treated according to the dosing formulae for pregnant patients.

Nursing Mothers

ATryn will be present in breast milk at levels estimated to be 1/50 to 1/100 of its concentration in the blood. This level is the same as that estimated to be present in breast milk of normal lactating women which is not known to be harmful to breastfed neonates. However, caution should be exercised when ATryn is administered to a nursing woman. Use only if clearly needed.

In 2 reproductive toxicology studies performed in rats, antithrombin (Recombinant) was administered to pregnant dams at doses up to 210 mg/kg/day, resulting in supraphysiologic plasma levels of antithrombin. Pups were allowed to breastfeed and were monitored for changes in prothrombin (PT) or aPTT, as well as pup viability, body weight at birth, growth, and development. In these studies, there were no adverse effects in offspring who consumed milk from dams treated with ATryn.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of ATryn did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ATryn Description

ATryn for Injection is a nanofiltered, sterile, terminally heat treated, lyophilized dosage form. Antithrombin (Recombinant), active ingredient of ATryn, is a recombinant human antithrombin. It is a 432 amino acid glycoprotein with a molecular weight of approximately 57,215 Daltons. The molecular formula is: C2191H3457N583O656S18. Antithrombin (Recombinant) is produced by recombinant DNA technology using genetically engineered goats into which the DNA coding sequence for human antithrombin has been introduced along with a mammary gland specific DNA sequence, which directs the expression of the antithrombin into the milk. The goats in which antithrombin (Recombinant) is produced are USDA certified scrapie-free, and controlled for specific pathogens.

The amino acid sequence of Antithrombin (Recombinant) is identical to that of human plasma-derived antithrombin. Antithrombin (Recombinant) and plasma-derived antithrombin both contain six cysteine residues forming three disulphide bridges and 3-4 N-linked carbohydrate moieties. The glycosylation profile of Antithrombin (Recombinant) is different from plasma-derived antithrombin, which results in an increased heparin affinity. When assayed in the presence of excess of heparin the potency of the recombinant product is not different from that of plasma-derived product.

Each vial of ATryn is tested for potency stated on the product label using a reference standard calibrated against the World Health Organization international standard for antithrombin concentrate. In addition to Antithrombin (Recombinant), each vial of the product contains 100 mg glycine, 79 mg sodium chloride, and 26 mg sodium citrate. When reconstituted with 10 mL Sterile Water for Injection, the pH is approximately 7.0. Following reconstitution, the solution may be further diluted into 0.9% sodium chloride for injection.

ATryn does not contain any preservatives nor is it formulated with human plasma proteins. Antithrombin (Recombinant) is affinity purified using a heparin immobilized resin and contains no detectable heparin (<0.0002 IU heparin per IU antithrombin) in the final product.

The purification and drug product manufacturing processes have been validated to demonstrate its capacity for removal and/or inactivation of viruses4. Results of removal and/or inactivation for each of the steps are shown in Table 4.

Table 4: Viral Clearance Results (log10 reductions)

Process Step	Pseudorabies Virus	Xenotropic Murine Retrovirus	Human Adenovirus	Porcine Parvovirus
NA = Not Applicable since log10 reduction was less than 1.0.
Tangential Flow Filtration	≥5.1
Affinity Chromatography	1.6	1.2	NA	1.4
Nanofiltration		≥3.8	≥6.3	≥3.7
Ion Exchange Chromatography	3.6	1.0	≥7.1	NA
Hydrophobic Interaction Chromatography	≥5.6	≥4.4	≥4.8	≥5.7
Heat Treatment	2.8	≥5.0	≥1.8	2.4
Total Reduction	≥18.7	≥15.4	≥20.0	≥13.2

In addition, although the goats are from a closed, USDA certified scrapie-free herd, the purification process was challenged to remove prions. The manufacturing steps were shown capable of achieving the following log10 reductions: 2.0 (tangential filtration), 2.2 (affinity column), ≥ 3.3 (ion exchange column), ≥ 3.8 (hydrophobic interaction column).

ATryn - Clinical Pharmacology

Mechanism of Action

Antithrombin (AT) plays a central role in the regulation of hemostasis. AT is the principal inhibitor of thrombin and Factor Xa5, the serine proteases that play pivotal roles in blood coagulation. AT neutralizes the activity of thrombin and Factor Xa by forming a complex which is rapidly removed from the circulation. The ability of antithrombin to inhibit thrombin and Factor Xa can be enhanced by greater than 300 to 1000 fold when AT is bound to heparin.

Pharmacodynamics

Hereditary AT deficiency causes an increased risk of venous thromboembolism (VTE). During high-risk situations such as surgery or trauma or for pregnant women, during the peri-partum period, the risk of development of VTEs as compared to the normal population in these situations is increased by a factor 10 to 506,7.

In hereditary antithrombin deficient patients ATryn restores (normalizes) plasma AT activity levels during peri-operative and peri-partum periods.

Pharmacokinetics

In an open-label, single dose pharmacokinetic study, male and female patients (≥ 18 years of age) with hereditary AT deficiency, received either 50 (n = 9, all females) or 100 (n = 6, 2 males and 4 females) IU/kg ATryn intravenously. These patients were not in high-risk situations. The baseline corrected pharmacokinetic parameters for antithrombin (Recombinant) are summarized in Table 5.

Table 5: Baseline Corrected Mean Pharmacokinetic Parameters (%CV)

Parameter	50 IU/kg	100 IU/kg
CL (mL/hr/kg)	9.6 (34.4)	7.2 (15.3)
Half-life (hrs)	11.6 (84.7)	17.7 (60.9)
MRT (hrs)	16.2 (74.9)	20.5 (40.2)
Vss (mL/kg)	126.2 (37.4)	156.1 (43.4)

Incremental recovery [mean (%CV)] was 2.24 (20.2) and 1.94 (14.8) %/IU/kg body weight for 50 and 100 IU/kg, respectively.

Population pharmacokinetic analysis of hereditary deficient patients in a high risk situation revealed that the clearance and volume of distribution in pregnant patients were (1.38 L/h and 14.3 L respectively) which are higher than non-pregnant patients (0.67 L/h and 7.7 L respectively). Therefore, distinct dosing formulae for surgical and pregnant patients should be used (see 2.2, Recommended Dose and Schedule).

As compared to plasma derived antithrombin, ATryn has a shorter half-life and more rapid clearance (approximately nine and seven times, respectively).

Pharmacokinetics may be influenced by concomitant heparin administration, as well as surgical procedures, delivery, or bleeding. AT activity monitoring (see 2.2, Recommended Dose and Schedule) should be performed to properly treat such patients.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis: No carcinogenicity data for ATryn are available in animals or humans.

Mutagenesis and Genotoxicity: ATryn was not mutagenic when tested in the Ames bacterial test and in in vitro cytogenetic assays nor was it shown to be genotoxic when tested in an in vivo test to assess chromosomal aberration.

Impairment of Fertility: No studies have been conducted to evaluate the effects of ATryn on fertility in humans.

Animal Toxicology and/or Pharmacology

Pharmacokinetic and toxicokinetic (1 single, 2 repeated dose) studies of antithrombin (Recombinant) were performed in mice, rats, dogs and monkeys. In toxicokinetic studies in monkeys the area under the curve was 3-4 times greater than in the rat at all doses used.

The toxicological profile of antithrombin (Recombinant) administered by the intravenous route as bolus injections and infusions has been evaluated in both single- and repeat-dose studies performed in rats, dogs, and monkeys across a range of doses from 2.1 to 360 mg/kg. The highest doses in the single dose toxicity studies in rats and dogs were 360 mg/kg and 210 mg/kg, respectively. Toxicities observed were limited to transient injection site swelling observed in rats and dogs at the highest doses tested, and increased AST at highest dose in the dog study, both resolved during recovery period.

The highest dose in the 28-day repeated-dose toxicity study in rats was 360 mg/kg/day. The toxicity at this dose was limited to transient limb swelling and local injection site bruising and swelling. The highest dose in the 14-day repeated-dose toxicity study in monkeys was 300 mg/kg/day or approximately 7-8 times human dose. Toxicities observed in female monkeys at this dose included internal bleeding, hematological changes and liver toxicity, with one out of three female animals showing multifocal hepatic necrosis. Both sexes showed increased AST and ALK on day 15, with both parameters returning to normal by day 22. There was no adverse effect in monkeys dosed with 120 mg/kg/day.

Clinical Studies

The efficacy of ATryn to prevent the occurrence of venous thromboembolic events was assessed by comparing the incidence of the occurrence of such events in 31 ATryn treated hereditary AT deficient patients with the incidence in 35 human plasma-derived AT treated hereditary AT deficient patients. Data on ATryn-treated patients were derived from two prospective, single-arm, open-label studies. Data on plasma AT treated patients were collected from a prospectively designed concurrently conducted retrospective chart review. Patients in both studies had confirmed hereditary AT deficiency (AT activity ≤ 60% of normal) and a personal history of thromboembolic events. Patients had to be treated in the peri-operative and peri-partum period. ATryn was administered as a continuous infusion for at least 3 days, starting one day prior to the surgery or delivery. Plasma AT was administered for at least two days as single bolus infusions. Due to the retrospective nature of the study, dosing was done with the locally available AT concentrate according to the local practice.

The occurrence of a venous thromboembolic event was confirmed if signs and symptoms for such events were confirmed by a specific diagnostic assessment, or when treatment for an event was initiated based on diagnostic imaging, without the presence of signs and symptoms. The efficacy was assessed during treatment with AT and up to 7 days after stopping AT treatment.

In the ATryn-treated group there was one confirmed diagnosis of an acute deep vein thrombosis (DVT). The incidence of any thromboembolic event from the start of treatment to 7 days after last dosing is summarized by treatment group in Table 6 as are the Clopper-Pearson exact 95% CI for the proportion of patients with a thromboembolic event and the exact 95% lower confidence bound for the difference between treatments.

Table 6: Overall Incidence of Any Confirmed Thromboembolic Event

Plasma AT				ATryn
No. of Pts. Assessed	No. of Pts. With Events	% of Pts. With Events	95% CI*	No. of Pts. Assessed	No. of Pts. With Events	% of Pts. With Events	95% CI	Lower 95% Confidence Bound of Difference
The 95% confidence intervals were calculated using Clopper-Pearson methodology. AT=Antithrombin; No.=Number; Pts.=Patients; CI=Confidence Interval
35	0	0.0	0.00, 10.00	31	1	3.2	0.08, 16.70	-0.167

The lower 95% confidence bound of difference between treatment groups was -0.167, a value that is greater than the pre-specified lower confidence bound of -0.20. This demonstrates that ATryn was non-inferior to plasma AT in terms of the prevention of peri-operative or peri-partum thromboembolic events.

Supportive data come from a study in the same population with 5 hereditary AT deficient patients treated on 6 occasions in a compassionate use program and provides additional reassurance of the efficacy of ATryn. None of these patients reported a thromboembolic event.2

REFERENCES

1. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia 2008;14:1229-39.


2. Konkle BA, Bauer KA, Weinstein R, Greist A, Holmes HE, Bonfiglio J. Use of recombinant human antithrombin in patients with congenital antithrombin deficiency undergoing surgical procedures. Transfusion 2003 March;43(3):390-4.


3. Edmunds T, Van Patten SM, Pollock J et al. Transgenically produced human antithrombin: structural and functional comparison to human plasma-derived antithrombin. Blood 1998 June 15;91(12):4561-71.


4. Echelard Y, Meade H, Ziomek C. The first biopharmaceutical from transgenic animals: ATryn. Modern Biopharmaceuticals 2005;995-1016.


5. Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs 2007;67(10):1429-40.


6. Buchanan GS, Rodgers GM, Ware Branch. The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation. Best Pract Res Clin Obstet Gynaecol 2003 June;17(3):397-411.


7. Walker ID, Greaves M, Preston FE. Investigation and management of heritable thrombophilia. Br J Haematol 2001;114:512-28.

How Supplied/Storage and Handling

Dosage Form

NDC 67386-521-51

Approximately 1750 IU/vial in a sterile white to off-white lyophilized powder for reconstitution. Each carton contains one single dose vial of ATryn.

The actual potency of ATryn is stated on the vial label and carton.

Storage and Handling

Store ATryn refrigerated at between 2-8°C (36-46°F).

Do not use product beyond the expiration date printed on the package. Discard unused portions.

Patient Counseling Information

Inform patients that allergic-type hypersensitivity reactions are possible and instruct them to inform their physicians about any past or present known hypersensitivity to goats or goat milk proteins prior to treatment with ATryn. Inform patients of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis and to notify their health care provider immediately if these events develop.

Inform patients about the risk of bleeding when ATryn is administered with other anticoagulants and instruct them to notify their physicians of any bleeding events while on treatment with ATryn.

Manufacturer:

GTC Biotherapeutics, Inc.

Framingham, MA 01702, U.S.A.

U.S. License No. 1794

Marketed by:

Lundbeck Inc.

Deerfield, IL 60015, U.S.A.

® Trademark of Lundbeck Inc.

Revised: April 2009

PRINCIPAL DISPLAY PANEL

NDC 67386-521-51

Vial:

Carton:

Package:

  

ATryn  antithrombin (recombinant)  injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 67386-521 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ANTITHROMBIN ALFA (ANTITHROMBIN ALFA) ANTITHROMBIN ALFA 1750 [iU]  in 10 mL

Inactive Ingredients Ingredient Name Strength GLYCINE   SODIUM CHLORIDE   SODIUM CITRATE

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 67386-521-51 1 VIAL In 1 CARTON contains a VIAL 1 10 mL In 1 VIAL This package is contained within the CARTON (67386-521-51)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
BLA	BLA125284	02/06/2009

Labeler - Lundbeck Inc. (018343595)

Establishment
Name	Address	ID/FEI	Operations
GTC Biotherapeutics, Inc.		807934260	ANALYSIS

Establishment
Name	Address	ID/FEI	Operations
Lonza Biologics Inc.		093149750	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Medimmune, LLC		190639906	MANUFACTURE

Revised: 06/2010Lundbeck Inc.

More ATryn resources

• ATryn Side Effects (in more detail)
• ATryn Use in Pregnancy & Breastfeeding
• ATryn Drug Interactions
• ATryn Support Group
• 0 Reviews for ATryn - Add your own review/rating

• ATryn Monograph (AHFS DI)


• ATryn MedFacts Consumer Leaflet (Wolters Kluwer)


• ATryn Consumer Overview

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Avandaryl

Generic Name: glimepiride and rosiglitazone (glye MEP ir ide and ROE si GLI ta zone)

Brand Names: Avandaryl

What is glimepiride and rosiglitazone?

Glimepiride and rosiglitazone is a combination of two oral diabetes medicines that help control blood sugar levels.

Glimepiride and rosiglitazone is for people with type 2 diabetes. This medication is not for treating type 1 diabetes. Glimepiride and rosiglitazone is not recommended for use with insulin.

Taking glimepiride and rosiglitazone may increase your risk of serious heart problems, such as heart attack or stroke. Therefore, glimepiride and rosiglitazone is available only to certain people with type 2 diabetes that cannot be controlled with other diabetes medications.

Glimepiride and rosiglitazone is available only under a special program called Avandia-Rosiglitazone Medicines Access Program. You must be registered in the program and sign documents stating that you understand the risks and benefits of taking this medication.

Glimepiride and rosiglitazone may also be used for purposes not listed in this medication guide.

What is the most important information I should know about glimepiride and rosiglitazone?

Taking glimepiride and rosiglitazone may increase your risk of serious heart problems, such as heart attack or stroke. Therefore, glimepiride and rosiglitazone is available only to certain people with type 2 diabetes that cannot be controlled with other diabetes medications. Do not use glimepiride and rosiglitazone if you have type 1 diabetes, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

Before taking glimepiride and rosiglitazone, tell your doctor if you have congestive heart failure or heart disease, a history of heart attack or stroke, liver or kidney disease, an enzyme deficiency called G6PD, adrenal or pituitary gland disorders, or eye problems caused by diabetes.

Women may be more likely than men to have bone fractures in the upper arm, hand, or foot while taking glimepiride and rosiglitazone. Talk with your doctor if you are concerned about this possibility.

What should I discuss with my healthcare provider before taking glimepiride and rosiglitazone?

You should not use glimepiride and rosiglitazone if you have advanced heart failure if you are in a state of diabetic ketoacidosis (call your doctor for treatment).

To make sure you can safely take glimepiride and rosiglitazone, tell your doctor if you have any of these other conditions:

• 
  

  congestive heart failure, heart disease, a history of heart attack or stroke;

  
  


• 
  

  an enzyme deficiency called glucose-6-phosphate dehydrogenase deficiency (G6PD);

  
  


• 
  

  liver disease or kidney disease;

  
  


• 
  

  adrenal or pituitary gland disorders; or

  
  


• 
  

  eye problems caused by diabetes.

  
  

Certain oral diabetes medications may increase your risk of serious heart problems. However, not treating your diabetes can damage your heart and other organs. Talk to your doctor about the risks and benefits of treating your diabetes with glimepiride and rosiglitazone. Women may be more likely than men to have bone fractures in the upper arm, hand, or foot while taking glimepiride and rosiglitazone. Talk with your doctor if you are concerned about this possibility. FDA pregnancy category C. Do not use glimepiride and rosiglitazone if you are pregnant. It is not known whether this medication will harm an unborn baby. Similar diabetes medications have caused severe hypoglycemia in newborn babies whose mothers had used the medication near the time of delivery. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Some women using glimepiride and rosiglitazone have started having menstrual periods, even after not having a period for a long time due to a medical condition. You may be able to get pregnant if your periods restart. Talk with your doctor about the need for birth control. It is not known whether glimepiride and rosiglitazone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using glimepiride and rosiglitazone.

How should I take glimepiride and rosiglitazone?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Take glimepiride and rosiglitazone with your first meal of the day.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office. Visit your doctor regularly.

Know the signs of low blood sugar (hypoglycemia) and how to recognize them: headache, hunger, weakness, sweating, tremors, irritability, or trouble concentrating.

Always keep a source of sugar available in case you have symptoms of low blood sugar. Sugar sources include orange juice, glucose gel, candy, or milk. If you have severe hypoglycemia and cannot eat or drink, use an injection of glucagon. Your doctor can give you a prescription for a glucagon emergency injection kit and tell you how to give the injection.

Check your blood sugar carefully during a time of stress or illness, if you travel, exercise more than usual, drink alcohol, or skip meals. These things can affect your glucose levels and your dose needs may also change.

Your doctor may want you to stop taking glimepiride and rosiglitazone for a short time if you become ill, have a fever or infection, or if you have surgery or a medical emergency.

Ask your doctor how to adjust your dose if needed. Do not change your medication dose or schedule without your doctor's advice. Store at room temperature, protected from moisture, heat, and light.

See also: Avandaryl dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. A glimepiride and rosiglitazone overdose can cause life-threatening hypoglycemia.

Symptoms of severe hypoglycemia include extreme weakness, blurred vision, sweating, trouble speaking, tremors, stomach pain, confusion, and seizure (convulsions).

What should I avoid while taking glimepiride and rosiglitazone?

Avoid drinking alcohol. It can lower your blood sugar. Avoid exposure to sunlight or tanning beds. This medication can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Glimepiride and rosiglitazone side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have any of these serious side effects:

• 
  

  feeling short of breath, even with mild exertion;

  
  


• 
  

  swelling or rapid weight gain;

  
  


• 
  

  pale skin, feeling light-headed, rapid heart rate, trouble concentrating, fever, confusion or weakness;

  
  


• 
  

  changes in your vision;

  
  


• 
  

  chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling; or

  
  


• 
  

  nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

  
  

Less serious side effects may include:

• 
  

  headache;

  
  


• 
  

  gradual weight gain; or

  
  


• 
  

  cold symptoms such as stuffy nose, sneezing, sore throat.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect glimepiride and rosiglitazone?

Tell your doctor about all other medications you use, especially:

• 
  

  delavirdine (Rescriptor);

  
  


• 
  

  gemfibrozil (Lopid);

  
  


• 
  

  any other diabetes medications you use;

  
  


• 
  

  antibiotics such as rifampin (Rifater, Rifadin, Rifamate) or sulfisoxazole (Pediazole, and others);

  
  


• 
  

  antifungal medications such as fluconazole (Diflucan), ketoconazole (Nizoral), miconazole (Oravig), or voriconazole (Vfend);

  
  


• 
  

  heart or blood pressure medication such as amiodarone (Cordarone, Pacerone), carvedilol (Coreg), losartan (Hyzaar, Cozaar), nicardipine (Cardene), or torsemide (Demadex);

  
  


• 
  

  pain or arthritis medicine such as flurbiprofen (Ansaid), ibuprofen (Advil, Motrin), indomethacin (Indocin), mefenamic acid (Ponstel), or piroxicam (Feldene); or

  
  


• 
  

  seizure medicine such as carbamazepine (Carbatrol, Equetro, Tegretol) or phenobarbital (Solfoton).

  
  

You may be more likely to have hyperglycemia (high blood sugar) if you also take other drugs that can raise blood sugar, such as:

• 
  

  isoniazid;

  
  


• 
  

  diuretics (water pills);

  
  


• 
  

  steroids (prednisone and others);

  
  


• 
  

  niacin (Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, and others);

  
  


• 
  

  phenothiazines (Compazine and others);

  
  


• 
  

  thyroid medicine (Synthroid and others);

  
  


• 
  

  birth control pills and other hormones; and

  
  


• 
  

  diet pills or medicines to treat asthma, colds or allergies.

  
  

You may be more likely to have hypoglycemia (low blood sugar) if you also take:

• 
  

  exenatide (Byetta);

  
  


• 
  

  probenecid (Benemid);

  
  


• 
  

  aspirin or other salicylates (including Pepto-Bismol);

  
  


• 
  

  a blood thinner such as warfarin (Coumadin, Jantoven);

  
  


• 
  

  sulfa drugs (Bactrim, Septra, Sulfatrim, SMX-TMP, and others);

  
  


• 
  

  a monoamine oxidase inhibitor (MAOI);

  
  


• 
  

  other oral diabetes medications, especially acarbose (Precose), metformin (Glucophage), miglitol (Glyset), pioglitazone (Actos, Duetact, Actoplus Met), or other drugs that contain rosiglitazone (Avandia, Avandamet).

  
  

This list is not complete and other drugs may interact with glimepiride and rosiglitazone. Tell your doctor about all medications you use. This includes prescription, over the counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Avandaryl resources

• Avandaryl Side Effects (in more detail)
• Avandaryl Dosage
• Avandaryl Use in Pregnancy & Breastfeeding
• Drug Images
• Avandaryl Drug Interactions
• Avandaryl Support Group
• 0 Reviews for Avandaryl - Add your own review/rating

• Avandaryl Prescribing Information (FDA)


• Avandaryl Advanced Consumer (Micromedex) - Includes Dosage Information


• Avandaryl MedFacts Consumer Leaflet (Wolters Kluwer)


• Avandaryl Consumer Overview

Compare Avandaryl with other medications

• Diabetes, Type 2

Where can I get more information?

• Your pharmacist can provide more information about glimepiride and rosiglitazone.

See also: Avandaryl side effects (in more detail)

Avapro

Generic Name: Irbesartan
Class: Angiotensin II Receptor Antagonists
VA Class: CV805
Chemical Name: 2 - Butyl - 3 - [[2′(1H - tetrazol - 5 - yl)[1,1′ - biphenyl] - 4 - yl]methyl] - 1,3 - diazaspiro[4.4]non - 1 - en - 4 - one
Molecular Formula: C₂₅H₂₈N₆O₃S•½C₄H₄ O₄
CAS Number: 138402-11-6

• 
  

  May cause fetal and neonatal morbidity and mortality if used during pregnancy.^{1 26 71 72} (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  
  


• 
  

  If pregnancy is detected, discontinue the drug as soon as possible.^{1 26 72}

  
  

Introduction

Angiotensin II receptor (AT₁) antagonist.^{1 2 4 5 6 21 22 23}

Uses for Avapro

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).^{1 2 3 4 5 6 14 15 16 17 18 20 21 22 23}

One of several preferred initial therapies in hypertensive patients with chronic kidney disease, diabetes mellitus, or heart failure.⁶⁰

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.⁶⁰

Diabetic Nephropathy

Management of diabetic nephropathy manifested by elevated S_cr and proteinuria (urinary protein excretion >300 mg daily) in patients with type 2 diabetes mellitus and hypertension.¹

A first-line agent in the treatment of diabetic nephropathy in such patients.^{37 39}

CHF

A second-line agent in the treatment of CHF†; should be used only in those intolerant of ACE inhibitors.^{25 38 41}

Avapro Dosage and Administration

General

Hypertension

• 
  

  Irbesartan in fixed combination with hydrochlorothiazide tablets can be used for initial treatment of hypertension in patients who are likely to need multiple drugs to achieve their BP goals.²⁶ Consider potential benefits and risks of initiating therapy with the fixed combination of irbesartan and hydrochlorothiazide.²⁶

  
  

Administration

Oral Administration

Administer orally once daily without regard to meals.^{1 21}

Dosage

Adults

Hypertension

Monotherapy

Oral

Initially, 150 mg once daily in adults without intravascular volume depletion.¹ Adjust dosage at approximately monthly intervals (more aggressively in high-risk patients) to achieve BP control.⁶⁰ In adults with depletion of intravascular volume, the usual initial dosage is 75 mg once daily.^{1 24}

Usual dosage: 150–300 mg once daily; no additional therapeutic benefit with higher dosages or with twice-daily dosing.¹

Combination Therapy

Oral

If BP is not adequately controlled by monotherapy with irbesartan or hydrochlorothiazide, can switch to fixed-combination tablets (irbesartan 150 mg and 12.5 mg hydrochlorothiazide; then irbesartan 300 mg and hydrochlorothiazide 12.5 mg), administered once daily.²⁶ Can increase dosage to irbesartan 300 mg and hydrochlorothiazide 25 mg daily, if needed, to control BP.²⁶

In patients receiving fixed-combination tablets as initial therapy, the usual starting dosage is irbesartan 150 mg and hydrochlorothiazide 12.5 mg once daily.²⁶ May increase dosage after 1–2 weeks of therapy to a maximum of irbesartan 300 mg and hydrochlorothiazide 25 mg once daily.²⁶

Diabetic Nephropathy

Oral

Initial dosage of 75 mg once daily used in clinical trial.¹ Increase dosage to target maintenance dosage of 300 mg once daily.¹ No data available on effects of lower dosages.¹

Special Populations

Hepatic Impairment

No initial dosage adjustments necessary.^{1 26}

Renal Impairment

No initial dosage adjustments necessary.^{1 26}

Irbesartan/hydrochlorothiazide fixed combination not recommended in patients with severe renal impairment.²⁶

Geriatric Patients

No initial dosage adjustments necessary.^{1 26}

Volume- and/or Salt-depleted Patients

Correct volume and/or salt depletion prior to initiation of therapy or initiate therapy using lower initial dosage (75 mg once daily).^{1 24 26} Fixed-combination tablets containing irbesartan and hydrochlorothiazide are not recommended as initial therapy in patients with intravascular volume depletion.²⁶

Cautions for Avapro

Contraindications

• 
  

  Known hypersensitivity to irbesartan or any ingredient in the formulation.^{1 26}

  
  

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when drugs that act directly on the renin-angiotensin system (e.g., angiotensin II receptor antagonists, ACE inhibitors) are used during the second and third trimesters of pregnancy.^{1 26} (See Boxed Warning.) ACE inhibitors also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.^{71 72}

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.^{71 72}

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.^{1 72} Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.¹³

Hypotension

Possible symptomatic hypotension, particularly in volume- and/or salt-depleted patients (e.g., those treated with diuretics or undergoing dialysis).^{1 26} (See Volume- and/or Salt-depleted Patients under Dosage and Administration.)

Transient hypotension is not a contraindication to additional doses; may reinstate therapy cautiously after BP is stabilized (e.g., with volume expansion).^{1 26}

Malignancies

In July 2010, FDA initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis found a modest but statistically significant increase in risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist compared with control.^{120 121 123 126} However, subsequent studies, including a larger meta-analysis conducted by FDA, have not shown such risk.^{126 127 128 129} Based on currently available data, FDA has concluded that angiotensin II receptor antagonists do not increase the risk of cancer.¹²⁶

Sensitivity Reactions

Anaphylactoid reactions and/or angioedema possible;^{1 26} not recommended in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.⁷³

General Precautions

Renal Effects

Possible oliguria, progressive azotemia, and, rarely, acute renal failure and/or death in patients with severe CHF.^{1 26}

Increases in BUN and S_cr possible in patients with unilateral or bilateral renal artery stenosis.^{1 26}

Use of Fixed Combinations

When used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.²⁶

Specific Populations

Pregnancy

Category D.²⁶ (See Boxed Warning.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.^{1 26} Discontinue nursing or the drug.^{1 26}

Pediatric Use

Dosages of up to 4.5 mg/kg once daily did not appear to effectively lower BP in pediatric patients 6–16 years of age.¹ Not studied in children <6 years of age.¹

Safety and efficacy of the fixed-combination preparation containing irbesartan and hydrochlorothiazide not established.²⁶

Geriatric Use

No substantial differences in safety or efficacy of irbesartan monotherapy or fixed-combination containing irbesartan and hydrochlorothiazide relative to younger adults, but increased sensitivity cannot be ruled out.^{1 26}

Renal Impairment

Use with caution.¹

Deterioration of renal function may occur.^{1 26} (See Renal Effects under Cautions.)

Use of irbesartan in fixed combination with hydrochlorothiazide is not recommended in patients with severe renal impairment.²⁶

Blacks

BP reduction may be smaller in black patients compared with nonblack patients; use in combination with a diuretic.^{1 26 60 69 70}

Common Adverse Effects

Diarrhea, dyspepsia/heartburn, fatigue; also, dizziness, orthostatic dizziness, and orthostatic hypotension in patients with diabetic nephropathy.¹

Interactions for Avapro

Metabolized principally by CYP2C9.^{1 26} Does not substantially induce or inhibit CYP1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4.^{1 26}

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (decreased irbesartan metabolism) with CYP2C9 inhibitors.^{1 26}

Specific Drugs

Drug	Interaction	Comments
Digoxin	Pharmacologic and/or pharmacokinetic interactions unlikely1 26
Hydrochlorothiazide	Pharmacokinetic interactions unlikely1 26 Additive hypotensive effects1 26
Nifedipine	Decreased irbesartan metabolism in vitro; alteration of irbesartan pharmacokinetics not observed in vivo1 26
NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors	Possible deterioration of renal function in geriatric, volume-depleted, or renally impaired patients1 Possible reduced antihypertensive effects1	Monitor renal function periodically1
Tolbutamide	Possible decreased irbesartan metabolism26
Warfarin	Pharmacologic and/or pharmacokinetic interaction unlikely1 26

Avapro Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration generally achieved 1.5–2 hours after oral dose.¹ Absolute bioavailability is about 60–80%.^{1 26}

Onset

Antihypertensive effect evident within 2 weeks, with maximum BP reduction after 2–4 weeks.^{1 26}

Food

Food does not affect bioavailability.^{1 26}

Distribution

Extent

Crosses the placenta and is distributed in the fetus in animals.^{1 26}

Crosses the blood-brain barrier poorly, if at all, in animals.^{1 15}

Distributed into milk in rats; not known whether distributed into human milk.^{1 26}

Plasma Protein Binding

90% (principally albumin and α₁-acid glycoprotein).^{1 26}

Elimination

Metabolism

Undergoes hepatic metabolism by glucuronide conjugation and oxidation (principally by CYP2C9) to inactive metabolites.^{1 26}

Elimination Route

Eliminated in urine and feces (via bile).^{1 26}

Half-life

Terminal elimination half-life: 11–15 hours.¹

Special Populations

Not removed by hemodialysis.^{1 26} Pharmacokinetics not substantially altered by hemodialysis or renal impairment.^{1 26}

Stability

Storage

Oral

Tablets

15–30°C.^{1 26}

Actions

• 
  

  Blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects.^{1 21 22 23 26}

  
  


• 
  

  Does not interfere with response to bradykinins and substance P.^{1 5 6 21}

  
  

• 
  

  Does not share the ACE inhibitor common adverse effect of dry cough.^{1 5 6 20 21 26}

  
  

Advice to Patients

• 
  

  Risks of use during pregnancy.^{1 26}

  
  


• 
  

  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{1 26}

  
  

• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{1 26}

  
  

• 
  

  Importance of informing patients of other important precautionary information.^{1 26} (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Irbesartan

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	75 mg	Avapro	Bristol-Myers Squibb, (also promoted by Sanofi-Synthelabo)
		150 mg	Avapro	Bristol-Myers Squibb, (also promoted by Sanofi-Synthelabo)
		300 mg	Avapro	Bristol-Myers Squibb, (also promoted by Sanofi-Synthelabo)

Irbesartan Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	150 mg with Hydrochlorothiazide 12.5 mg	Avalide	Bristol-Myers Squibb, (also promoted by Sanofi-Synthelabo)
		300 mg with Hydrochlorothiazide 12.5 mg	Avalide	Bristol-Myers Squibb, (also promoted by Sanofi-Synthelabo)
		300 mg with Hydrochlorothiazide 25 mg	Avalide	Bristol-Myers Squibb, (also promoted by Sanofi-Synthelabo)

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 01/2012. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Avalide 150-12.5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$111.99 or 90/$320.98

Avalide 300-12.5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$122.99 or 90/$352.96

Avalide 300-25MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$122.95 or 90/$345.09

Avapro 150MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$92.99 or 90/$247.98

Avapro 300MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$111.99 or 90/$299.96

Avapro 75MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$87.99 or 90/$232.96

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2012, Selected Revisions December 23, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Bristol-Myers Squibb Company. Avapro (irbesartan) tablets prescribing information. New York, NY; 2011 Apr.

2. van den Meiracker AH, Admiraal PJJ, Janssen JA et al. Hemodynamic and biochemical effects of the AT₁ receptor antagonist irbesartan in hypertension. Hypertension. 1995; 25:22-9. [PubMed 7843749]

3. Ellis ML, Patterson JH. A new class of antihypertensive therapy: angiotensin II receptor antagonists. Pharmacotherapy. 1996; 16:849-60. [IDIS 374571] [PubMed 8888079]

4. Bauer JH, Reams GP. The angiotensin II type 1 receptor antagonists: a new class of antihypertensive drugs. Arch Intern Med. 1995; 155:1361-8. [IDIS 350333] [PubMed 7794084]

5. Burnier M, Buclin T, Biollaz J et al. Pharmacokinetic-pharmacodynamic relationships of three angiotensin II receptor antagonists in normal volunteers. Kidney Int. 1996; 49(Suppl 55):S-24–S-29.

6. Velasquez MT. Angiotensin II receptor blockers: a new class of hypertensive drugs. Arch Fam Med. 1996; 5:351-356. [PubMed 8640326]

7. Anon. Valsartan for hypertension. Med Lett Drugs Ther. 1997; 39:43-4. [PubMed 9137296]

8. Pitt B, Segal R, Martinez FA et al for the ELITE study investigators. Randomized trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997; 349:747-52. [IDIS 381678] [PubMed 9074572]

9. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The 1984 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1984; 144:1045-57. [IDIS 184763] [PubMed 6143542]

10. Anon. Drugs for hypertension. Med Lett Drugs Ther. 1995; 37:45-50. [PubMed 7760767]

11. Joint National Committee on Detection, Evaluation, and Treatment of High Blod Pressure. The 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1988; 148:1023-38. [IDIS 242588] [PubMed 3365073]

12. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med. 1993; 153:154-83. [IDIS 309043] [PubMed 8422206]

13. US Food and Drug Administration. Dangers of ACE inhibitors during second and third trimesters of pregnancy. FDA Med Bull. 1992; 22:2.

14. Pool JL, Guthrie RM, Littlejohn T et al. The antihypertensive effects of irbesartan in patients with mild-to-moderate hypertension. Am J Hypertens. 1996; 9:152A.

15. Fogari R, Zanchetti A, Moran S et al et al. Once-daily irbesartan provides full 24-hour ambulatory blood pressure control. J Hypertens. 1997; 15(Suppl 4):S113.

16. Stumpe KO, Haworth D, Höglund C et al et al. Comparison of the angiotensin II receptor antagonist, irbesartan, and atenolol for the treatment of hypertension. J Hypertens. 1997; 15(Suppl 4):S115.

17. Larochelle P, Flack JM, Hannah S et al et al. Irbesartan versus enalapril in severe hypertension. Am J Hypertens. 1997; 10:131A.

18. Mimran A, Ruilope L, Kerwin L et al et al. Comparison of the angiotensin II receptor antagonist, irbesartan, with the full dose range of enalapril for the treatment of hypertension. J Hypertens. 1997; 15(Suppl 4):S117.

19. Cazaubon C, Gougat J, Bousquet F et al. Pharmacological characterization of SR 47436, a new nonpeptide AT₁ subtype angiotensin II receptor antagonist. J Pharmacol Exp Ther. 1993; 265: 826-34. [PubMed 8496828]

20. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med. 1997; 157:2413-46. [IDIS 395691] [PubMed 9385294]

21. Anon. Irbesartan for hypertension. Med Lett Drugs Ther. 1998; 40:18-9. [PubMed 9465857]

22. Kossler-Taub K, Littlejohn T, Elliott W et al. Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan, in mild-to-moderate hypertension. Am J Hypertens. 1998; 11:445-53. [PubMed 9607383]

23. Larochelle P, Flack JM, Marbury TC et al. Effects and tolerability of irbesartan versus enalapril in patients with severe hypertension. Am J Cardiol. 1997; 80:1613-5. [IDIS 399095] [PubMed 9416950]

24. Bristol-Myers Squibb Company. Princeton, NJ: Personal communication.

25. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Part II. Management of heart failure: approaches to the prevention of heart failure. Am J Cardiol. 1999; 83:9-38A.

26. Bristol-Myers Squibb Company. Avalide (irbesartan-hydrochlorothiazide) tablets prescribing information. Princeton, NJ; 2008 Nov.

27. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension. 2000; 35:1021-4. [PubMed 10818056]

28. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension. 2000; 35:1019-20. [PubMed 10818055]

29. Merck & Co, Inc. Results of second heart-failure study with Cozaar presented at American Heart Association scientific sessions. West Point, PA; 1999 Nov 10. Press release from Yahoo web site.

30. Food and Drug Administration. Avapro (irbesartan) and Avalide (irbesartan/hydrochlorothiazide) tablets [May 9, 2000: Bristol-Myers Squibb]. MedWatch drug labeling changes. Rockville, MD; May 2000. From FDA website.

31. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000; 36:646-61. [IDIS 452007] [PubMed 10977801]

32. Hansson L, Zanchetti A, Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998; 351:1755-62. [IDIS 409003] [PubMed 9635947]

33. Pitt B, Segal R, Martinez FA et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997; 349:747-52. [IDIS 381678] [PubMed 9074572]

34. American Diabetes Association. Clinical Practice Recommendations 2001. Position Statement. Diabetic nephropathy. Diabetes Care. 2001; 24(Suppl 1):S69-72.

35. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2001; 24(Suppl 1):S33-43.

36. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2002; 25:134-47. [IDIS 479088] [PubMed 11772914]

37. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2002; 25(Suppl 1):S33-43.

38. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). 2001. From ACC website. Accessed July 25, 2002.

39. American Diabetes Association. Clinical Practice Recommendations 2002. Position Statement. Diabetic nephropathy. Diabetes Care. 2002; 25(Suppl 1):S85-9.

40. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001; 345:1667-75. [IDIS 473009] [PubMed 11759645]

41. Novartis. Diovan (valsartan) tablets prescribing information. East Hanover, NJ; 2002 Jul.

42. Williams CL, Hayman LL, Daniels SR et al. Cardiovascular health in childhood: a statement for health professional from the Committee on Atherosclerosis, Hypertension, and Obesity in the Young (AHOY) of the Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2002; 106:143-60. [PubMed 12093785]

43. Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345:851-60. [IDIS 469606] [PubMed 11565517]

44. Blankfield RP. Angiotensin-receptor blockers, type 2 diabetes, and renoprotection. N Engl J Med. 2002: 346;705. Letter.

45. Lewis EJ. Angiotensin-receptor blockers, type 2 diabetes, and renoprotection. N Engl J Med. 2002: 346;706. Letter.

46. Williams MA, Fleg JL, Ades PA et al. Secondary prevention of coronary heart disease in the elderly (with emphasis on patients ≥ 75 years of age). An American Heart Association Scientific Statement from the Council on Clinical Cardiology Subcommittee on Exercise, Cardiac rehabilitation, and Prevention. Circulation. 2002; 105:1735-43. [PubMed 11940556]

47. Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345:861-9. [IDIS 469607] [PubMed 11565518]

48. Parving HH, Lehnert H, Bröchner-Mortensen J et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001; 345:870-6. [IDIS 469608] [PubMed 11565519]

49. Remuzzi G. Slowing the progression of diabetic nephropathy. N Engl J Med. 1993; 329:1496-7. [PubMed 8413463]

50. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)

51. Kaplan NM. Choice of initial therapy for hypertension. JAMA. 1996; 275:1577-80. [IDIS 365188] [PubMed 8622249]

52. Viberti G, Mogensen CE, Groop LC et al. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA. 1994; 271:275-9. [IDIS 324307] [PubMed 8295285]

53. Fournier A. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1994; 330:937. [PubMed 8114873]

54. Kasiske VL, Kalil RSN, Ma JZ et al. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med. 1993; 118:129-138. [IDIS 308066] [PubMed 8416309]

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