Inlacin® Therapy in Patients with Type-2 Diabetes Mellitus (The Prospective Surabaya-Inlacin® Study) Askandar Tjokroprawiro Sri Murtiwi Surabaya Diabetes and Nutrition Center – Dr. Soetomo Teaching Hospital Faculty of Medicine Airlangga University, Surabaya Prospective study on DLBS3233 (Inlacin®) which is called Surabaya-Inlacin® Study (SIS) has been per-
The American Society of Hypertension, Inc. • MES 24th Annual Scientific Meeting and Exposition • The San Francisco Marriott • May 6 – May 9, 2009 health-care reform offers challenges,
opportunities for ash members
Economic crisis has long-term implications for research
Th e com bi n ed ch a llenges of
health-care reform and economic stress mean significant changes are ahead for aca- demic medicine.
"It is a remarkable time that we're in now. We are living through great change. In the next five or so years, the underpinnings of what we're used to doing are going to be chal- lenged," said Samuel O. Thier, MD, Professor of Medicine and Health Care Policy at Har- vard Medical School. Dr. Thier presented the keynote lecture, "Academic Medicine and Registration Desk Hours
the Economy: What Would Darwin Advise?" at Thursday's plenary session.
Friday 5:30 a m to 6:00 p m
"On the 200th anniversary of Darwin's Saturday 5:30 to 10:00 a m
birth, it's helpful to ask: How would he think about this change? He had a simple Scientific and Technical
idea that changed science and even changed the way that we think about change," Dr. Thier said. "Darwin thought that distant biologic predecessors had evolved on the Friday 9:30 a m to 12:45 p m
basis of external stresses and their ability Samuel O. Thier, MD Lunch 11:45 a m to 12:45 p m to function with those stresses. Those who medical centers must think about how to organize and deliver care. And since ASH High Tea 2:30 to 3:30 p m were able to cope with those stresses were move ahead with the science while address- members are major deliverers of care, and successful and evolved, those who were not ing the challenges of funding and reform. since you are people who are producing the ASH Information / CME Desk
"It is obvious that we will not be permit- new knowledge to improve that care, what- Visit the ASH Information / CME Desk in the The current progression of science is ted to continue on the present path. We are ever change is going to happen is going to Golden Gate Foyer across from the exhibit unmatched in history, and those in academic going to be making changes in the ways we Health-care reform, continued on page 2 hall for information on ASH programs.
2009 Annual Scientific
Meeting Corporate Sponsors
The American Society of Hypertension
wishes to acknowledge the following
Plenary Session II Friday morning corporate sponsors for their generous Don't miss this Friday morning's plenary session, which begins at 8:15 a.m. in the Yerba Buena Bal room – Salon 9. Several support of the ASH 24th Annual notable speakers will present talks on timely topics in hypertension, including a lecture by cardiovascular specialist Graham Scientific Meeting.
Boehringer Ingelheim Pharmaceuticals, Inc. 8:15 a.m. — Genetic Variations in Human Hypertension.
9:15 a.m. — Debate: Do We Need New Risk Factors?
Daiichi Sankyo, Inc. Daniel T. O'Connor, MD Jay N. Cohn, MD, and Wil iam C. Cushman, MD Merck & Co., Inc. 8:45 a.m. — Salt: From Evidence to Worldwide
Novartis Pharmaceuticals Corporation Graham MacGregor, MD Visit us at Booth #205
ash Times • friday saturday • may 8–9 • san francisco
health-care reform, Role of hypertension specialist in
continued from page 1affect you. It's important for you to under- The other lessons for ASH members research and therapy examined
stand that and participate in the discussions are clear. of how these changes are to come about. "Reaffirm your ASH mission and values, Lifestyle intervention, pharmacotherapy keys Don't sit on the sidelines and wait for the adhere to them, and make judgments based on storm to pass — take the opportunity to play them. Review the changes from the perspec- to pre-diabetes management an important role in the changes to come," tive of your mission and what is best for your patients. You have to be sure that as you are ana- The ASH Annual Scientific meeting pros and cons of morbidity/mortality trials.
"Darwin saw the importance of exter- lyzing and arguing for what is best at academic theme, "Health Care 2009: The Role of the "The guidelines note that randomization nal factors in survival and extinction. He medical centers going forward, that you keep Hypertension Specialist" was highlighted in is the safest procedure to avoid bias in the re- thought that successful evolution of species your patients first," he said. "Understand your presentations by three speakers at Thursday's sults. In general, the large number of patients was associated with chance and was largely opportunities and the risks to research and Plenary Session, which was organized around guarantees the power to detect differences in unplanned. But that's not always the case," clinical care and stay involved in the discus- the meeting's three concurrent tracks: transla- primary endpoints of clinical importance," Dr. Dr. Thier said. "Our sion. Hypertension is tional issues in hypertension, therapy of hyper- Mancia said. species is one of the a major public health tension, and pathobiology of hypertension. "The guidelines also note the limitations of Darwin saw the importance of few that's able to an- concern. It is easily morbidity/mortality trials," he said. ticipate events and to external factors in survival and diagnosed. It is easily Inflammation and adaptive immunity
Among the limitations are determining adjust or even modify treated. There is a doc- Markers of inflammation are commonly the applicability to clinical practice, and also extinction. He thought that suc- those events. And, umented cost/benefit encountered in cardiovascular disease. the fact that nonresponders are kept on the therefore, it's impor- cessful evolution of species was in terms of prevention "Innate and adaptive immunity are highly initial treatment, so results are from a mixture tant for us to think and treatment of heart interactive. And there seems to be an interplay of responders and nonresponders. associated with chance and was about what we're go- attack and stroke. And between oxidation and inflammation," said Several factors limit the duration of ran- largely unplanned. But that's not there's also the prom- David G. Harrison, MD, Chief of Cardiology domized clinical trials, including cost, mar- ise of value added to at Emory University, who addressed "Roles keting needs, patency expiration, and the always the case. Our species is one that NIH funding the healthcare sys- of Inflammation and Adaptive Immunity in instability of patients and investigators, Dr. is flat and there has of the few that's able to anticipate tem by phenotype and Hypertension." been contraction and genotype data.
Dr. Harrison described research indicating "One problem is that trials last four to five events and to adjust or even modify consolidation in big "At t he pol ic y that angiotensin II-induced hypertension leads years, and we use this information to make pharma and in bio- those events. And, therefore, it's im- level, support pre- to vascular T-cell infiltration. The activated T- treatment decisions for patients who may have technology. This has vention, which is one cells have a propensity to enter visceral fat. life expectancies of 20 years or more," he said. portant for us to think about what meant that for aca- of your key goals. "Another study indicated that in humans "The purpose of the trials is to try to delay demic medical cen- we're going to do. Support research in there is a correlation between BMI and visceral or prevent the progression from a relatively ters it can be risky to general, you have the fat concentration. This seems to be in visceral low-risk condition to a high-risk condition. invest in people and – Samuel O. Thier, MD history of possibilities fat as opposed to subcutaneous fat. So in hu- Because once a high-risk condition is reached, in facilities. "How- for the phenotype and mans the accumulation of cells seems to be it's almost irreversible," he said.
ever, those that have been willing to take that that is going to give you a lot of information. concentrated in visceral fat," he said. risk have had successful recruiting and reten- Lifestyle interventions are a major area of "Research indicates that if you remove Managing pre-diabetes
tion efforts and the changes are going to favor expertise for ASH members. And in the oxidation or if you remove inflammatory cells, There are 57 million adults in the United those who are willing to take some risks and clinical area, educating the public and other you get a low level of hypertension. It's a level of States with pre-diabetes. The criteria for defin- marshal their resources and strategize about health-care professionals is an important part hypertension that as clinicians we would say is ing pre-diabetes are impaired fasting glucose, how they want to go forward," he said. of what you do and you need to be organized prehypertension," Dr. Harrison said.
impaired glucose tolerance, or both.
The opportunities for ASH members in- to do that." "In a study of people with prehyperten- "There are two models for the progression clude expanded research. For a number of years, "We're in a time of major change. The sion, that prehypertension is stimulating from pre-diabetes to type 2 diabetes: low insu- academic medical centers have supported their change could be terrific. The science and po- an inflammatory response," he said. "If you lin secretion and low insulin resistance," said academic mission with the margins generated tential clinical benefits are phenomenal. But treat this inflammation, you can prevent the Alan J. Garber, MD, PhD, of Baylor College from inpatient and outpatient dollars, but that the economic stresses are going to be major development of full hypertension. If you don't of Medicine in Houston, who spoke on "The support is likely to diminish or even disappear. constraints on what you can accomplish," treat the inflammation, the patient develops a Diagnosis and Treatment of the Patient with So it's important to think about where funding Dr. Thier concluded. "It's important to stay full-blown, inflammatory response that then Pre-diabetes." will come from, Dr. Thier said. "I think indus- in the game and to be flexible. Be sure that leads to severe hypertension." "The clinical risks and consequences of try will be placing more research at academic you know what you want to get done, but not treating pre-diabetes are substantial," Dr. sites. This is going to move the long-term risks understand that you must listen to the argu- Limitations of outcome trials
Garber said. The microvascular disease risks to your institutions," he said. ments in the opposite direction." l In his presentation on "Outcome Trials in include retinopathy, neuropathy, and nephropa- Hypertension: More Limitations that We Used thy. The cardiovascular risks include heart dis- to Think?" Giuseppe Mancia, MD, Milan, ease, stroke, and peripheral vascular diseases.
Italy, described the value and the limitations "Lifestyle interventions are generally Board of directors appoints editor of event-based, or morbidity/mortality, ran- effective in preventing or controlling pre- domized trials.
diabetes," he said. "To address high-risk car- The American Society of Hypertension events or recurrent strokes. He is also Dr. Mancia described guidelines from the diovascular factors, pharmacotherapy may also Board of Directors recently appointed an active participant in trials involving European Society of Hypertension, which list the be necessary." l Michael Weber, MD, Professor of Medicine patients with diabetic and non-diabetic at the State University of New York Downstate Medical College of Medicine in Dr. Weber succeeds Marvin Moser, M.D., Brooklyn, as Editor-in-Chief of The Journal FACP, Clinical Professor of Medicine at Yale of Clinical Hypertension — an official University School of Medicine.
journal of the society. Dr. Moser, who served as Editor-in-Chief Scientific Poster Presentations Dr. Weber's career has primarily of The Journal of Clinical Hypertension Posters will be displayed in Golden Gate Hal Non-Pharmacological Therapy (Alternative focused on hypertension and preventive since its inception in 1999, has chaired Medicine; Diet; Physical Activity) cardiology. He was one of the founders several national committees that Friday, May 8
of the American Society of Hypertension established guidelines for the diagnosis Posters on Display: 9:30 a.m. to 4:00 p.m.
and has served as president of the society. and treatment of hypertension. He has Poster Viewing: 2:30 to 3:30 p.m.
He is a fel ow of the American College of received numerous awards from the Pediatric Hypertension . . . (P356 – P359) Clinical Trials . . . . . . (P257 – P300) Physicians, American College of Cardiology, International Society of Hypertension, the Preclinical Models/Experimental Hypertension and American Heart Association. Dr. Weber National Heart Lung & Blood Institute, the has served on the Cardiovascular and American Society of Hypertension, and Renal Drugs Advisory Board of the Food several medical universities for his research Neural Hormonal Mechanisms and Drug Administration and continues as and treatment efforts in hypertension.
(Renin; Neural Control; Vasoactive Autacoids) Vascular Injury/Inflammation and Remodeling a consultant to that agency. Dr. Moser is the author of more than His current research interests focus on 500 scientific publications and 11 books Late-Breaking Posters . . . (LBP1 – LBP14) clinical trials of patients with hypertension and has lectured extensively in the United and those at high risk of cardiovascular States and abroad. l
Powerful BP efficacy.
For your hypertensive patients.
For your goals.
t Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or
WARNING: USE IN PREGNANCY
without a history of allergy or bronchial asthma, but are more likely in patients When pregnancy is detected, discontinue AVAPRO or AVALIDE as soon as
with such a history possible. When used in pregnancy during the second and third trimesters,
t Thiazide diuretics have been reported to cause exacerbation or activation of drugs that act directly on the renin-angiotensin system can cause injury and
systemic lupus erythematosus even death to the developing fetus. [See Warnings and Precautions: Fetal/
Neonatal Morbidity and Mortality.]
t Lithium generally should not be given with thiazidest Thiazides should be used with caution in patients with severe renal disease and in patients with impaired hepatic function or progressive liver disease, AVAPRO is indicated for the treatment of hypertension. It may be used alone since minor alterations of fluid and electrolyte balance may precipitate or in combination with other antihypertensive agents.
AVAPRO is also indicated for the treatment of diabetic nephropathy with an t In placebo-controlled hypertension studies, there were no significant differences in adverse events (AEs) between AVAPRO and placebo. Adverse elevated serum creatinine and proteinuria (>300 mg/day) in patients with type events that occurred in at least 1% of patients treated with AVAPRO and at a 2 diabetes and hypertension. In this population, AVAPRO reduces the rate of higher incidence vs placebo included diarrhea (3% vs 2%), dyspepsia/heartburn progression of nephropathy as measured by the occurrence of doubling of serum (2% vs 1%), and fatigue (4% vs 3%) creatinine or end-stage renal disease (need for dialysis or renal transplantation).
t Additionally, in a study of hypertensive type 2 diabetic patients with renal AVALIDE is indicated for the treatment of hypertension.
disease (proteinuria ≥900 mg/day), the reported AEs for AVAPRO were similar AVALIDE may be used in patients whose blood pressure is not adequately to those seen in hypertension studies, with the exception of an increased controlled on monotherapy.
incidence of orthostatic symptoms; AVAPRO compared to placebo (both AVALIDE may also be used as initial therapy in patients who are likely to need groups received adjunctive antihypertensives): dizziness (10.2% vs 6.0%), multiple drugs to achieve their blood pressure goals.
orthostatic dizziness (5.4% vs 2.7%) and orthostatic hypotension (5.4% vs 3.2%), respectively. In patients with proteinuria, monitor serum potassium The choice of AVALIDE as initial therapy for hypertension should be based on an t In placebo-controlled hypertension studies, the most common adverse assessment of potential beneﬁ ts and risks and may be shaped by considerations experiences reported with AVALIDE that occurred in ≥1% of patients and at such as baseline blood pressure, target goal, and likelihood of achieving goal a higher incidence vs placebo included fatigue (7% vs 3%), musculoskeletal compared to monotherapy. pain (7% vs 5%), dizziness (8% vs 4%), and nausea/vomiting (3% vs 0%). In a study with AVALIDE used as initial therapy in moderate hypertension, the Important Safety Information
most common incidences of pre-speciﬁ ed adverse experiences reported that occurred in ≥1% of patients were: dizziness (3.0%, 3.8%, and 1.0%), headache t Because of the hydrochlorothiazide component, AVALIDE is contraindicated (5.5%, 3.8%, and 4.8%) and hyperkalemia (1.2%, 0%, and 1.0%) in AVALIDE, in patients with anuria or hypersensitivity to sulfonamide-derived drugs AVAPRO, and HCTZ, respectively. In a study with AVALIDE used as initial t In patients with volume or sodium depletion (eg, patients vigorously treated therapy in severe hypertension, the most common incidences of pre-speciﬁ ed with diuretics or on dialysis), such depletion should be corrected prior to adverse experiences reported that occurred in ≥1% were: dizziness (3.6% and administration of AVAPRO or AVALIDE, or a lower initial dose of AVAPRO 4.0%) and headache (4.3% and 6.6%) in AVALIDE and AVAPRO, respectively (75 mg) should be used, to avoid possible symptomatic hypotension Please see Brief Summary of full Prescribing Information on adjacent pages.
2009 Bristol-Myers Squibb Sanofi-Synthelabo Partnership Printed in the USA AVAPRO® (irbesartan) Tablets
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients Brief Summary of Prescribing Information. For complete prescribing information consult official package inserts.
receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral WARNING: USE IN PREGNANCY
fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal When pregnancy is detected, discontinue AVAPRO or AVALIDE as soon as possible. When used in pregnancy during the
disturbances such as nausea and vomiting.
second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.
to the developing fetus. [See Warnings and Precautions: Fetal/Neonatal Morbidity and Mortality.]
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also INDICATIONS AND USAGE
sensitize or exaggerate the response of the heart to the toxic effects of digitalis (eg, increased ventricular irritability).
Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.
AVAPRO is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Nephropathy in Type 2 Diabetic Patients
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
AVAPRO is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension. In this population, AVAPRO reduces the rate of progression of nephropathy as measured by the occurrence of In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics.
doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation) [see Clinical Pharmocology: Clinical Studies in Thus latent diabetes mellitus may become manifest during thiazide therapy.
AVAPRO Full Prescribing Information].
The antihypertensive effects of the drug may be enhanced in the post sympathectomy patient.
If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.
AVALIDE® Tablets is indicated for the treatment of hypertension.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
AVALIDE may be used in patients whose blood pressure is not adequately controlled on monotherapy.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known AVALIDE may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals.
disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
The choice of AVALIDE as initial therapy for hypertension should be based on an assessment of potential benefits and risks and may be shaped by considerations such as baseline blood pressure, target goal, and likelihood of achieving goal compared to monotherapy.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
DOSAGE AND ADMINISTRATION [See Dosage and Administration for AVAPRO and AVALIDE (2) in respective Full Prescribing Information Inserts.]
Volume- and Salt-Depleted Patients
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
A lower initial dose of AVAPRO (75 mg) is recommended in patients with depletion of intravascular volume or salt (eg, patients treated vigorously with diuretics or on hemodialysis) [see Warnings and Precautions: Hypotension in Volume- or Salt-Depleted Patients].
Impaired Renal Function
AVAPRO (irbesartan) and AVALIDE (irbesartan-hydrochlorothiazide):
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals.
In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe congestive heart Renal impairment. The usual regimens of therapy with AVALIDE may be followed as long as the patient's creatinine clearance is >30 mL/min. In failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with patients with more severe renal impairment, loop diuretics are preferred to thiazides, so AVALIDE is not recommended.
acute renal failure and/or death. Irbesartan would be expected to behave similarly. In studies of ACE inhibitors in patients with unilateral or bilateral C6?2= 2CE6CJ DE6?@D:D :?4C62D6D :? D6CF> 4C62E:?:?6 @C +% 92G6 366? C6A@CE65 *96C6 92D 366? ?@ <?@H? FD6 @7 :C36D2CE2? :? A2E:ents with unilateral or bilateral renal artery stenosis, but a similar effect should be anticipated.
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.
Information for Patients
WARNINGS AND PRECAUTIONS
Fetal/Neonatal Morbidity and Mortality
Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin- angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.
Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women.
AVALIDE: [See Patient Counseling Information: Pregnancy.]
Several dozen cases have been reported in the world literature in patients who were taking angiotensin-converting-enzyme inhibitors. When pregnancy is detected, AVAPRO should be discontinued as soon as possible.
The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios No significant drug-drug pharmacokinetic (or pharmacodynamic) interactions have been found in interaction studies with hydrochlorothiazide, has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal digoxin, warfarin, and nifedipine.
limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the known cytochrome CYP 2C9 substrates/ arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
inhibitors sulphenazole, tolbutamide and nifedipine. However, in clinical studies the consequences of concomitant irbesartan on the pharmaco- These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.
5J?2>:4D@7H2C72C:?H6C6?68=:8:3=6 2D65@? in vitro data, no interaction would be expected with drugs whose metabolism is dependent upon Mothers whose embryos and fetuses are exposed to an angiotensin Il receptor antagonist only during the first trimester should be so informed.
:D@6?KJ>6D @C Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of AVAPRO as soon as possible.
In separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide, or digoxin, irbesartan administration for 7 days had Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found.
no effect on the pharmacodynamics of warfarin (prothrombin time) or pharmacokinetics of digoxin. The pharmacokinetics of irbesartan were not In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be affected by coadministration of nifedipine or hydrochlorothiazide.
performed to assess the intraamniotic environment.
AVALIDE: [See Drug Interactions.]
If oligohydramnios is observed, AVAPRO should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), Carcinogenesis, Mutagenesis, Impairment of Fertility
be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
No evidence of carcinogenicity was observed when irbesartan was administered at doses of up to 500/1000 mg/kg/day (males/females, Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and respectively) in rats and 1000 mg/kg/day in mice for up to 2 years. For male and female rats, 500 mg/kg/day provided an average systemic exposure hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis to irbesartan (AUC may be required as means of reversing hypotension and/or substituting for disordered renal function.
0-24 hour, bound plus unbound) about 3 and 11 times, respectively, the average systemic exposure in humans receiving the maximum recommended dose (MRD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administered to females only) provided an average When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses of 50 mg/kg/day, 180 mg/kg/day, and systemic exposure about 21 times that reported for humans at the MRD. For male and female mice, 1000 mg/kg/day provided an exposure to 650 mg/kg/day), increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses irbesartan about 3 and 5 times, respectively, the human exposure at 300 mg/day.
*50 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD], 300 mg/day, on a body surface area basis).
Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forward gene- Subcutaneous edema was observed in fetuses at doses *180 mg/kg/day (about 4 times the MRHD on a body surface area basis). As these mutation assay). Irbesartan was negative in several tests for induction of chromosomal aberrations (in vitro-human lymphocyte assay; in vivo-mouse anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was limited to gestation days 6 to 15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times the MRHD on a body surface area basis) had a slight increase Irbesartan had no adverse effects on fertility or mating of male or female rats at oral doses )650 mg/kg/day, the highest dose providing a systemic in early resorptions and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in rats and rabbits.
exposure to irbesartan (AUC0-24 hour, bound plus unbound) about 5 times that found in humans receiving the maximum recommended dose of Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan.
AVALIDE: [See Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility.]
AVALIDE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, Pregnancy Categories C (first trimester) and D (second and third trimesters)
neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Similar renal findings occur in reproductive toxicology studies in See Warnings and Precautions: Fetal/Neonatal Morbidity and Mortality.
rats. Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.
AVALIDE: [See Use in Specific Populations: Pregnancy.]
Hypotension in Volume- or Salt-Depleted Patients
Excessive reduction of blood pressure was rarely seen (<0.1%) in patients with uncomplicated hypertension. Initiation of antihypertensive It is not known whether irbesartan is excreted in human milk, but irbesartan or some metabolite of irbesartan is secreted at low concentration in therapy may cause symptomatic hypotension in patients with intravascular volume- or sodium-depletion, eg, in patients treated vigorously with diuretics or in patients on dialysis. Such volume depletion should be corrected prior to administration of AVAPRO, or low starting dose should be nursing or discontinue the drug, taking into account the importance of the drug to the mother.
used [see Dosage and Administration in AVAPRO Full Prescribing Information].
AVALIDE: [See Use in Specific Populations: Nursing Mothers.]
If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower blood pressure effectively in pediatric patients ages 6 to AVALIDE:
Excessive reduction of blood pressure was rarely seen in patients with uncomplicated hypertension treated with irbesartan alone (<0.1%) or with AVAPRO has not been studied in pediatric patients less than 6 years old.
irbesartan-hydrochlorothiazide (approximately 1%). Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with intravascular volume- or sodium-depletion, eg, in patients treated vigorously with diuretics or in patients on dialysis. Such volume depletion should AVALIDE: [See Use in Specific Populations: Pediatric Use.]
be corrected prior to administration of antihypertensive therapy.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Of 4925 subjects receiving AVAPRO in controlled clinical studies of hypertension, 911 (18.5%) were 65 years and over, while 150 (3.0%) were 75 years and over. No overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity AVALIDE:
of some older individuals cannot be ruled out. [See Clinical Pharmacology: Pharmacokinetics, Special Populations, and Clinical Studies in AVAPRO Full Prescribing Information.] AVALIDE: [See Use in Specific Populations: Geriatric Use.]
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.
Systemic Lupus Erythematosus
AVAPRO has been evaluated for safety in more than 4300 patients with hypertension and about 5000 subjects overall. This experience includes Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
1303 patients treated for over 6 months and 407 patients for 1 year or more. Treatment with AVAPRO was well-tolerated, with an incidence of adverse events similar to placebo. These events generally were mild and transient with no relationship to the dose of AVAPRO.
In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event was required in 3.3% of patients treated with AVAPRO, versus 4.5% of patients given placebo.
Lithium generally should not be given with thiazides. [See Drug Interactions.] In placebo-controlled clinical trials, the following adverse event experiences reported in at least 1% of patients treated with AVAPRO (n=1965) and Electrolyte and Metabolic Imbalances
at a higher incidence versus placebo (n=641), excluding those too general to be informative and those not reasonably associated with the use of drug because they were associated with the condition being treated or are very common in the treated population, include: diarrhea (3% vs 2%), dyspepsia/heartburn (2% vs 1%), and fatigue (4% vs 3%).
In double-blind clinical trials of various doses of irbesartan and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 7.5% versus 6.0% for placebo; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was The following adverse events occurred at an incidence of 1% or greater in patients treated with irbesartan, but were at least as frequent or more <1.0% versus 1.7% for placebo. No patient discontinued due to increases or decreases in serum potassium. On average, the combination of frequent in patients receiving placebo: abdominal pain, anxiety/nervousness, chest pain, dizziness, edema, headache, influenza, musculoskeletal irbesartan and hydrochlorothiazide had no effect on serum potassium. Higher doses of irbesartan ameliorated the hypokalemic response to pain, pharyngitis, nausea/vomiting, rash, rhinitis, sinus abnormality, tachycardia, and urinary tract infection.
Irbesartan use was not associated with an increased incidence of dry cough, as is typically associated with ACE inhibitor use. In placebo-controlled studies, the incidence of cough in irbesartan-treated patients was 2.8% versus 2.7% in patients receiving placebo.
The incidence of hypotension or orthostatic hypotension was low in irbesartan-treated patients (0.4%), unrelated to dosage, and similar to the The following have been very rarely reported in post-marketing experience: urticaria; angioedema (involving swelling of the face, lips, pharynx, incidence among placebo-treated patients (0.2%). Dizziness, syncope, and vertigo were reported with equal or less frequency in patients receiving and/or tongue); increased liver function tests; jaundice; and hepatitis. Hyperkalemia has been rarely reported.
irbesartan compared with placebo.
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
In addition, the following potentially important events occurred in less than 1% of the 1965 patients and at least 5 patients (0.3%) receiving irbesartan in clinical studies, and those less frequent, clinically significant events (listed by body system). It cannot be determined whether these events were causally related to irbesartan: The following adverse reactions have been identified during post-approval use of AVALIDE. Because these reactions are reported voluntarily from a Body as a Whole: fever, chills, facial edema, upper extremity edema population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, arrhythmic/conduction disorder, cardio-respiratory (2) frequency of reporting, or (3) strength of causal connection to AVALIDE.
arrest, heart failure, hypertensive crisis The following have been very rarely reported: urticaria; angioedema (involving swelling of the face, lips, pharynx, and/or tongue); and hepatitis.
Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria Hyperkalemia has been rarely reported.
Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout Very rare cases of jaundice have been reported with irbesartan.
Gastrointestinal: constipation, oral lesion, gastroenteritis, flatulence, abdominal distention Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Musculoskeletal/Connective Tissue: extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, joint stiffness, bursitis, Nervous System: sleep disturbance, numbness, somnolence, emotional disturbance, depression, paresthesia, tremor, transient ischemic attack, cerebrovascular accident Renal/Genitourinary: abnormal urination, prostate disorder In controlled clinical trials, clinically important differences in laboratory tests were rarely associated with administration of AVAPRO.
Respiratory: epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea, wheezing Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.7% of patients with essential hypertension treated with AVAPRO alone versus 0.9% on placebo. [See Warnings and Precautions: Impaired Renal Function.] Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain, conjunctivitis, other eye disturbance, eyelid abnormality, ear abnormality Hematologic: Mean decreases in hemoglobin of 0.2 g/dL were observed in 0.2% of patients receiving AVAPRO compared to 0.3% of placebo-treated Nephropathy in Type 2 Diabetic Patients
patients. Neutropenia (<1000 cells/mm3) occurred at similar frequencies among patients receiving AVAPRO (0.3%) and placebo-treated patients (0.5%).
In clinical studies in patients with hypertension and type 2 diabetic renal disease, the adverse drug experiences were similar to those seen in Nephropathy in Type 2 Diabetic Patients
patients with hypertension with the exception of an increased incidence of orthostatic symptoms (dizziness, orthostatic dizziness, and orthostatic hypotension) observed in IDNT (proteinuria *900 mg/day, and serum creatinine ranging from 1.0-3.0 mg/dL). In this trial, orthostatic symptoms Hyperkalemia: In IDNT (proteinuria *900 mg/day, and serum creatinine ranging from 1.0-3.0 mg/dL), the percent of patients with hyperkalemia occurred more frequently in the AVAPRO (irbesartan) group (dizziness 10.2%, orthostatic dizziness 5.4%, orthostatic hypotension 5.4%) than in the (>6 mEq/L) was 18.6% in the AVAPRO group versus 6.0% in the placebo group. Discontinuations due to hyperkalemia in the AVAPRO group were placebo group (dizziness 6.0%, orthostatic dizziness 2.7%, orthostatic hypotension 3.2%).
2.1% versus 0.4% in the placebo group.
Clinical Trials Experience
In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of AVALIDE.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in 2.3% and 1.1%, respectively, compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The adverse reaction information from clinical of patients with essential hypertension treated with AVALIDE alone. No patient discontinued taking AVALIDE due to increased BUN. One patient trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
discontinued taking AVALIDE due to a minor increase in serum creatinine.
Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with AVALIDE alone, one patient was discontinued due to elevated liver enzymes.
AVALIDE Tablets has been evaluated for safety in 1694 patients treated for essential hypertension in 6 clinical trials. In Studies I through IV with AVALIDE, no adverse events peculiar to this combination drug product have been observed. Adverse events have been limited to those that were Serum Electrolytes: [See Warnings and Precautions.] reported previously with irbesartan or hydrochlorothiazide (HCTZ). The overall incidence of adverse events was similar with the combination and placebo. In general, treatment with AVALIDE was well tolerated. For the most part, adverse events have been mild and transient in nature and have AVAPRO: [See Warnings and Precautions: Drug Interactions.]
not required discontinuation of therapy. In controlled clinical trials, discontinuation of AVALIDE therapy due to clinical adverse events was required in only 3.6%. This incidence was significantly less (p=0.023) than the 6.8% of patients treated with placebo who discontinued therapy.
In these double-blind controlled clinical trials, the following adverse events reported with AVALIDE occurred in *1% of patients, and more often on the irbesartan-hydrochlorothiazide combination than on placebo, regardless of drug relationship: No significant drug-drug interactions have been reported with irbesartan. [See Clinical Pharmacology.]Hydrochlorothiazide When administered concurrently the following drugs may interact with thiazide diuretics: Alcohol, Barbiturates, or Narcotics: potentiation of orthostatic hypotension may occur.
Antidiabetic Drugs (oral agents and insulin): dosage adjustment of the antidiabetic drug may be required.
Other Antihypertensive Drugs: additive effect or potentiation.
Cholestyramine and Colestipol Resins: absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
Corticosteroids, ACTH: intensified electrolyte depletion, particularly hypokalemia.
Pressor Amines (eg, Norepinephrine): possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal Muscle Relaxants, Nondepolarizing (eg, Tubocurarine): possible increased responsiveness to the muscle relaxant.
Lithium: should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.
Refer to the package insert for lithium preparations before use of such preparations with AVALIDE. [See Warnings and Precautions.] Non-steroidal Anti-inflammatory Drugs: in some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when AVALIDE Tablets and non-steroidal anti- inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
USE IN SPECIFIC POPULATIONS
Musculoskeletal Pain AVAPRO: [See Warnings and Precautions: Pregnancy.]
Dizziness Orthostatic Pregnancy Category D. [See Warnings and Precautions.] AVALIDE contains both irbesartan (an angiotensin II receptor antagonist) and hydrochlorothiazide (a thiazide diuretic). When administered during the Abnormality Urination second or third trimester of pregnancy, drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death.
Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and The following adverse events were also reported at a rate of 1% or greater, but were as, or more, common in the placebo group: headache, sinus possibly other adverse reactions that have occurred in adults. AVALIDE can cause fetal harm when administered to a pregnant woman. If this drug is abnormality, cough, URI, pharyngitis, diarrhea, rhinitis, urinary tract infection, rash, anxiety/nervousness, and muscle cramp.
used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Adverse events occurred at about the same rates in men and women, older and younger patients, and black and non-black patients.
Angiotensin II receptor antagonists, like irbesartan, and angiotensin converting enzyme (ACE) inhibitors exert similar effects on the renin-angiotensin Adverse events in Studies V and VI were similar to those described above in Studies I through IV.
system. In several dozen published cases, ACE inhibitor use during the second and third trimesters of pregnancy was associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios was also reported, presumably from decreased fetal renal function. In this setting, oligohydramnios was associated with fetal limb contractures, craniofacial Other adverse events that have been reported with irbesartan, without regard to causality, are listed below: deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus were also reported, Body as a Whole: fever, chills, orthostatic effects, facial edema, upper extremity edema although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.
Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, hypotension, syncope, arrhythmic/conduction disorder, cardio-respiratory arrest, heart failure, hypertensive crisis When pregnancy occurs in a patient using AVALIDE, the physician should discontinue AVALIDE treatment as soon as possible. The physician should inform the patient about potential risks to the fetus based on the time of gestational exposure to AVALIDE (first trimester only or later). If exposure Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria occurs beyond the first trimester, an ultrasound examination should be done.
Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout In rare cases when another antihypertensive agent cannot be used to treat the pregnant patient, serial ultrasound examinations should be performed Gastrointestinal: diarrhea, constipation, gastroenteritis, flatulence, abdominal distention to assess the intraamniotic environment. Routine fetal testing with non-stress tests, biophysical profiles, and/or contraction stress tests may be Musculoskeletal/Connective Tissue: musculoskeletal trauma, extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, appropriate based on gestational age and standards of care in the community. If oligohydramnios occurs in these situations, individualized decisions joint stiffness, bursitis, muscle weakness about continuing or discontinuing AVALIDE treatment and about pregnancy management should be made by the patient, her physician, and experts in the management of high risk pregnancy. Patients and physicians should be aware that oligohydramnios may not appear until after the fetus has Nervous System: anxiety/nervousness, sleep disturbance, numbness, somnolence, vertigo, emotional disturbance, depression, paresthesia, tremor, sustained irreversible injury.
transient ischemic attack, cerebrovascular accident Infants with histories of in utero exposure to AVALIDE should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, these Renal/Genitourinary: prostate disorder infants may require blood pressure and renal perfusion support. Exchange transfusion or dialysis may be required to reverse hypotension and/or Respiratory: cough, upper respiratory infection, epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea, wheezing support decreased renal function.
Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain, conjunctivitis Irbesartan crosses the placenta in rats and rabbits. In pregnant rats given irbesartan at doses greater than the maximum recommended human dose (MRHD), fetuses showed increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla. Subcutaneous edema also occurred in fetuses at doses about 4 times the MRHD (based on body surface area). These anomalies occurred when pregnant rats received Other adverse events that have been reported with hydrochlorothiazide, without regard to causality, are listed below: irbesartan through Day 20 of gestation but not when drug was stopped on gestation day 15. The observed effects are believed to be late gestational Body as a Whole: weakness effects of the drug. Pregnant rabbits given oral doses of irbesartan equivalent to 1.5 times the MRHD experienced a high rate of maternal mortality Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation and abortion. Surviving females had a slight increase in early resorptions and a corresponding decrease in live fetuses [see Nonclinical Toxicology].
Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan.
Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including When pregnant mice and rats were given hydrochlorothiazide at doses up to 3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the pneumonitis and pulmonary edema, anaphylactic reactions MRHD) during their respective periods of major organogenesis, there was no evidence of fetal harm.
Metabolic: hyperglycemia, glycosuria, hyperuricemia A development toxicity study was performed in rats with doses of 50/50 mg/kg/day and 150/150 mg/kg/day irbesartan-hydrochlorothiazide.
Although the high dose combination appeared to be more toxic to the dams than either drug alone, there did not appear to be an increase in toxicity Musculoskeletal: muscle spasm to the developing embryos.
Nervous System/Psychiatric: restlessness Renal: renal failure, renal dysfunction, interstitial nephritis AVAPRO: [See Warnings and Precautions: Nursing Mothers.]
Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis Special Senses: transient blurred vision, xanthopsia It is not known whether irbesartan is excreted in human milk, but irbesartan or some metabolite of irbesartan is secreted at low concentration in the milk of lactating rats.
In the moderate hypertension Study V (mean SeDBP between 90 and 110 mmHg), the types and incidences of adverse events reported for patients Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to treated with AVALIDE were similar to the adverse event profile in patients on initial irbesartan or HCTZ monotherapy. There were no reported events discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
of syncope in the AVALIDE treatment group and there was one reported event in the HCTZ treatment group. The incidences of pre-specified adverse events on AVALIDE, irbesartan, and HCTZ, respectively, were: 0.9%, 0%, and 0% for hypotension; 3.0%, 3.8%, and 1.0% for dizziness; 5.5%, 3.8%, and 4.8% for headache; 1.2%, 0%, and 1.0% for hyperkalemia; and 0.9%, 0%, and 0% for hypokalemia. The rates of discontinuation due to adverse AVAPRO: [See Warnings and Precautions: Pediatric Use.]
events on AVALIDE, irbesartan alone, and HCTZ alone were 6.7%, 3.8%, and 4.8%.
In the severe hypertension (SeDBP *110 mmHg) Study VI, the overall pattern of adverse events reported through 7 weeks of follow-up was similar Safety and effectiveness in pediatric patients have not been established.
in patients treated with AVALIDE as initial therapy and in patients treated with irbesartan as initial therapy. The incidences of the pre-specified adverse events on AVALIDE and irbesartan, respectively, were: 0% and 0% for syncope; 0.6% and 0% for hypotension; 3.6% and 4.0% for dizziness; 4.3% and 6.6% for headache; 0.2% and 0% for hyperkalemia; and 0.6% and 0.4% for hypokalemia. The rates of discontinuation due to adverse AVAPRO: [See Warnings and Precautions: Geriatric Use.]
events were 2.1% and 2.2%. [See Clinical Studies (14.2) in AVALIDE Full Prescribing Information.] AVALIDE:
Of 1694 patients receiving AVALIDE in controlled clinical studies of hypertension, 264 (15.6%) were 65 years and over, while 45 (2.7%) were 75 years
and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. [See Clinical Pharmacology and Clinical Studies (14) in AVALIDE Full Prescribing Information.] AVAPRO (irbesartan) and AVALIDE (irbesartan-hydrochlorothiazide):
The pharmacokinetics of irbesartan were not altered in patients with renal impairment or in patients on hemodialysis. Irbesartan is not removed by No data are available in regard to overdosage in humans. However, daily doses of 900 mg for 8 weeks were well tolerated. The most likely hemodialysis. No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also manifestations of overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. Irbesartan is not volume depleted. [See Warnings: Hypotension in Volume- or Salt-Depleted Patients and Dosage and Administration in AVAPRO Full Prescribing removed by hemodialysis.
To obtain up-to-date information about the treatment of overdosage, a good resource is a certified regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians' Desk Reference (PDR). In managing overdose, consider the possibilities of The pharmacokinetics of irbesartan were not altered in patients with renal impairment or in patients on hemodialysis. Irbesartan is not removed by multiple-drug interactions, drug-drug interactions, and unusual drug kinetics in the patient.
hemodialysis. No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also Laboratory determinations of serum levels of irbesartan are not widely available, and such determinations have, in any event, no established role volume depleted. [See Warnings and Precautions.] in the management of irbesartan overdose.
Acute oral toxicity studies with irbesartan in mice and rats indicated acute lethal doses were in excess of 2000 mg/kg, about 25- and 50-fold the AVAPRO and AVALIDE:
maximum recommended human dose (300 mg) on a mg/m2 basis, respectively.
The pharmacokinetics of irbesartan following repeated oral administration were not significantly affected in patients with mild to moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.
The most common signs and symptoms of overdose observed in humans are those caused by electrolyte depletion (hypokalemia, hypochloremia, AVAPRO: [See Warnings and Precautions: Drug Interactions.]
hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.
No significant drug-drug pharmacokinetic (or pharmacodynamic) interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, and nifedipine.
In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the known cytochrome CYP 2C9 Mechanism of Action
substrates/inhibitors sulphenazole, tolbutamide and nifedipine. However, in clinical studies the consequences of concomitant irbesartan on the AVAPRO and AVALIDE:
pharmacodynamics of warfarin were negligible. Concomitant nifedipine or hydrochlorothiazide had no effect on irbesartan pharmacokinetics. Based on in vitro data, no interaction would be expected with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes 1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4.
Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II).
Angiotensin II is the principal pressor agent of the renin-angiotensin system (RAS) and also stimulates aldosterone synthesis and secretion by In separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide, or digoxin, irbesartan administration for 7 days had adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth.
no effect on the pharmacodynamics of warfarin (prothrombin time) or the pharmacokinetics of digoxin. The pharmacokinetics of irbesartan were Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT not affected by coadministration of nifedipine or hydrochlorothiazide.
1 angiotensin II receptor.
There is also an AT2 receptor in many tissues, but it is not involved in cardiovascular homeostasis.
Irbesartan is a specific competitive antagonist of AT1 receptors with a much greater affinity (more than 8500-fold) for the AT1 receptor than for the Carcinogenesis, Mutagenesis, Impairment of Fertility
AT2 receptor, and no agonist activity.
AVAPRO: [See Warnings and Precautions: Carcinogenesis, Mutagenesis, Impairment of Fertility.]
Blockade of the AT1 receptor removes the negative feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II do not overcome the effects of irbesartan on blood pressure.
Irbesartan does not inhibit ACE or renin or affect other hormone receptors or ion channels known to be involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Because irbesartan does not inhibit ACE, it does not affect the response to bradykinin; whether this has No carcinogenicity studies have been conducted with the irbesartan-hydrochlorothiazide combination.
clinical relevance is not known.
Irbesartan-hydrochlorothiazide was not mutagenic in standard in vitro tests (Ames microbial test and Chinese hamster mammalian- cell forward gene-mutation assay). Irbesartan-hydrochlorothiazide was negative in tests for induction of chromosomal aberrations (in vitro—human lymphocyte assay; in vivo—mouse micronucleus study).
The combination of irbesartan and hydrochlorothiazide has not been evaluated in definitive studies of fertility.
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum No evidence of carcinogenicity was observed when irbesartan was administered at doses of up to 500/1000 mg/kg/day (males/females, potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse respectively) in rats and 1000 mg/kg/day in mice for up to 2 years. For male and female rats, 500 mg/kg/day provided an average the potassium loss associated with these diuretics.
systemic exposure to irbesartan (AUC0-24hours, bound plus unbound) about 3 and 11 times, respectively, the average systemic exposure The mechanism of the antihypertensive effect of thiazides is not fully understood.
in humans receiving the maximum recommended dose (MRD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administered to females only) provided an average systemic exposure about 21 times that reported for humans at the MRD. For male and female mice, 1000 mg/kg/day provided an exposure to irbesartan about 3 and 5 times, respectively, the human exposure at 300 mg/day.
AVAPRO and AVALIDE:
Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was negative in several tests for induction of chromosomal aberrations (in vitro—human In healthy subjects, single oral irbesartan doses of up to 300 mg produced dose-dependent inhibition of the pressor effect of angiotensin II infusions.
lymphocyte assay; in vivo—mouse micronucleus study).
Inhibition was complete (100%) 4 hours following oral doses of 150 mg or 300 mg and partial inhibition was sustained for 24 hours (60% and 40% Irbesartan had no adverse effects on fertility or mating of male or female rats at oral doses )650 mg/kg/day, the highest dose at 300 mg and 150 mg, respectively).
providing a systemic exposure to irbesartan (AUC0-24hours, bound plus unbound) about 5 times that found in humans receiving the In hypertensive patients, angiotensin II receptor inhibition following chronic administration of irbesartan causes a 1.5- to 2-fold rise in angiotensin maximum recommended dose of 300 mg/day.
II plasma concentration and a 2- to 3-fold increase in plasma renin levels. Aldosterone plasma concentrations generally decline following irbesartan administration, but serum potassium levels are not significantly affected at recommended doses.
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no In hypertensive patients, chronic oral doses of irbesartan (up to 300 mg) had no effect on glomerular filtration rate, renal plasma flow or filtration evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in fraction. In multiple dose studies in hypertensive patients, there were no clinically important effects on fasting triglycerides, total cholesterol, HDL- male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocar- cholesterol, or fasting glucose concentrations. There was no effect on serum uric acid during chronic oral administration and no uricosuric effect.
cinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 g/mL, and in the Aspergillus AVAPRO and AVALIDE:
nidulans non-disjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.
Irbesartan is an orally active agent that does not require biotransformation into an active form. The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60% to 80%. Following oral administration of irbesartan, peak plasma concentrations of Animal Toxicology and/or Pharmacology
irbesartan are attained at 1.5 to 2 hours after dosing. Food does not affect the bioavailability of irbesartan.
Reproductive Toxicology Studies
Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range.
AVAPRO: [See Warnings and Precautions: Fetal/Neonatal Morbidity and Mortality.]
The terminal elimination half-life of irbesartan averaged 11 to 15 hours. Steady-state concentrations are achieved within 3 days. Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing.
When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses of 50, 180, and 650 mg/kg/day), increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses *50 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD], 300 mg/day, on a body surface area basis). Subcutaneous edema was observed in fetuses at doses *180 mg/kg/day (about 4 times the MRHD on a body surface area When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.
basis). As these anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was Metabolism and Elimination
limited to gestation days 6 to 15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg AVAPRO and AVALIDE:
irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times the MRHD on a body surface area basis) had a slight increase in early resorptions and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in rats and rabbits.
Irbesartan is metabolized via glucuronide conjugation and oxidation. Following oral or intravenous administration of 14C-labeled irbesartan, more PATIENT COUNSELING INFORMATION
than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan. The primary circulating metabolite is the inactive irbesartan glucuronide conjugate (approximately 6%). The remaining oxidative metabolites do not add appreciably to irbesartan's pharmacologic activity.
AVAPRO: [See Warnings and Precautions: Information for Patients.]
Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either oral or intravenous administration of 14C-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide.
In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes indicated irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was Female patients of childbearing age should be told that use of drugs like AVALIDE during the second or third trimesters of pregnancy can cause negligible. Irbesartan was neither metabolized by, nor did it substantially induce or inhibit, isoenzymes commonly associated with drug metabolism serious problems in the fetus and infant including: low blood pressure, poor development of skull bones, kidney failure, and death. These effects (1A1, 1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition of 3A4.
have not occurred with drug exposure limited to the first trimester. Women using AVALIDE who become pregnant should notify their physician as soon as possible.
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.
Patients using AVALIDE should be told that they may feel lightheaded, especially during the first days of use. Patients should inform their physician if they feel lightheaded or faint. If fainting occurs, the patient should stop using AVALIDE and contact the prescribing doctor.
Patients using AVALIDE should be told that getting dehydrated can lower their blood pressure too much and lead to lightheadedness and possible AVAPRO and AVALIDE:
fainting. Dehydration may occur with excessive sweating, diarrhea, or vomiting and with not drinking enough liquids.
Irbesartan Irbesartan is 90% bound to serum proteins (primarily albumin and 1-acid glycoprotein) with negligible binding to cellular components of blood. The Manufactured by: Bristol-Myers Squibb Company, Princeton, New Jersey 08543 USA average volume of distribution is 53 to 93 liters. Total plasma and renal clearances are in the range of 157 to 176 mL/min and 3.0 to 3.5 mL/min, respectively. With repetitive dosing, irbesartan accumulates to no clinically relevant extent.
Distributed by: Bristol-Myers Squibb Sanofi-Synthelabo Partnership, New York, New York 10016 Studies in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain barrier and placenta. Irbesartan is excreted in the milk of lactating rats.
Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
AVAPRO: 1192327A3, 1192328A3 AVAPRO: [See Warnings and Precautions: Pediatric Use.]
AVALIDE: 1190017A3, 1190018A4 AVALIDE:
Irbesartan-hydrochlorothiazide pharmacokinetics have not been investigated in patients <18 years of age.
AVAPRO and AVALIDE:
No gender-related differences in pharmacokinetics were observed in healthy elderly (age 65 to 80 years) or in healthy young (age 18 to 40 years)
subjects. In studies of hypertensive patients, there was no gender difference in half-life or accumulation, but somewhat higher plasma concen- trations of irbesartan were observed in females (11% to 44%). No gender-related dosage adjustment is necessary.
In elderly subjects (age 65 to 80 years), irbesartan elimination half-life was not significantly altered, but AUC and Cmax values were about 20% to
50% greater than those of young subjects (age 18 to 40 years). No dosage adjustment is necessary in the elderly.
In healthy black subjects, irbesartan AUC values were approximately 25% greater than whites; there were no differences in Cmax values.
AVAPRO: The power of
proven renal protection to help
slow the progression of nephropathy
in hypertensive patients with
type 2 diabetes.
(see indications statement below).* Important Safety Information
WARNING: USE IN PREGNANCY
t In patients with volume or sodium depletion (eg, patients When pregnancy is detected, discontinue AVAPRO as
vigorously treated with diuretics or on dialysis), such soon as possible. When used in pregnancy during the
depletion should be corrected prior to administration of second and third trimesters, drugs that act directly on the
AVAPRO, or a lower initial dose of AVAPRO (75 mg) should renin-angiotensin system can cause injury and even death
be used, to avoid possible symptomatic hypotension to the developing fetus. [See Warnings: Fetal/Neonatal
t In placebo-controlled hypertension studies, there were no significant differences in adverse events (AEs) between AVAPRO and placebo. Adverse events that occurred in at least 1% of patients treated with AVAPRO and at a higher incidence AVAPRO (irbesartan) is indicated for the treatment of vs placebo included diarrhea (3% vs. 2%), dyspepsia/heartburn hypertension. It may be used alone or in combination with (2% vs 1%) and fatigue (4% vs 3%) other antihypertensive agents.
t Additionally, in a study of hypertensive type 2 diabetic AVAPRO is also indicated for the treatment of diabetic patients with renal disease (proteinuria ≥900 mg/day), the nephropathy with an elevated serum creatinine and reported AEs for AVAPRO were similar to those seen in proteinuria (>300 mg/day) in patients with type 2 diabetes hypertension studies, with the exception of an increased and hypertension. In this population, AVAPRO reduces the incidence of orthostatic symptoms; AVAPRO compared to rate of progression of nephropathy as measured by the placebo (both groups received adjunctive antihypertensives): occurrence of doubling of serum creatinine or end-stage dizziness (10.2% vs 6.0%), orthostatic dizziness (5.4% vs 2.7%) renal disease (need for dialysis or renal transplantation). and orthostatic hypotension (5.4% vs 3.2%), respectively. In patients with proteinuria, monitor serum potassium Please see Brief Summary of full Prescribing Information on adjacent pages.
2009 Bristol-Myers Squibb Sanofi-Synthelabo Partnership Printed in the USA ash Times • friday saturday • may 8 • san francisco
ash publishes position papers for specialists in
The ameRican socieTy of hypeRTen-
with ambulatory BP and inverse associations This position paper updates concepts on Lindheimer, MD; Sandra Taler, MD; and sion, Inc. recognizes the importance of provid- with the degree of BP reduction from day to hypertension management in patients with Gary Cunningham, MD. It was published ing guidance regarding the practicing needs night. Self-monitoring of the BP (or home BP diabetes. It focuses on clinical outcomes lit- in the Journal of the American Society of of designated specialists in clinical hyperten- monitoring) also has advantages in evaluating erature published within the past three years Hypertension 2008: 2(6): 484 – 494. (No- sion, and other health care providers treating patients with hypertension, especially those and incorporates these observations into vember/December 2008) and reprinted in hypertensive patients. To meet this chal- already on drug modifications of the April 2009 issue of JCH. lenge, the ASH Board of Directors approved treatment, but less established guide- This position paper summarizes the an initiative to establish a Hypertension is known about its While neither ABPM nor self-BP monitor- lines. While the clinical spectrum of hypertension in preg- relation to future ing are mandatory for the routine diag- fundamentals of nancy, focusing on preeclampsia. Recent The Hypertension Writing Group is ca rd iovasc u la r t reat ment a nd research breakthroughs relating to etiol- composed of invited authors and overseen events. Data de- nosis of hypertension, these modalities goal blood pres- ogy are briefly reviewed. Topics include by a steering committee that reports to the rived from ambula- can enhance the ability for identification s u r e s r e m a i n classification of the different forms of ASH Board of Directors. The position papers tory BP monitoring unchanged, ap- hypertension during pregnancy, status of address topics in hypertension research that a (ABPM) allow the of white-coat and masked hypertension proaches to spe- the tests available to predict preeclampsia, traditional single guidelines paper would not identification of and evaluate the extent of BP control in cific patient-re- and strategies to prevent preeclampsia cover in depth. As of May 2009, the Society high-risk patients, lated issues have and to manage this serious disease. The has published three position papers. independent from patients on drug therapy.
changed. This up- use of antihypertensive drugs in preg- The first paper, "When and How to Use the BP obtained date focuses on nancy and the prevention and treatment Self (Home) and Ambulatory Blood Pres- in the clinic or office setting. While neither questions such as what to do when a patient of the convulsive phase of preeclampsia, sure Monitoring," was written by Thomas G. ABPM nor self-BP monitoring are manda- has an elevated potassium level when therapy eclampsia, with intravenous MgSO4 is Pickering, MD, DPhil, and William B. White, tory for the routine diagnosis of hypertension, is initiated and whether combinations of also highlighted. MD, and was published in the Journal of the these modalities can enhance the ability for agents that block the renin-angiotensin The impact of the position papers has American Society of Hypertension (JASH) 2008: identification of white-coat and masked hyper- system still be used. In addition, there are been substantial. Press conferences were or- 2(3):119 – 124. (May/June 2008). The paper tension and evaluate the extent of BP control updates from trials, just published and in ganized around the first two papers, which was reprinted in the November 2009 issue of in patients on drug therapy.
press, that focus on related management resulted in significant media coverage.
The Journal of Clinical Hypertension (JCH).
The second ASH position paper on "Treat- issues influencing cardiovascular outcomes A fourth paper on "Dietary Approaches This position paper focuses on the im- ment of Hypertension in Patients with Diabetes: in persons with diabetes. Last, an updated to Lower Blood Pressure" written by Law- portance of out-of-office blood pressure (BP) An Update" was written by George L. Bakris, MD, algorithm is provided that incorporates many rence J. Appel, MD, MPH, will be published measurement for the clinical management of and James R. Sowers, MD, and was published in of the new findings and is suggested as a start- in the July issue of JCH. patients with hypertension and its complica- The Journal of Clinical Hypertension 2008: 10(9): ing point to achieve blood pressure goals.
A series of papers on the "Pharmaco- tions. Studies have supported direct and in- 707 – 713. (October 2008). It was reprinted in the The third position paper on "Hyperten- logic Therapy of Hypertension" will be dependent associations of cardiovascular risk March/April 2009 issue of JASH.
sion in Pregnancy" was written by Marshall published in the Fall of 2009. l late-breaking trials session features study
of hypertension in nfl players
a laTe-bReaking clinical TRials average in several things. They have lower comparison with an average 25-year-old man,"
and New Research session this afternoon will blood sugar, they don't smoke, their lipids are Dr. Vogel said. "Being so fit balances out the ef- include a talk on Cardiovascular Risk Factors relatively equivalent, but their blood pressure is fect of weight. However, in retirement from the These sessions will provide an opp- in Active National Football League Players by higher. We are trying to find out why. We don't game, they are no longer as physically active." ortunity for interaction and consultation Robert A. Vogel, MD, who is Professor of really know yet." Dr. Vogel and his colleagues began their with professionals who have expertise in a Medicine at the University of Maryland School However, retired NFL players have cardio- research in 2004 under sponsorship of an NFL specific area. Attendees wil be admitted of Medicine in Baltimore and Co-Chair of the vascular risks roughly equivalent to an age- charity fund to promote and monitor cardio- on a first-come, first-served basis. NFL subcommittee on cardiovascular health. vascular health among players. His 30-minute address begins at 3:30 p.m. "In screening for cardiovascular health, Friday, May 8 – 11:45 a.m. to 12:45 p.m.
today, Friday, May 8, in Yerba Buena Ballroom However, retired NFL players have we do not just measure blood pressure. — Salon 9.
We do very sophisticated tests, especially Uric Acid cardiovascular risks roughly equiv- Dr. Vogel will present preliminary informa- in the retired players, including CT scans, Takahiko Nakagawa, MD, Aurora, CO tion on the results of research he has done into alent to an age-adjusted, size- coronary calcium scans, carotid ultrasound for Yerba Buena Bal room — Salon 1 the cardiovascular health of active and retired plaque and intima-media thickness, echocar- adjusted population. A former NFL NFL players, concentrating on hypertension. diograms, and C-reactive protein testing. Headaches "We have early evidence that active NFL player who weighs 300 pounds I think this type of screening is indicative of Dara G. Jamieson, MD, New York, NY players have elevated blood pressure that is where medicine is going in the future, toward wil have the cardiovascular health approximately 10 to 15 mmHg higher than a more robust way of looking for cardiovascular Yerba Buena Bal room — Salon 3 an age-adjusted population. Their blood pres- of a 300-pound non-athlete, so disease beyond blood pressure and choles- sure is mostly in the pre-hypertension range, terol levels," he said. "The number one cause of Hypertension in Children and Adolescents eventual y, their size catches up averaging about 130 mmHg systolic," he said. death in the United States is cardiovas- Bonita Falkner, MD, Philadelphia, PA "The reasons are hypothetical at this point, but cular disease, and yet we don't screen Yerba Buena Bal room — Salon 4 they certainly may include strength training, – Robert A. Vogel, MD for it. We check blood pressure, but high salt intake, and the use of NSAIDs. These Sleep Apnea are the kinds of things we are looking at in an We have screening tests for colon cancer, Virend K. Somers, MD, DPhil, Rochester, MN ongoing study focused on the causes." adjusted, size-adjusted population. A former breast cancer, and prostate cancer that Professional football players differ from an NFL player who weighs 300 pounds will have look for the disease itself and not just the Yerba Buena Bal room — Salon 5 age-matched population in a number of ways. the cardiovascular health of a 300-pound non- risk factors." They are generally 75 pounds heavier than av- athlete, so eventually, their size catches up with Dr. Vogel hopes that hypertension spe- Nutraceuticals erage and usually about five inches taller than them, he said.
cialists who attend his talk will learn that it's Matthew Sorrentino, MD, Chicago, IL most men their age.
"In active players, there appears to be a important to look for cardiovascular disease Yerba Buena Bal room — Salon 6 "Interestingly, they don't have a lot of balancing effect of physical activity. They may beyond the risk factors. "I believe that carotid body fat. In fact, they have less body fat than be 75 pounds heavier than average, but they screening, coronary screening, and other so- a 75-pound lighter American man of the same are very physically active. It's the old debate of phisticated tests need to be made part and age," Dr. Vogel said. "If you look at their car- fat vs. fit, and most active players are fit from parcel of our efforts to prevent heart disease," diovascular risk factors, they do better than a cardiovascular point of view, certainly in he said. l y Save the Date y
ASH 25th Annual Scientific Meeting
May 1-4, 2010 • New York, New York ash Times • friday saturday • may 8–9 • san francisco
Mission Street Fourth Street Blue Ribbon Poster Session Market Street san francisco • may 8–9 • friday saturday • ash Times
international Society For Vascular Health 312
one pierce place, suite 295e
1600 Jfk blvd., suite 1800
87 Rue de l'assomption,
itasca, il 60143
philadelphia, pa 19103
75016 paris france.
one health plaza
east hanover, nJ 07936
AtCor Medical's SphygmoCor® systems, featured in more Elsevier is proud to publish the Journal of the American than 400 published studies, are the global gold standard Society of Hypertension, the official journal of the The International Society for Vascular Health (ISVH) is a Novartis Pharmaceuticals is dedicated to discovering, for noninvasive central blood pressure/arterial stiffness American Society of Hypertension Please stop by our not-for-profit charity established under French law in 1901. developing, manufacturing, and marketing prescription assessment Major studies have found: booth to view the latest issue of the journal and browse The society aims to be a catalyst for clinical cooperation drugs that meet our customers' medical needs and • Elevated central pressure is a superior independent our other books and journals in the field of hypertension between health-care professionals in disciplines such as improve their quality of life Please visit the Novartis exhibit predictor of cardiovascular risk cardiovascular therapy, thrombosis, nephrology, lipidology, where our sales representatives will be available to discuss • 70 percent of patients with high normal blood pressure Forest Pharmaceuticals, inc.
and a broad spectrum of others to actively promote had central pressures equivalent with those of patients 13600 shoreline drive
worldwide vascular health. The society's President and with stage 1 hypertension st. louis, mo 63045
Editor-in-Chief of the its journal Vascular Health & Risk Omron Healthcare
Management is Pr Roland Asmar of the Cardiovascular • Patients with central pulse pressure I 50mmHg are at Institute in Paris 1200 lakeside drive
significantly higher risk for cardiovascular events bannockburn, il 60015
Kent Scientific Corporation
Forest Pharmaceuticals, Inc., welcomes you to San Pharmaceuticals, inc
1116 litchfield street
Francisco! We invite you to visit our exhibit where our Torrington, cT 06790
900 Ridgebury Road,
professional representatives will welcome the opportunity Omron Healthcare, Inc , in Bannockburn, IL, is the North Ridgefield, cT 06877
to discuss and answer any questions regarding our and South American sales and marketing office of product Bystolic® (nebivolol ) tablets Omron Healthcare Group, a leading manufacturer and Please visit our website at www.bystolic.com.
distributor of blood pressure monitors for home use Kent Scientific Corporation serves medical and research Omron Heathcare offers innovative products and medical Gilead Sciences inc.
scientists as a worldwide provider of integrated solutions devices for use in sites ranging from hospitals to the home Boehringer Ingelheim Pharmaceuticals, Inc , the U S 333 lakeside drive
for pre-clinical research and drug discovery advancement in the blood pressure monitoring, fitness diagnostics, subsidiary of Boehringer Ingelheim in Germany, operates foster city, ca 94404
As the world leader in non-invasive blood pressure thermometry, and respiratory categories globally in 47 countries with about 39,800 employees. products for mice and rats, we enable our customers to The company is committed to researching, developing, achieve results that are fast, consistent, and exceedingly sanofi–aventis u.S.
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Sanofi-aventis U S is an affiliate of sanofi-aventis, a leading global pharmaceutical company that discovers, develops, and distributes therapeutic solutions to improve the lives Three franklin plaza
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of everyone Sanofi-aventis is listed in Paris (EURONEXT: BpTRU Medical Devices is the Canadian inventor and Lippincott, Williams & Wilkins offers specialized SAN) and in New York (NYSE: SNY). manufacturer of the BpTRU automated blood pressure philadelphia, pa 19101
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discarding the first reading and averaging the remaining pharmaceutical company with a powerful combination journal Hypertension, the Journal of the American Heart five it reduces "white coat hypertension." These proven of skills to discover and deliver innovative medicines We Association, and The Journal of Hypertension, the official patented technologies help to consistently identify and offer a number of programs to support effective health journal of the International Society of Hypertension and manage hypertension management strategies and improve patient care Please the European Society of Hypertension visit our exhibit to learn more about our products Introducing statMAP — a revolutionary new class of blood Cardiodynamics — the iCG Company
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validated, and reliable systems complete with four cuffs, built-in actigraphy, and Windows-based software. Microlife Medical Home Solutions Inc is dedicated to Purchase, lease, and short-term rental options are meeting the needs of physicians and their busy practices available Great service and support for your clinic We Our tools and solutions offer a systematic and evidence- also specialize in supporting the stringent requirements of The Cardiology Career Network is a member of HoMedics innovative technologies and advanced features based method for assessment, diagnosis, and treatment clinical trials (Phase I through Phase IV) including unique HEALTHeCAREERS Network, an onTargetjobs, Inc., give consumers the tools needed to proactively and of hypertension and obesity Microlife is committed to features for PK/PD studies company The online portal offers recruitment, advertising, effectively manage their health Our line of blood pressure providing physicians with the means to implement new and career opportunities paired with enhanced, industry- monitors feature clinically proven accuracy with Smart modes of patient-centered care that are efficient, effective, W.a. Baum Co., inc.
specific access to thousands of cardiology job seekers, Measure® technology, Supersize Digits® for easy reading, 620 oak street
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international Society of Hypertension
minneapolis, mn 55445
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The Baum Company manufactures a complete line of north Vancouver, british columbia V7m 3m7
mercury-gravity and aneroid clinical sphygmomanometers equipped with calibrated V-Lok inflation systems. How many of your patients with diabetes, hypertension Additionally, we offer stethoscopes, a full line of latex and and cardiovascular disease have undiagnosed chronic non-latex replacement parts, decorated and disposable CVRx, Inc has developed an implantable device for the kidney disease? One in nine U S adults has chronic kidney cuffs and cuffs designed for use with automated NIPB treatment of hypertension in patients who cannot control The International Society of Hypertension invites you to disease Early detection can help prevent progression to monitors Baum products are sold through an international their blood pressure with medications and lifestyle participate in the 23rd Scientific Meeting, which takes kidney failure. Visit booth 508 to learn how your patients network of medical/surgical supply dealers.
modifications The Rheos™ Barorefliex Hypertension place September 26 to 30, 2010, in Vancouver, British and clinicians can benefit from the National Kidney Therapy™ System is an investigational device and currently Columbia, Canada. The scientific program will include Foundation's educational tools, resources, and screening is in clinical trials in the United States and Europe keynote presentations, industry and investigator initiated symposia, oral and poster presentations, public forums, 350 main street
an exhibition, and of course a diverse social program Nature Publishing Group
malden, ma 02148
highlighting Vancouver and the surrounding area Two hilton court
75 Varick street, 9th floor
parsippany, nJ 07054
international Society on
new york, new york 10013-1917
Hypertension in Blacks, inc.
Wiley publishes an enormous range of top quality consumer, professional, educational, and research 157 summit View drive
Nature Publishing Group brings leading scientific and material. Wiley-Blackwell, the scientific, technical, Please visit Daiichi Sankyo, Inc , marketer of mcdonough, ga 30253
medical research to your desktop The NPG portfolio medical and scholarly publishing business of John Wiley Azor™ (amlodipine and olmesartan medoxomil), Benicar® combines the continued excellence of Nature, its & Sons, is the leading society publisher and offers peer- (olmesartan medoxomil), and Benicar® HCT® (olmesartan associated research and review journals, and more than reviewed primary research and evidence-based medicine 45 leading academic and society journals in the life, across 1,250 online journals, books, reference works, physical, and clinical sciences. Visit booth 318 for Founded in 1986, the International Society on data dancer Medical Systems
Hypertension in Blacks, Inc is a non-profit organization 1644 laurel street
of health-care professions and leaders in cardiovascular Zona Health
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and eliminate racial and ethnic health disparities in 1681 Route des dolines — bat hb4 bp 313
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education, targeted clinical research, and facilitation of phone: 33 (0) 497 245300
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that pairs patients with physicians in the diagnosis and We host an annual conference, membership, and other Zona Plus™ is an innovative handheld device clinically treatment process Data Dancer organizes home blood proven to significantly reduce high blood pressure for pressure results providing performance feedback that more than 93 percent of users by using the device just is easy to understand, comprehensive and essential in NicOx is a pharmaceutical company committed to 12 minutes a day The Zona Plus focuses on shifting the achieving treatment goals. Our software products (Limbo, developing nitric oxide–donating drugs that address vagal tone from sympathetic to parasympathetic and Tango, and Salsa) are designed to track established important unmet medical needs and targeting the improving endothelial dysfunction by improving nitric treatments, assess the quality of home measurements, therapeutic areas of inflammatory and cardiometabolic oxide production Clinical trials support the effectiveness and to provide treatment performance across multiple trial diseases NicOx is maximizing the value of its broad of Zona Plus for improving these indicators product portfolio through in-house development of drug candidates and partnerships with major pharmaceutical ash Times • friday saturday • may 8–9 • san francisco
Role of salt in blood pressure often misunderstood
A series of talks this morning wil look at potential causes as wel as management strategies for salt-sensitive hypertension
While ingesTion of salT cleaRly kidney are critically important for the control at the root of salt-sensitive hypertension. The tension may be causing problems, he said. "By
plays a role in hypertension, there are many of sodium in water excretion. Defects in the endothelin A receptor system contributes to giving the blocker, you may be blocking some variables and emerging findings suggest tubular and vascular elements within the renal elevating blood pressure by direct constriction of the good effects of the endothelin system." new treatments on the horizon. Hyperten- medulla, particularly the renal endothelin of arteries and veins.
sion specialists will hear about interesting system, can lead to salt-sensitive hypertension, "In a healthy person, the kidney senses Advances offer new treatment
developments and theories regarding salt said David Pollock, MD, Regents Professor, your salt intake and will excrete it to keep your techniques
sensitivity during the session, "Salt-Sensitive Medical College of Georgia.
pressure normal. Our hypothesis is that people Renovascular disease is one of the most Hypertension," which takes place from 10:00 Dr. Pollock, who will be presenting "Is the who have a defect in the renal medullary func- common causes of secondary hypertension, to 11:30 a.m., Saturday, May 9, in Yerba Buena cause in the renal medulla?" said it's clear that tion, in particular, the endothelin B receptor said Stephen Textor, MD, Professor of Medi- Ballroom — Salon 7.
Americans consume far too much salt, and that pathway, are not able to eliminate enough salt cine and Vice Chair of the Division of Neph- at least 60 percent to 70 percent of people with and water and they retain fluid, becoming rology and Hypertension at the Mayo Clinic. Renal medulla defects may
hypertension are salt-sensitive.
hypertensive," Dr. Pollock said.
Dr. Textor's will present "A Clinical Case in play a role
Research shows that an imbalance be- Additionally, endothelin antagonists Renovascular Hypertension." Structures within the renal medulla of the tween endothelin A and B receptors may be already on the market for pulmonary hyper- "It's a bit of a controversial area right now because anti-hypertensive drug therapy has proven good, but at the same time there have been a lot of advances in techniques for opening up blood vessels like angioplasty and stenting," Dr. Textor said. "The controversy is over when and where to use each of those. It's hard to know if opening up those blood vessels really adds much benefit for most patients." Featuring the Latest in Hypertension
Dr. Textor will discuss which situations call for moving ahead with therapy, and which Visit Nature Publishing Group at Booth #318 for your don't. He expects the question-and-answer portion of the talk to yield fruitful discussion.
FREE Sample Copies of:
"We will look at when to move ahead with renal vascular therapy and when to rely on anti-hypertensive drug therapy — and when not to," he said. "We're living in a time when ONLINE ISSN:1348-4214 PRINT ISSN:0916-9636 the trial results are ambiguous. Some think American Journal we're doing too many procedures. Because AJH nature publishing group volume 21 number 1 january 2008
Offi cial Journal of the of these questions hypertension specialists Research Japanese Society of Hypertension www.nature.com/jhh EDITORIALS
Volume ?? Number ? AJH Joins the Nature Family
35 Inverse Relationship Between Ambulatory Arterial Stiffness
Michael H. Alderman Index and Glomerular Filtration Rate in Arterial Hypertension
are really going to have to weigh in on the Giuseppe Mulè, Santina Cottone, Paola Cusimano, Francesca Incalcaterra, Maria Giandalia, Miriam Costanzo, Emilio Nardi, Telmisartan Treatment Decreases Visceral Fat
Blood Pressure Variability: The Challenge of Variation
Alessandro Palermo, Calogero Geraci, Renato Costa Accumulation and Improves Serum Levels of Adiponectin
and Giovanni Cerasola Hypoxia-Induced Cardiac Remodeling in Sleep Apnea
and Vascular Inﬂ ammation Markers in Japanese
Plasma Renin Activity for Predicting Antihypertensive Drug
41 Changing Relationship Between Home and Office Blood
Syndrome: Involvement of the Renin-Angiotensin-
individual cases." Pressure With Increasing Age in Children: The Arsakeion
Daisuke CHUJO, Kunimasa YAGI, Akimichi ASANO Jon D. Blumenfeld School Study
Yoshikazu MIWA and Toshiyuki SASAGURI George S. Stergiou, Vayia C. Rarra and Nikolaos G. Yiannes Independent Determinants of Second Derivative of
NEWS AND VIEWS
the Finger Photoplethysmogram among Various
47 Recent Ventricular Repolarization Markers in Resistant
Cardiovascular Risk Factors in Middle-Aged Men
The renin-angiotensin system and treatment of
Hypertension: Are They Different from the Traditional QT
Aortic Pulse Wave Velocity and Carotid-Femoral Pulse
Toshiaki OTSUKA, Tomoyuki KAWADA, Masao KATSUMATA hypertension Albuminuria is common and reversible
Wave Velocity: Similarities and Discrepancies
Improved diastolic function by central sympathetic inhibition
Gil F. Salles, Claudia R.L. Cardoso, Sharon M. Leocadio and Piotr PODOLEC, Grzegorz KOPEC Angiotensin II Receptor Blocker Reduces Oxidative
Elizabeth S. Muxfeldt Stress and Attenuates Hypoxia-Induced Left Ventricular
The Metabolic Syndrome as a Prohypertensive State
54 Improvement of Cardiac Diastolic Function by Long-term
Relationship between Oxidative Stress and Essential
Remodeling in Apolipoprotein E−Knockout Mice
Chika YAMASHITA, Tetsuya HAYASHI Giuseppe Mulè and Giovanni Cerasola Centrally Mediated Sympathetic Inhibition in One-Kidney,
Ramón RODRIGO, Hernán PRAT, Walter PASSALACQUA Elderly benefit from treatment
Ventricular Repolarization in Hypertension:
One-Clip Hypertensive Rabbits
Inhibition of Vascular Angiotensin-Converting Enzyme by
Isabelle L. Signolet, Pascal P. Bousquet and Laurent J.P. Monassier Joint Impact of Smoking and Hypertension on
Telmisartan via the Peroxisome Proliferator−Activated
Claudio Passino and Michele Emdin RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM Cardiovascular Disease and All-Cause Mortality in Japan: Receptor a Agonistic Property in Rats
61 Predictors of Blood Pressure Response to the Angiotensin
NIPPON DATA80, a 19-Year Follow-Up
Shinji TAKAI, Denan JIN, Maki KIMURA Receptor Blocker Candesartan in Essential Hypertension
Atsushi HOZAWA, Tomonori OKAMURA, Yoshitaka MURAKAMI Vincent J. Canzanello, Evelyn Baranco-Pryor, Frederic Gene Polymorphism of Myospryn (Cardiomyopathy-
10 Pretreatment Plasma Renin Activity Levels Correlate With
Rahbari-Oskoui, Gary L. Schwartz, Eric Boerwinkle, Doctors should not be reluctant to treat C-Reactive Protein, Left Ventricular Mass Index, and Risk Associated 5) Is Associated with Left Ventricular Wall
the Blood Pressure Response to Telmisartan in Essential
Stephen T. Turner and Arlene B. Chapman of Cardiovascular Disease in Essential Hypertension 1177
Thickness in Patients with Hypertension
67 Ascorbic Acid Decreases the Binding Affinity of the AT1
Yoshio IWASHIMA, Takeshi HORIO Hironori NAKAGAMI, Yasushi KIKUCHI Junichi Minami, Toshihiko Ishimitsu and Hiroaki Matsuoka Receptor for Angiotensin II
Obesity, adiposity, and 14 Carryover Effects After Cessation of Drug Treatment:
Patrice C. Leclerc, Christophe D. Proulx, Guillaume Arguin, Renal Protective Effect in Hypertensive Patients:
Angiotensin-Converting Enzyme Inhibitor
Trophies or Dreams?
Simon Bélanger, Fernand Gobeil Jr, Emanuel Escher, Richard Leduc The High Doses of Angiotensin II Receptor Blocker
Suppresses Activation of Calcineurin in Renovascular
people over 80 to get their blood pressure Thomas Lumley, Kenneth M. Rice and Bruce M. Psaty and Gaétan Guillemette (HARB) Study
Plasma visfatin levels in 72 Effects of an ARB on Endothelial Progenitor Cell Function and
Mitsuru OHISHI, Takashi TAKAGI Hongzhuan SHENG, Jianhua ZHU Cardiovascular Oxidation in Hypertension
17 Relationship Between the Metabolic Syndrome and
Yi Yu, Noboru Fukuda, En-Hui Yao, Taro Matsumoto, Functional Polymorphism of the Myeloperoxidase Gene
Systemic Distribution of Salusin Expression in the Rat
the Development of Hypertension in the Hong Kong
Naohiko Kobayashi, Ryo Suzuki, Yoshiko Tahira, Takahiro Ueno in Hypertensive Nephrosclerosis Dialysis Patients 1193
Endothelial activation Cardiovascular Risk Factor Prevalence Study-2 (CRISPS2)
and Koichi Matsumoto Kent DOI, Eisei NOIRI, Rui MAEDA Noriko SUZUKI, Masayoshi SHICHIRI and microalbuminuria in down, said William J. Elliott, MD, PhD, Bernard M.Y. Cheung, Nelson M.S. Wat, Y. B. Man, Sidney Tam, Effects of Short-Term Hypocaloric Diet on Sympatho-
C. H. Cheng, Gabriel M. Leung, Jean Woo, Edward D. Janus, C. P. Lau, 78 Calcium Channel Blockers Suppress Cytokine-induced
Vagal Interaction Assessed by Spectral Analysis of Heart
T. H. Lam and Karen S.L. Lam Activation of Human Neutrophils
Rate and Blood Pressure Variability during Stress Tests
Torsades de Pointes: A Rare Complication of an Extra-
23 Hydroxyhydroquinone Interferes With the Chlorogenic
Etsuko Shima, Masataka Katsube, Takayuki Kato, Maki Kitagawa, in Obese Hypertensive Patients
Acid-induced Restoration of Endothelial Function in
Fumihiko Hato, Masayuki Hino, Tatsuji Takahashi, Hisakazu Fujita Terunao ASHIDA, Chikako ONO and Takao SUGIYAMA Heiko METHE, Martin HINTERSEER Spontaneously Hypertensive Rats
and Seiichi Kitagawa Yakima, Wash.
Atsushi Suzuki, Akihiko Fujii, Hiroko Jokura, Ichiro Tokimitsu, Tadashi Hase and Ikuo Saito 85 Blood Pressure Variability Causes Spurious Identification of
28 Upregulation of Endothelial and Inducible Nitric Oxide
Hypertension in Clinical Studies: A Computer Simulation Study
Synthase Expression by Reactive Oxygen Species
Martin J. Turner and Johan M. van Schalkwyk Junhui Zhen, Hua Lu, Xiu Q. Wang, Nosratola D. Vaziri and CONTINUED ON NEXT PAGE
Along with Gary Mitchell, MD, Norwood, Mass., Dr. Elliott will discuss a patient case his- tory and the overlap of salt-sensitive hyperten- www.nature.com/ajh www.nature.com/hr www.nature.com/jhh sion with systolic hypertension in the elderly, particularly those over 80 years in age.
The HYVET study abstract in the May 1, 2008, New England Journal of Medicine showed Nature Publishing Group is proud to publish three journals spanning the breadth that patients above 80 benefit from treatment, of hypertension – the American Journal of Hypertension, Hypertension Research Dr. Elliott said.
and Journal of Human Hypertension. Each of these journals offers unique features "As people become older they become more salt-sensitive and their arteries stiffen as well as the latest research covering: and the systolic blood pressure goes up and diastolic blood pressure goes down. People used to think that's okay (as a normal part of • molecular biology
aging) and therefore not worth treating, but • neurophysiology
now it's known that lowering blood pressure is beneficial," he said.
"In the olden days, people over 80 would argue with me that it doesn't pay to take medication to reduce blood pressure. People are still stuck with the idea that because their diastolic blood pressure is below 90 mmHg, • clinical and experimental hypertension
that they're okay. They're wrong," he said. "Systolic blood pressure is not something to • cardiovascular biology.
Racial differences offer clues
For many years it's been widely formu- lated the mechanism by which salt causes the pressor effect is through the kidney, but the true mechanism has never really been es- tablished, said Curtis Morris, MD, Professor of Medicine, Pediatrics and Radiology at the University of California, San Francisco.
Salt, continued on next page san francisco • may 8–9 • friday saturday • ash Times
Satellite Symposia speakers to address clinical relevancy
The latest information on new Vascular stiffness and inf lammation rosis. "We looked at why people with COPD diastolic pressure. If clinicians do a more concepts, treatments, devices, and may be underlying risk factors for hyper- had stiff aortas and found that they had aortic detailed analysis, they can obtain much more techniques will be examined during tension and cardiovascular disease. In the calcification. We also looked at people with information about the risk of cardiovascular industry-supported satel ite symposia. first part of Saturday afternoon's session on osteoporosis and found that they morbidity and mortality. I will All symposia take place in the Yerba "Arterial Evaluation: Clinically Relevant?" were at high cardiovascular risk focus mainly on people with Buena Bal room Salon 7 at the San which takes place from 4:00 to 5:30 p.m. as well because when calcium pre-hypertension or normoten- Francisco Marriott.
in Yerba Buena Ballroom — Salon 8, two comes out of their bones, it goes sion. I will address the issue of speakers will assess the role of vascular into their arteries. So there is a whether arterial elasticity or Friday, May 8
health in hypertension and the various ways link between osteoporosis and stiffness can provide extended of evaluating vascular health. The session is vascular complications," he said. information beyond arterial 5:30 – 8:00 a.m.
Antihypertensive Combinations co-sponsored by ASH and the International "People with osteoporosis may blood pressure measurement for Blood Pressure and Beyond: A Society for Vascular Health.
well be hypertensive and may for the prediction of cardiovas- John R. Cockcroft, MD, Professor of well have systolic hypertension, cular events as well the develop- Cardiology at the Wales Heart Research which can be difficult to treat. ment of hypertension in these Chair: William J. Elliott MD, PhD Institute, Cardiff, UK, will examine the role So clinicians should consider Daniel Duprez, MD, PhD people," Dr. Duprez said.
Supported by an educational grant from of vascular health in chronic obstructive pul- people with osteoporosis at high He will discuss carotid fem- Dai chi Sankyo Inc. monary disease (COPD) and osteoporosis risk for cardiovascular events.
oral pulse-wave velocity as one method of and how these conditions are "It's been suggested that assessing cardiovascular disease risk. This 5:30 – 8:00 p.m.
related to hypertension.
statins have effects beyond measurement assesses the difference in time Defining Resistant Hypertension and "COPD is actually a vascu- cholesterol reduction, and one from when the waveform from the heart New Therapeutic Pathways lar disease, and a lot of people of those effects is to reduce reaches the carotid and the femoral artery.
Chair: Henry R. Black, MD with COPD die of cardiovas- inf lammation. It's also been He will also describe a method to analyze Supported by an educational grant from cular disease. Smoking doesn't shown that statins improve the blood pressure curve or waveform at Gilead Sciences Medical Affairs. explain all the mortality risk. bone density. Statins may be the level of the radial artery and a method One indication that COPD is a the ideal drug for people with to measure cross-sectional compliance or Saturday, May 9
vascular disease is that people COPD and osteoporosis." with COPD have inflammation Daniel Duprez, MD, PhD, "Changes in arterial elasticity should be 5:30 – 8:00 a.m.
outside the lungs, or systemic Professor of Medicine, Donald detected as early as possible to prevent the Improving Cardiovascular Risk Factor inflammation, which may dam- John R. Cockcroft, MD and Patricia Garofalo Chair in development of hypertension and cardio- Management in Community-Based age the arteries. I will show data Preventive Cardiology, Direc- vascular disease. These changes will help us Practices: Prototypical Chal enges and Practical Solutions demonstrating that people with COPD have tor of the Lipid Clinic, Director of Research predict who will develop arterial hyperten- increased arterial stiffness and evidence of of the Rasmussen Center for Cardiovascular sion and, in the future, help us determine Chair: Brent M. Egan, MD arterial damage," Dr. Cockcroft said. "When Disease Prevention, and Associate Director when to start treatment to maintain vascular Supported by an educational grant from clinicians see patients with COPD, they of the Cardiovascular Clinical Trial Center health," Dr. Duprez said.
Merck & Co., Inc. should check the patients' cardiovascular at the University of Minnesota, Minne- The second part of this program will risk factors and treat those risk factors. I apolis, will present an overview of different feature a debate of the question, "Are the Dif- will show some data that clinicians should methods of evaluating arterial stiffness or ferent Vascular Effects of Antihypertensives even consider giving statins to people with elasticity, including pulse-wave velocity Clinically Relevant?" Arguing the pro side is Gary F. Mitchell, MD, Norwood, Mass., Salt, Dr. Cockcroft will also describe his re- "Blood pressure measurements only and debating the con is James D. Cameron, continued from page 12 search linking arterial stiffness with osteopo- assess two extreme points — systolic and MBBS, MD, Melbourne, Australia. l For unknown reasons, salt-sensitivity is particularly frequent and severe in African- Americans, even in those who are not hyper- tensive when not ingesting excessive amounts Awards to be presented at final Dr. Morris, whose speech is entitled Friday, May 8, 2009
"What Causes Salt-Sensitive Hypertension? Posters on Display: 9:30 a.m. to 4:00 p.m.
Renal Salt Retention or Increased Peripheral Poster Viewing: 2:30 to 3:30 p.m.
Resistance?" has looked at racial differences Don't miss Saturday's Awards Plenary Session, which begins at 8:15 a.m. in the in salt-sensitive hypertension.
Yerba Buena Bal room – Salon 9. Several honor lectures will be presented, including P-308: Hypertension Treatment and Control
In recent studies of such normotensive the Robert Tigerstedt Award Lecture and the Young Scholars Awards. among 28 Physician Practices across the African-American conducted by Dr. Morris US: Results of the Hypertension: Assessment of Treatment To Target (HATT) Study and his colleagues, said he they were surprised 8:15 a.m. — Welcome and Introduction 9: 24 a.m. — Renal Heme Oxygenase
Daniel A. Bel etti, Jenifer L. Wogen, Christopher to fund that in those who were salt-resistant, and Hypertension. David E. Stec, PhD blood pressure and systemic vascular resis- 8:20 a.m. — Robert Tigerstedt Award
tance actually decreased substantially during Lecture: Angiotensin Type-2 (AT2) 9:41 a.m.
P-359: Successful Treatment of Acute
the first three days of salt-loading — an ap- Receptors: Understanding Their Role in Presentation of the First Marvin Moser Hypertension in Children with Isradipine parently normal response. It appeared that Cardiovascular and Renal Function. Clinical Hypertension Award to Domenic Yosuke Miyashita, Do Peterson, Joseph Flynn the failure of this response to occur in the Robert M. Carey, MD A. Sica, MD.
salt-sensitive subjects, in combination with a normal increase in cardiac output, accounted Young Scholars Award Lectures
Announcement of ASH 2009 Young Audio recordings for their initial increase in blood pressure in response to salt loading. 8:50 a.m. — Aldosterone Signaling
Investigator-in-Training Abstract "In the African Americans we studied, you through Cholesterol-Rich Domains: Competition Award Recipients.
Implications in Hypertension. can't invoke a kidney abnormality that causes a positive salt balance as the reason for why the Glaucia E. Cal era, PhD Audio recordings on CD-ROM blood pressure went up," he said.
(including select speaker presentations For some time it was assumed that both so- 9: 07 a.m. — Identification of Genetic
as PDFs) from the scientific sessions and dium and chloride were needed to make blood Susceptibility to Hypertension and satel ite symposia will be for sale through pressure rise, but it was found that sodium the Metabolic Syndrome in the Lyon AVMG in the Mission Street Tunnel.
citrate would not make the blood pressure rise. Hypertensive Rat. Anne E. Kwitek, PhD You may also download the individual Yet the studies were not performed on African sessions in MP3 format to your computer Americans until Dr. Morris' research.
post-conference. Visit our e-commerce During his talk, Dr. Morris will share fur- store at www.ash-us.org. l ther details of his research as he discusses poten- tial causes of salt-sensitive hypertension. l ash Times • friday saturday • may 8–9 • san francisco
panel to discuss bp management in this population
saTUR day moR ning's session on clude physical activity, meditation, and pro- of hypertension just by weight loss is vari-
"Obesity is strongly associated with "Blood Pressure Management in the Obese gressive muscle relaxation," Dr. Foreyt said. able and incomplete, and the benefits may be difficult-to-control hypertension and an Person" will feature a panel of experts "Psychological factors can have a significant somewhat temporary. Hypertension is usually increased need for a number of medications discussing various aspects of dealing with effect on blood pressure in obese patients. not the only co-morbidity of obe- to control hypertension. The hypertension in this population, including My talk will provide attendees with insights sity, and the information we have underlying reasons for that the psychological considerations, surgery into potential strategies that their patients is that bariatric surgery improves are multiple," Dr. Calhoun for obesity, and the management of resistant can learn to help manage the psychological survival over the long term for said. "My particular research aspects of high blood pressure." the obese population." interest has been in aldosterone The session will take place Bruce M. Wolfe, MD, Profes- What is not know is whether excess as an underlying cause from 10:00 to 11:30 a.m., Sat- sor of Surgery at Oregon Health obesity is as big a survival risk if of resistant hypertension. My urday, May 9, in Yerba Buena & Science University, Portland, the patient's hypertension is well colleagues and I have found this Ballroom — Salon 8.
will acquaint attendees with the treated at all times using modern to be particularly true of obese John P. Foreyt, PhD, Profes- reasons for performing surgery pharmacology.
patients. In our experience, sor of Medicine and Director for obese people with hyperten- "The prevalence of obesity blocking aldosterone can be an of the Behavioral Medicine sion and other co-morbidities.
and hypertension together is effective treatment for resistant Research Center at Baylor Col- "I will talk about the inci- high, and the relative risk of hypertension, especially in David A. Calhoun, MD lege of Medicine in Houston, dence of severe obesity, the death is raised by obesity itself. will examine the psychological incidence of complications or Treating hypertension alone will most likely He said he also believes resistant hy- side of this issue, focusing on co-morbidities of obesity in- help some patients but not enough because of pertension in obese people may be related the psychological factors af- cluding hypertension, the gen- other co-morbidities. Severe obesity is a life- to increased salt sensitivity. Another as- fecting blood pressure in obese eral criteria for surgery, and the threatening condition with or without hyper- sociated feature of obesity is sleep apnea, individuals and how health-care John P. Foreyt, PhD choices for surgical treatment," tension, and surgery is an effective treatment which contributes to difficulty in treating professionals can help patients Dr. Wolfe said.
that is acceptably safe," Dr. Wolfe said.
manage these psychological factors.
The primary choice for surgery is gastric David A. Calhoun, MD, Professor of "Therapy for resistant hypertension "I plan to discuss behavioral strategies, bypass followed by adjustable gastric band- Medicine in the Vascular Biology and Hyper- in these patients includes effective use including strategies to raise patients' aware- ing. Infrequently done is biliopancreatic tension Program at the University of Alabama of diuretics and aldosterone antagonists ness of their lifestyle factors affecting their diversion. And the latest innovation is sleeve at Birmingham, will highlight the association and evaluating and treating sleep ap- blood pressure and specific problem-solving gastrectomy. "Sleeve gastrectomy is the between obesity and resistant hypertension nea. I will also emphasize dietary reco strategies that can be used to help them man- stomach part of biliopancreatic diversion and discuss the management of resistant mendations, especially salt restriction," age their blood pressure. These strategies in- with duodenal switch," he said. "Resolution hypertension in obese individuals.
Dr. Calhoun said. l sex hormones affect multiple
2009 ASH Elections mechanisms related to blood pressure Treasurer
Franz H. Messerli, MD Directors-at-Large, ASH Board of Directors:
John D. Bisognano, MD, PhD
dURing yesTeRday's session "sex hormone's affect on other cardiovascular studies show estrogen downgrades renin-
Hormones and Blood Pressure," two experts on concerns such as myocardial ischemia, anginal angiotensin system activity and offers anti- Daniel Levy, MD hormones and hypertension looked at the roles threshold, ejection fraction, and exercise capac- inflammatory and mild antioxidant properties Robert A. Phil ips, MD, PhD testosterone and estrogen play in regulating ity, for example.
among other benefits. Wil iam B. White, MD blood pressure as well as other cardiovascular "There seems to be an inverse relation- Other studies of women fol owing estrogen Chair, CME Committee
ship between testosterone, ejection fraction, loss show increased salt sensitivity, increased Robert A. Phil ips, MD, PhD Cardiologist and exercise capacity, etc.," Dr. Prisant said. "The body weight, increased sedentary behaviors, hypertension spe- lower the testosterone, the higher the blood increased insulin resistance, and increased Committee Members, CME Committee
cialist L. Michael Pri- prevalence of type 2 diabetes.
Jerry G. Back, MD sant, MD, Professor Following Dr. Prisant's presentation, the "Estradiol should offer protection," Dr. Reckel- Ali G. Gharavi, MD of Medicine at the session switched focus to estrogen. Noted hoff said. "So why did we get the results we did?" Michael A. Moore, MD Medical College of researcher Jane F. Reckelhoff, PhD, Professor One possibility she suggested is that in James A. Underberg, MD Georgia in Augusta, of Physiology at the University of Mississippi studies like the Women's Health Initiative, Allan B. Schwartz, MD looked at the affects Medical Center in Jackson, took to the stage therapy was started too long following the of testosterone dur- to present "What the Hypertension Specialist onset of menopause. Two new studies are look- Chair, Membership Committee
ing his talk "Endoge- L. Michael Prisant, Should Know about Estrogens and Meno- ing at hormone re- Daniel T. Lackland, DrPh nous and Exogenous MD placement therapy in Committee Member, Membership Committee
Testosterone and Blood Pressure." Dr. Reckelhoff reviewed well-known re- women who had their Wil iam J. El iott, MD, PhD Dr. Prisant reviewed the body of evidence sults from past studies of hormone replacement last period less than available from animal and human studies regard- in post-menopausal woman, which suggested three years before Committee Members, 2010 Nominating
ing testosterone's effects on blood pressure.
that such therapy not only failed to offer protec- starting therapy.
"Animal studies show that testosterone tion, but that it increased risk. "Another prob- F. Wilford Germino, MD increases blood pressure," he said. The Women's Health Initiative, for exam- lem is that you can't Richard H. Grimm, Jr., MD In the animal studies he discussed, Dr. ple, showed increased risks for cardiovascular separate menopause Shawna D. Nesbitt, MD Prisant demonstrated that there are a number disease, stroke, pulmonary embolism, and from aging," Dr. Christopher S. Wilcox, MD, PhD of mechanisms through which testosterone breast cancer. However, it also showed reduced Jane F. Reckelhoff, PhD Reckelhoff said. "If Committee Members, Public Policy &
affects blood pressure. In humans, however, risk of colorectal cancer, endometrial cancer, you give hormone replacement therapy to the evidence is limited.
and hip fracture. young women who have not been long without Jordan R. Asher, MD Dr. Prisant did review a few studies, includ- Dr. Reckelhoff said that since these stud- estrogen, they do just fine." Donald J. DiPette, MD ing a trial in which patients with low testoster- ies, most clinicians have stopped prescribing Another possibility, she said, is that scien- one levels were given the hormone.
hormone replacement therapy except in cases tists are looking at it the wrong way. It's pos- John M. Flack, MD "Testosterone does appear to lower blood where symptoms were severe enough to inter- sible, she said, that women may have a negative Jackson T. Wright, Jr. MD, PhD pressure if given acutely," he said. "And chronic fere with a woman's daily life.
reaction to testosterone — which increases Chair, Publications Committee
testosterone administration does not appear to However, she said, new findings suggest there's with age in women. L. Gabriel Navar, PhD increase blood pressure." more to consider regarding hormone replacement "A lack of testosterone in men may contrib- Other human studies on testosterone do therapy and cardiovascular protection.
ute to cardiovascular disease," she said. "But in Committee Member, Publications Committee
not directly examine its role in blood pres- Dr. Reckehoff reviewed animal studies women, maybe the opposite is true." l Suzanne Oparil, MD sure but seek to answer questions about the looking at the effects of estrogen. She said san francisco • may 8–9 • friday saturday • ash Times
session looks at hypertension management in
Populations around the world differ dividuals using appropriate therapies," Dr. may need to make additional efforts to make myocardial infarction," Dr. Deedwania said. in their risk for hypertension and their Margolis said.
sure they have adequate knowledge about "A very common coexisting condition in response to anti-hypertension medication. Few studies have focused on BP control hypertension, access to care and affordable South Asians with hypertension is diabetes. Saturday morning's session on Management in Hispanics, and ALLHAT provides an medications, and good doctor-patient com- Diabetes is up to four times more frequent of Hypertension in Special Populations will excellent source of data. She said the study munication," Dr. Margolis said.
in South Asians compared with Caucasians. bring together physicians with expertise in demonstrates that BP control in Hispanic pa- Prakash C. Deedwania, MD, Professor of South Asians who have both hypertension managing hypertension in Hispanic, South tients is an achievable goal and should there- Medicine at the University of California, San and diabetes are at significantly greater risk Asian, East Asian, and African American fore be declared a public health priority.
Francisco, School of Medicine, and Chief of of myocardial infarction and other complica- populations. The session will take place "The low rate of BP control in Hispan- Cardiology with the VA Central California tions related to MI." from 10:00 to 11:30 a.m. in Yerba Health Care System and the UCSF Program Gordon Fong, MD, PhD, Director of Buena Ballroom — Salons 9.
at Fresno, will examine the treatment of hy- Cardiology Services at the University of Karen Margolis, MD, MPH, Hypertension is as prominent in South pertension in South Asian populations.
California San Francisco Medical Center, Senior Clinical Investigator with "Hypertension is as prominent in South will discuss the prevalence of hypertension, Asian populations as it is in Caucasians, HealthPartners Research Foun- Asian populations as it is in clinical trials of hypertension, dation, Minneapolis, and As- and it may occur even more frequently in Caucasians, and it may occur and specific treatment issues in sociate Professor of Medicine at even more frequently in South East Asian populations.
South Asians. In addition, the treatment the University of Minnesota, will Asians. In addition, the treat- Morbidity and mortality re- review information about blood approaches may be different for South ment approaches may be dif- lated to hypertension are higher pressure control in Hispanic ferent for South Asians because in East Asian populations than Asians because there have not been participants from the ALLHAT there have not been large studies in whites, and early identifica- (Antihypertensive and Lipid- large studies looking at the differential looking at the differential effect tion and treatment with anti- Lowering Treatment to Prevent of various anti-hypertension hypertension medications are effect of various anti-hypertension drugs Heart Attack Trial) study, which drugs in these patients," Dr. particularly important. Since had the largest number of His- in these patients.
2004, China has embarked panic participants of any hyper- He said South Asian patients on an early vascular disease Prakash C. Deedwania, MD tension trial.
– Prakash C. Deedwania, MD have a low tolerance for very detect ion prog ra m to tr y "I will discuss trends in na- high doses of calcium channel blockers, to prevent cardiovascular events in tional data on BP control in His- therefore clinicians need to modify the doses hypertensive patients.
panics and other racial and ethnic in these individuals. Finally, Shawna D. Nesbitt, MD, MS, As- groups as well as the possible reasons why ics in the United States does not appear to "I will talk about the increasing prob- sociate Professor of Internal Medicine at the BP control in Hispanic people has lagged be the result of biological factors. BP can be lem of hypertension associated with other University of Texas Southwestern Medical behind other groups. The ALLHAT results controlled in more than two-thirds of His- cardiovascular risk factors that many South Center at Dallas, will talk about the manage- suggest that BP is equally easily controlled panics using inexpensive, commonly avail- Asians have, which puts them at significantly ment of hypertension in African American in Hispanics as in non-Hispanic white in- able generic medications. Hispanic patients higher risk of coronary artery disease and populations. l ASH Specialist Program Inc., Board ASH launches education initiative of Directors establish Association Last month ASH President Henry In developing the ASH of Hypertension Specialists R. Black, MD, announced the launch Hypertension Accreditation Program, of a new educational initiative in Dr. Black and Curriculum Committee These are perilous times, particularly To advocate for legislation to provide hypertension and related cardiovascular members Jan N. Basile, M.D., Joseph in the arena of health care. Although increased support for patients with disease — the ASH Hypertension L. Izzo, Jr., M.D., and Committee hypertension remains the most important hypertension, e.g. home blood pressure Accreditation Program — to enhance Chairman Robert A. Phillips, M.D., cardiovascular problem facing the U.S. the level of education of health Ph.D., worked with Thornton Medical population, those who are most expert in To establish a CPT code for care providers, pharmaceutical sales Communications, an independent dealing with this problem — designated cardiovascular risk assessments that representatives, medical journalists, medical education company, to adapt specialists in clinical hypertension — have hypertension specialists could perform.
and other disseminators of health- the Clinical Hypertension Review no place at the negotiating table. To establish at the national and care information. While this rigorous Course for sales representatives. To meet this chal enge, the Board of local level credentialing criteria for academic program will be tailored to The curriculum content focuses on Directors of the ASH Specialists Program technology related to hypertension — meet the educational needs of each of the science on which hypertension Inc., in collaboration with the ASH Board e.g. ambulatory blood pressure recording the intended target groups, it is designed and cardiovascular disease is based of Directors established the Association of and interpretation, measures of vascular to improve all participants' understanding and will examine mechanisms that Hypertension Specialists (AHS) as a Special compliance, and estimation of central of hypertension and related cardiovascular regulate blood flow, pathways to heart Interest Group within ASH.
disease, improve the flow of information disease and organ involvement, as well The AHS will serve as an advocacy To meet with members of the and create partnerships between health- as social and economic disparities that medical insurance industry to negotiate care providers who seek to improve group dedicated to promoting increased affect diagnosis, treatment, control, patient outcomes. and compliance.
recognition for expertise in the diagnosis and promote recognition and increased The ASH Hypertension Accreditation Beginning in June 2009, ASH and treatment of hypertension and reimbursement for hypertension specialists.
Program is based on the Society's will begin the Accreditation providing increased resources for the To host forums during the annual Clinical Hypertension Review Course, Program. ASH will train more than care of patients with hypertension. The meeting of the American Society of which emphasizes state-of-the-art 700 Daiichi Sankyo, Inc. sales team inaugural session of the Association of Hypertension, and at other meetings, to scientific principles and evidence- members in the first year of the Hypertension Specialists took place on learn of ways to improve the practice of based clinical practice. The content of program and intends to offer the Wednesday, May 06, at the ASH Annual the hypertension specialists, including the the Program focuses on epidemiology, program to representatives of other Scientific Meeting.
incorporation of new technology.
pathophysiology, treatment, clinical pharmaceutical companies thereafter. The initial goals of the Association of To devise brief presentations for use trials, and includes patient case To achieve accreditation, sales by national and local speakers when presentations — which ful y enhances representatives will be required to To obtain a medical specialty code presenting to policy makers — i.e. and expands the ASH educational complete approximately 10 hours of description from AMA and CMS to identify government, insurance industry, hospital mission. Dai chi Sankyo, Inc., which home study before the live course, 13 a hypertension specialist.
collaborated with ASH on the training hours of intense classroom training In col aboration with ASH, negotiate Since no group has taken up the role of concept, will be the first pharmaceutical during 2.5 days, six hours of homework with CMS to recognize a higher level of acting as an advocate for the hypertension company to have its sales force enrolled during the training program, and pass service, and thus reimbursement, when a specialists that deal with this major U.S. for the ASH Hypertension Accreditation a 1.5 hour written exam administered hypertension specialist sees patients with health care issue, the AHS wil fil this ash Times • friday saturday • may 8–9 • san francisco
headaches can have multiple causes in hypertensive
patients, speaker says
headaches aRe a common, almosT
Preeclampsia and eclampsia both occur migraines are the most common types of also need to avoid triggers in their diets, such universal complaint from patients, yet in the period around delivery — either be- headaches that bring individuals to a doc- as cheap red wine, processed meats, or smelly people with headaches do not always get the fore, during, or up to six weeks after delivery. tor's attention. People with tension-type cheeses," she said.
treatment they need. During the session on Eclampsia is preeclampsia with seizures. headaches generally take over-the-counter Migraine pain is generally unresponsive Resistant Hypertension Both have symptoms of medications and don't seek a doctor's help, to over-the-counter medications, such as Friday morning from headaches, elevated blood Dr. Jamieson said.
aspirin, acetaminophen, or ibuprofen. 10:00 to 11:30 a.m. in Ye- pressure, brisk muscle- "People with migraine headaches have "Most patients with migraines com- rba Buena Ballroom — stretch reflexes, and pro- relatively severe pain that is sharp or stab- monly require triptan medications, such teinuria, she said.
Jamieson, MD, Associ- "PR ES is a neuro- bing. Feeling ate Professor of Clinical logic disorder that in- pressure is more People with migraine headaches have who have fre- Neurology at Weill Cor- cludes elevated blood common with relatively severe pain that is sharp or stab- quent disabling nell Medical College in pressure and character- ten s ion-t y pe New York, will explain istic changes on MRI headaches. Pain bing or throbbing. Feeling pressure is more aches need to "What the Hypertension in the posterior part with nausea or common with tension-type headaches. be given a pre- Specialist Should Know of the brain as well as sensitiv it y to About Headaches." headaches. Clinicians movement or Pain with nausea or sensitivity to move- tion to decrease need to treat the pa- light or sound ment or light or sound or smel is more the frequency think that headaches in tient's hypertension first or smell is more hypertensive patients and then the other signs common with common with migraine headaches.
are caused only by high of the neurologic syn- migraine head- blood pressure. Elevated – Dara G. Jamieson, MD Dara G. Jamieson, MD blood pressure is rarely addition to headaches, said.
the cause of their headaches. Most patients patients usually present with confusion, vi- have either tension-type headaches or mi- sual changes, and seizures. One of the major million Americans have chronic, disabling might require a preventative medication graines," Dr. Jamieson said. "However, some causes, but not the only cause of PRES is migraines. These headaches are poorly that also lowers blood pressure, such as a specific types of headaches can be related unexpectedly elevated blood pressure," Dr. recognized, and only about half of these calcium channel blocker or propranolol," to acutely elevated blood pressure. These Jamieson said. "People with PRES are quite individuals are diagnosed and treated for Dr. Jamieson said. "Hypertension special- hypertension-related headaches are most sick and need to be hospitalized. If left un- migraine.
ists should know that they should not give often seen in the setting of preeclampsia and treated, PRES can be life threatening. Their "In general, the treatment for migraines triptans to patients with chronic, untreated eclampsia with pregnancy and posterior re- blood pressure needs to be brought down as is lifestyle adjustment in terms of daily ex- hypertension. They need to manage the versible encephalopathy syndrome (PRES), quickly and effectively as possible." ercise, getting enough sleep, not skipping patient's blood pressure first before giving which may be associated with acute blood She said tension-type headaches are meals, avoiding dehydration, and trying to the patient a triptan for acute treatment pressure elevation among other causes." the most common types of headaches, and avoid stress. People with chronic migraines of migraine." l Pathobiology Session
expert to explore the role of uric acid in hypertension, renal disease
h y peRU R icemi a h as long been We and others have also performed clinical may be caused by its ability to inhibit en- tion of uric acid in 90 percent of hypertensive
considered a biologically inert marker of studies and demonstrated that lowering uric dothelial function. In animals given a high- subjects vs. zero percent of controls, and the hypertension, renal disease, and cardiovas- acid with allopurinol prevented the develop- fructose diet, allopurinol was able to lower relationship of uric acid with hypertension cular events, but new research is emerging ment of hypertension and renal disease." serum uric acid levels and prevent or reverse was linear and dramatic. In preliminary to suggest that elevated uric acid levels may studies, the lowering of uric acid resulted play a role in the pathogenetics of these in the normalization of blood pressure in My message is that hyperuricemia might have a causal four of five hypertensive adolescents," During Friday morning's Pathobiology Session on Genetic Insight into Hyperten- role in the development of hypertension, renal disease, Dr. Nakagawa's experimental animal sion, which takes place from 10:00 to 11:30 and metabolic syndrome. While our studies are not studies have also suggested that uric acid a.m. in Yerba Buena Ballroom — Salon may be a mediator of renal disease and its 7, Takahiko Nakagawa, MD, will address yet meant for the clinic, it is important for clinicians to progression. Hyperuricemia accelerates "What the Hypertension Specialist Should know about studies related to the pathogenesis of dis- renal disease progression in animal models Know About Uric Acid" and describe his through a mechanism linked to high blood and other investigators' findings about the ease states. I wil provide evidence that uric acid may pressure and COX-2-mediated, thrombox- potential pathologic role of hyperuricemia. have a role in hypertension. In the future, uric acid could ane-induced vascular disease, he said.
Dr. Nakagawa is Associate Professor of "My message is that hyperuricemia Medicine in the Division of Renal Disease become a novel target for treatment.
might have a causal role in the develop- and Hypertension at the University of Colo- – Takahiko Nakagawa, MD ment of hypertension, renal disease, and rado — Denver.
metabolic syndrome. While our studies are "Our animal data and recent epide- not yet meant for the clinic, it is important miologic studies suggest that uric acid has In his research, Dr. Nakagawa has sug- features of the metabolic syndrome.
for clinicians to know about studies related a pathologic role in hypertension, renal gested a causal role for uric acid in fructose- Studies of experimental models of hy- to the pathogenesis of disease states. I will disease, and the metabolic syndrome. Since induced metabolic syndrome, noting that peruricemia have found that elevated uric provide evidence that uric acid may have a hyperuricemia is often observed in patients, the worldwide epidemic of the metabolic acid levels result in the development of role in hypertension. In the future, uric acid it might be important for hypertension spe- syndrome, including hypertension, cor- hypertension, Dr. Nakagawa said. Hype- could become a novel target for treatment," cialists to know these experimental and clini- relates with elevations in serum uric acid ruricemia in animals reduces nitric oxide Dr. Nakagawa said. "It is evident that more cal data," Dr. Nakagawa said. "My colleagues levels as well as a marked increase in total levels and activates the renin-angiotensin studies on the role of uric acid in cardio- and I have done a number of studies with ani- fructose intake in the form of table sugar and system, which leads to uric acid-mediated vascular and renal disease are required. In mal models to demonstrate the causal role of high-fructose corn syrup.
renal microvascular disease.
particular, studies identifying the conditions uric acid in the development of hypertension, His animal data provide evidence that "Studies of new-onset essential hyperten- under which uric acid may be beneficial vs. renal disease, and the metabolic syndrome. uric acid's role in the metabolic syndrome sion in adolescents have reported an eleva- deleterious are critical." l Powerful efficacy
2 t n
in the overall population
0 o otrhe
In the COACH pivotal trial
AZOR 10/40 mg consistently provided significant reductions in mean SBP vs baseline
across many patient types1
Mean changes in SBP at Week 8 with AZOR 10/40 mg
Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40% to 60%, and a lower initial dose may be required A randomized, multicenter, double-blind, placebo-controlled factorial study (N=1940). Patients were randomized for 8 weeks of double-blind treatment. Mean baseline BP was 167/102 mm Hg for placebo in the overall population and 166/102 mm Hg for AZOR 10/40 mg in the overall population. Mean baseline SBP for AZOR 10/40 mg was 147 mm Hg in patients with Stage 1 hypertension (defined as: SBP 140–159 mm Hg or DBP 90–99 mm Hg), 171 mm Hg in mean SBP reduction
patients with Stage 2 hypertension (defined as: SBP ≥160 mm Hg in the overall
or DBP ≥100 mm Hg), 192 mm Hg in patients with severe hypertension (defined as: SBP ≥180 mm Hg), 171 mm Hg in patients with diabetes, 180 mm Hg in patients ≥65 years old, 168 mm Hg in African American patients, and 166 mm Hg in obese patients (BMI ≥30 kg/m2). Mean baseline SBP for placebo was 149 mm Hg in patients with Stage 1 hypertension, 170 mm Hg in patients with Stage 2 hypertension, 191 mm Hg in patients with severe hypertension, 176 mm Hg in patients with diabetes, 179 mm Hg in patients ≥65 years old, 168 mm Hg in African American patients, and 166 mm Hg in obese patients. Severe hypertension results presented are derived from a post hoc subanalysis of the pivotal trial. All other subgroup analyses were prespecified.1,2 P<0.0001 vs baseline.
*Mean SBP reduction with AZOR 10/40 mg (placebo: 5 mm Hg).
Mean BP baseline was 164/102 mm Hg in the overall population.2
Mean reductions in SBP with placebo were 2 mm Hg in patients with Stage 1 hypertension, 5 mm Hg in patients with Stage 2 hypertension, and 15 mm Hg in
patients with severe hypertension. Mean reductions in SBP with placebo were 15 mm Hg in patients with diabetes, 8 mm Hg in elderly patients, 4 mm Hg in
African American patients, and 5 mm Hg in obese patients.1
Decrease pill burden with one convenient tablet, once a day, and just one co-pay3,4
AZOR is available in 4 combinations of amlodipine and olmesartan medoxomil
Amlodipine 5 mg
AZOR 5/20 mg
AZOR 5/40 mg
Amlodipine 10 mg
AZOR 10/20 mg
AZOR 10/40 mg
Actual size of tablets.
based on overall population results with AZOR 10/40 mg in the COACH pivotal trial USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing
fetus. When pregnancy is detected, AZOR should be discontinued as soon as possible. See WARNINGS AND PRECAUTIONS, Fetal/Neonatal Morbidity and Mortality.
Please see following pages for important safety information and brief summary of prescribing information for AZOR.
References: 1. Data on file. Daiichi Sankyo, Inc. 2. Chrysant SG, Melino M, Karki S, Lee J, Heyrman R. The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind,
placebo-controlled, 8-week factorial efficacy and safety study. Clin Ther. 2008;30:587-604. 3. Taylor AA. Combination drug treatment of hypertension: have we come full circle? Curr Cardiol Rep. 2004;6:421-426. 4. Dezii CM. A retrospective study
of persistence with single-pill combination therapy vs. concurrent two-pill therapy in patients with hypertension. Manag Care. 2000;9(suppl 9):2-6.
2009 Daiichi Sankyo, Inc. Important safety information and study description
USE IN PREGNANCY
Since amlodipine is extensively metabolized by the liver and the When used in pregnancy during the second and third
plasma elimination half-life (t trimesters, drugs that act directly on the renin-angiotensin
1/2) is 56 hours in patients with severely impaired hepatic function, caution should be exercised when system can cause injury and even death to the developing fetus.
administering AZOR to patients with severe hepatic impairment.
When pregnancy is detected, AZOR should be discontinued as Laboratory Tests
soon as possible. See WARNINGS AND PRECAUTIONS, Fetal/
There was a greater decrease in hemoglobin and hematocrit in Neonatal Morbidity and Mortality.
the combination product compared to either component alone.
Hypotension in Volume- or Salt-Depleted Patients
The only adverse reaction that occurred in greater than or equal to In patients with an activated renin-angiotensin system, such as 3% of patients treated with AZOR and more frequently than placebo volume- and/or salt-depleted patients, symptomatic hypotension was edema. The placebo-subtracted incidence was 5.7% (5/20 mg), due particularly to the olmesartan component may occur after 6.2% (5/40 mg), 13.3% (10/20 mg), and 11.2% (10/40 mg). The initiation of treatment with AZOR. Treatment should start under edema incidence for placebo was 12.3%.
close medical supervision.
Adverse reactions seen at lower rates but at about the same or greater incidence as in patients receiving placebo included hypotension, Since the vasodilation attributable to amlodipine in AZOR is gradual orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, in onset, acute hypotension has rarely been reported after oral and nocturia.
administration. Nonetheless, caution, as with any other peripheral In individual clinical trials of amlodipine and olmesartan medoxomil, vasodilator, should be exercised when administering AZOR, particularly other commonly reported adverse reactions included headache, in patients with severe aortic stenosis.
dizziness, and flushing.
Severe Obstructive Coronary Artery Disease
AZOR COACH pivotal trial—study description
Patients, particularly those with severe obstructive coronary artery A randomized, multicenter, double-blind, placebo-controlled factorial disease, may develop increased frequency, duration, or severity of study (N=1940) to evaluate the efficacy and safety of AZOR across angina or acute myocardial infarction on starting calcium channel a range of doses and compared with monotherapy components. blocker therapy or at the time of dosage increase.
Patients were randomized to one of 12 treatment arms for 8 weeks Congestive Heart Failure
of double-blind treatment with placebo, amlodipine monotherapy In general, calcium channel blockers should be used with caution in (5 or 10 mg/day), olmesartan medoxomil monotherapy (10, 20, or patients with heart failure.
40 mg/day), or amlodipine/olmesartan medoxomil combination Impaired Renal Function
therapy (all possible combinations). Patients were not titrated to different doses.
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea Primary endpoint: mean change from baseline in trough SeDBP at nitrogen (BUN) have been reported. There has been no long-term use Week 8, using the last observation carried forward (LOCF) for patients of olmesartan medoxomil in patients with unilateral or bilateral renal who did not complete the protocol. Secondary endpoint was a mean artery stenosis, but similar effects would be expected with AZOR change from baseline in trough SeSBP at Week 8 (LOCF).
because of the olmesartan medoxomil component.
Mean baseline seated BP was 162–167/101–102 mm Hg.
Brief Summary – See package insert for full prescribing information.
transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant (amlodipine and olmesartan medoxomil) tablets
rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose (MRHD) on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m2 basis; higher USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-
doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, signifi- angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected,
cant decreases in pup birth weight and weight gain were observed at doses r1.6 mg/kg/day, and delays in devel- AZOR™ should be discontinued as soon as possible [see Warnings and Precautions (5.1)].
opmental milestones (delayed separation of ear auricular, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the 1 INDICATIONS AND USAGE
renal pelvis were observed at doses r8 mg/kg/day. The no observed effect dose for developmental toxicity in AZOR™ is indicated for the treatment of hypertension, alone or with other antihypertensive agents. This fixed rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.
combination drug is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION 5.2 Hypotension in Volume- or Salt-Depleted Patients
in the full prescribing information).
Olmesartan medoxomil. Symptomatic hypotension may occur after initiation of treatment with olmesartan
medoxomil. Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) may be particularly vulnerable. Treatment with AZOR™ 5 WARNINGS AND PRECAUTIONS
should start under close medical supervision. If hypotension does occur, the patient should be placed in the The adverse reactions of AZOR™ are generally related to those of each of its components.
supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the 5.1 Fetal/Neonatal Morbidity and Mortality
blood pressure has stabilized.
Olmesartan medoxomil. Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal
morbidity and death when administered to pregnant women. There have been several dozen cases reported in the world literature of patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is Amlodipine. Since the vasodilation attributable to amlodipine in AZOR™ is gradual in onset, acute hypotension has
detected, AZOR™ should be discontinued as soon as possible. During the second and third trimesters of preg- rarely been reported after oral administration. Nonetheless, caution, as with any other peripheral vasodilator, should nancy, these drugs have been associated with fetal injury that includes hypotension, neonatal skull hypoplasia, be exercised when administering AZOR™, particularly in patients with severe aortic stenosis.
anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably 5.4 Patients with Severe Obstructive Coronary Artery Disease
resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth duration, or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occur- the time of dosage increase. The mechanism of this effect has not been elucidated.
rences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine 5.5 Patients with Congestive Heart Failure
drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an Amlodipine. In general, calcium channel blockers should be used with caution in patients with heart failure.
angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III become pregnant, physicians should have the patient discontinue the use of AZOR™ as soon as possible. Rarely or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin- a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure).
to their fetuses and serial ultrasound examinations should be performed to assess the intra-amniotic environ- Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA class II/III heart fail- ment. If oligohydramnios is observed, AZOR™ should be discontinued unless it is considered life-saving for the ure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropri- on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.
ate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydram - nios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure 5.6 Patients with Impaired Renal Function
to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia.
Olmesartan medoxomil. Changes in renal function may be anticipated in susceptible individuals treated with
If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe 7 DRUG INTERACTIONS
congestive heart failure), treatment with angiotensin converting enzyme inhibitors and angiotensin receptor antag- 7.1 Drug Interactions with AZOR™
onists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or The pharmacokinetics of amlodipine and olmesartan medoxomil are not altered when the drugs are co-administered.
death. Similar effects may occur in patients treated with AZOR™ due to the olmesartan medoxomil component [See No drug interaction studies have been conducted with AZOR™ and other drugs, although studies have been con- Clinical Pharmacology (12.3) in the full prescribing information]. In studies of ACE inhibitors in patients with unilateral ducted with the individual amlodipine and olmesartan medoxomil components of AZOR™, as described below, or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported.
and no significant drug interactions have been observed.
There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery steno- 7.2 Drug Interactions with Amlodipine
sis, but similar effects would be expected with AZOR™ because of the olmesartan medoxomil component.
In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, 5.7 Patients with Hepatic Impairment
warfarin, and indomethacin.
Amlodipine. Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is
Effect of Other Agents on Amlodipine 56 hours in patients with severely impaired hepatic function, caution should be exercised when administering Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
AZOR™ to patients with severe hepatic impairment.
Grapefruit juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg 5.8 Laboratory Tests
in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine. Maalox® (antacid): AZOR™. There was a greater decrease in hemoglobin and hematocrit in the combination product compared to
Co-administration of the antacid Maalox® with a single dose of amlodipine had no significant effect on the either component. Other laboratory changes can usually be attributed to either monotherapy component.
pharmacokinetics of amlodipine. Sildenafil: A single 100 mg dose of sildenafil in subjects with essential Amlodipine. In post-marketing experience, hepatic enzyme elevations have been reported (6.2). Olmesartan
hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil medoxomil. In post-marketing experience, increased blood creatinine levels and hyperkalemia have been
were used in combination, each agent independently exerted its own blood pressure lowering effect.
Effect of Amlodipine on Other Agents 6 ADVERSE REACTIONS
Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted 6.1 Clinical Trials Experience
in no significant change in the steady state pharmacokinetic parameters of atorvastatin. Digoxin: Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not in normal volunteers.
reflect the rates observed in practice. AZOR™. The data described below reflect exposure to AZOR™ in more
Ethanol (alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharma co - than 1600 patients including more than 1000 exposed for at least 6 months and more than 700 exposed for kinetics of ethanol. Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin 1 year. AZOR™ was studied in one placebo-controlled factorial trial (see Section 14.1 in the full prescribing infor- prothrombin response time.
mation). The population had a mean age of 54 years and included approximately 55% males. Seventy-one AZOR™ (amlodipine and olmesartan medoxomil) tablets percent were Caucasian and 25% were Black. Patients received doses ranging from 5/20 mg to 10/40 mg orally once daily. The overall incidence of adverse reactions on therapy with AZOR™ was similar to that seen with correspond - In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin- ing doses of the individual components of AZOR™, and to placebo. The reported adverse reactions were converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti- generally mild and seldom led to discontinuation of treatment (2.6% for AZOR™ and 6.8% for placebo).
inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
Edema. Edema is a known, dose-dependent adverse effect of amlodipine but not of olmesartan medoxomil. The 7.3 Drug Interactions with Olmesartan Medoxomil
placebo-subtracted incidence of edema during the 8-week, randomized, double-blind treatment period was highest No significant drug interactions were reported in studies in which olmesartan medoxomil was co-administered with amlodipine 10 mg monotherapy. The incidence was significantly reduced when 20 mg or 40 mg of olmesartan with digoxin or warfarin in healthy volunteers. The bioavailability of olmesartan medoxomil was not significantly medoxomil was added to the 10 mg amlodipine dose.
altered by the co-administration of antacids [Al(OH)3/Mg(OH)2]. Olmesartan medoxomil is not metabolized by Placebo-Subtracted Incidence of Edema during the Double-Blind Treatment Period
the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce, or are metabolized by those enzymes are not expected.
8 USE IN SPECIFIC POPULATIONS
Olmesartan medoxomil. Pregnancy Categories C (first trimester) and D (second and third trimesters). [See
Warnings and Precautions (5.1)] Amlodipine. No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rab-
*12.3%=actual placebo incidence bits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on a mg/m2 basis) during their Across all treatment groups, the frequency of edema was generally higher in women than men, as has been respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg). However, litter size observed in previous studies of amlodipine. Adverse reactions seen at lower rates during the double-blind period was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased also occurred in the patients treated with AZOR™ at about the same or greater incidence as in patients receiving (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days placebo. These included hypotension, orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, and before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the nocturia. The adverse event profile obtained from 44 weeks of open-label combination therapy with amlodipine gestational period and the duration of labor in rats at this dose. There are no adequate and well-controlled stud- plus olmesartan medoxomil was similar to that observed during the 8-week, double-blind, placebo-controlled ies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Amlodipine. Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical
8.3 Nursing Mothers
trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In con- It is not known whether the amlodipine or olmesartan medoxomil components of AZOR™ are excreted in human trolled clinical trials directly comparing amlodipine (N=1730) in doses up to 10 mg to placebo (N=1250), discon- milk, but olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for tinuation of amlodipine due to adverse reactions was required in only about 1.5% of amlodipine-treated patients adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue and about 1% of placebo-treated patients. The most common side effects were headache and edema. The inci- the drug, taking into account the importance of the drug to the mother.
dence (%) of dose-related side effects was as follows: 8.4 Pediatric Use
The safety and effectiveness of AZOR™ in pediatric patients have not been established.
8.5 Geriatric Use
Of the total number of subjects in the double-blind clinical study of AZOR™, 20% (384/1940) were 65 years of age or older and 3% (62/1940) were 75 years or older. No overall differences in safety or effectiveness were observed between subjects 65 years of age or older and younger subjects.
8.6 Hepatic Impairment
For several adverse experiences that appear to be drug- and dose-related, there was a greater incidence in There are no studies of AZOR™ in patients with hepatic insufficiency, but both amlodipine and olmesartan women than men associated with amlodipine treatment as shown in the following table: medoxomil show moderate increases in exposure in patients with hepatic impairment. Use caution when admin- istering AZOR™ to patients with severe hepatic impairment.
8.7 Renal Impairment
There are no studies of AZOR™ in patients with renal impairment.
8.8 Black Patients
Of the total number of subjects in the double-blind clinical study of AZOR™, 25% (481/1940) were black patients.
AZOR™ was effective in treating black patients (usually a low-renin population), and the magnitude of blood pressure reduction in black patients approached that observed for non-black patients.
Olmesartan medoxomil. Olmesartan medoxomil has been evaluated for safety in more than 3825
There is no information on overdosage with AZOR™ in humans. patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience 17 PATIENT COUNSELING INFORMATION
included about 900 patients treated for at least 6 months and more than 525 for at least 1 year. Treatment with Physicians should instruct female patients of childbearing age about the consequences of second and third olmesartan medoxomil was well tolerated, with an incidence of adverse events similar to that seen with placebo.
trimester exposure to drugs that act on the renin-angiotensin system and they should be told that these conse- Events were generally mild, transient, and without relationship to the dose of olmesartan medoxomil. The over- quences do not appear to have resulted from intrauterine drug exposure that has been limited to the first all frequency of adverse events was not dose-related. Analysis of gender, age, and race groups demonstrated no trimester. These patients should be informed to report pregnancies to their physicians as soon as possible. [See differences between olmesartan medoxomil- and placebo-treated patients. The rate of withdrawals due to adverse Warnings and Precautions (5.1)].
events in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with olmesartan medoxomil and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse event that occurred in more than 1% of patients treated with olmesartan medoxomil and at a higher incidence in olmesartan medoxomil treated patients vs. placebo was dizziness (3% vs 1%).
Manufactured for Daiichi Sankyo, Inc., Parsippany, New Jersey 07054Manufactured by Daiichi Sankyo Europe GmbH, Germany 6.2 Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of the individual components of Copyright Daiichi Sankyo, Inc. 2007. All rights reserved.
AZOR™. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Amlodipine. The following post-marketing event has been reported infrequently where a causal relationship is
uncertain: gynecomastia. In post-marketing experience, jaundice and hepatic enzyme elevations (mostly consis- tent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
Olmesartan medoxomil. The following adverse reactions have been reported in post-marketing experience:
Body as a Whole: asthenia, angioedema. Gastrointestinal: vomiting. Musculoskeletal: rhabdomyolysis. Uro - genital System: acute renal failure. Skin and Appendages: alopecia, pruritus, urticaria.
Cut hypertension with AZOR
2 t n b mo
0 o otrhe
AZOR provides powerful efficacy plus proven tolerability
in the overall population of the COACH pivotal trial2
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, drugs
that act directly on the renin-angiotensin system can cause injury and
even death to the developing fetus. When pregnancy is detected, AZOR
should be discontinued as soon as possible. See WARNINGS AND
PRECAUTIONS, Fetal/Neonatal Morbidity and Mortality.
AZOR is indicated for the treatment of hypertension, alone or with other
AZOR is not indicated for the initial therapy of hypertension.
Please see preceding pages for important safety information
and brief summary of prescribing information for AZOR.
based on overall
population results with
AZOR 10/40 mg in the
COACH pivotal trial
(placebo: 5 mm Hg)
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