Olmesartan: Difference between revisions
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|adverseReactions=[[hypotension]]，[[dizziness]]，[[headache]] | |adverseReactions=[[hypotension]]，[[dizziness]]，[[headache]] | ||
|blackBoxWarningTitle= | |blackBoxWarningTitle=<span style="color:#FF0000;">WARNING: FETAL TOXICITY</span> | ||
<span style="color:#FF0000;">WARNING: FETAL TOXICITY</span> | |blackBoxWarningBody=*When pregnancy is detected, discontinue Olmesartan as soon as possible. | ||
|blackBoxWarningBody= | |||
*When pregnancy is detected, discontinue Olmesartan as soon as possible. | |||
*Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. | *Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. | ||
|fdaLIADAdult=<H4>[[Hypertension]]</H4> | |fdaLIADAdult=<H4>[[Hypertension]]</H4> | ||
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|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Olmesartan in pediatric patients. | |offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Olmesartan in pediatric patients. | ||
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Olmesartan in pediatric patients. | |offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Olmesartan in pediatric patients. | ||
|contraindications=Do not co-administer [[aliskiren]] with Olmesartan in patients with [[diabetes] | |contraindications=Do not co-administer [[aliskiren]] with Olmesartan in patients with [[diabetes]]. | ||
|warnings====Fetal Toxicity=== | |warnings====Fetal Toxicity=== | ||
Revision as of 16:47, 6 April 2015
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2], Rabin Bista, M.B.B.S. [3]
Disclaimer
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Black Box Warning
|
WARNING: FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
*When pregnancy is detected, discontinue Olmesartan as soon as possible.
|
Overview
Olmesartan is an Angiotensin 2 Receptor Blocker that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension，dizziness，headache.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Hypertension
- Dosing information
- Dosage must be individualized.
- Recommended starting dosage: 20 mg PO qd‘’‘ when used as monotherapy in patients who are not volume-contracted.
- For patients requiring further reduction in blood pressure after 2 weeks of therapy
- Dosage: 40 mg PO qd. Doses above 40 mg do not appear to have greater effect.
- Twice-daily dosing offers no advantage over the same total dose given once daily.
- No initial dosage adjustment is recommended for elderly patients.
- For patients with moderate to marked renal impairment (creatinine clearance <40 mL/min) or with moderate to marked hepatic dysfunction.
- For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate Olmesartan under close medical supervision and give consideration to use of a lower starting dose.
- Olmesartan may be administered with or without food.
- If blood pressure is not controlled by Olmesartan alone, a diuretic may be added. Olmesartan may be administered with other antihypertensive agents.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Olmesartan in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Olmesartan in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Hypertension
- Dosing information
- Dosage must be individualized.
- For children who can swallow tablets
- For patients who weigh 20 to <35 kg (44 to 77 lb)
- Recommended starting dosage: 10 mg PO qd
- For patients who weigh ≥35 kg
- Recommended starting dosage: 20 mg PO qd .
- For patients requiring further reduction in blood pressure after 2 weeks of therapy
- For patients who weigh <35 kg
- Maximum dosage: 20 mg PO qd’‘’
- For patients who weigh ≥35 kg
- Maximum dosage: 40 mg PO qd’‘’
- Children <1 year of age must not receive Olmesartan for hypertension.
- For children who cannot swallow tablets, the same dose can be given using an extemporaneous suspension as described below. Follow the suspension preparation instructions below to administer Olmesartan as a suspension.
Preparation of Suspension (for 200 mL of a 2 mg/mL suspension)
- Add 50 mL of Purified Water to an amber polyethylene terephthalate (PET) bottle containing twenty Olmesartan 20 mg tablets and allow to stand for a minimum of 5 minutes. Shake the container for at least 1 minute and allow the suspension to stand for at least 1 minute. Repeat 1-minute shaking and 1-minute standing for four additional times. Add 100 mL of Ora-Sweet®* and 50 mL of Ora-Plus®* to the suspension and shake well for at least 1 minute. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 4 weeks. Shake the suspension well before each use and return promptly to the refrigerator.
- Ora-Sweet® and Ora-Plus® are registered trademarks of Paddock Laboratories, Inc.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Olmesartan in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Olmesartan in pediatric patients.
Contraindications
Do not co-administer aliskiren with Olmesartan in patients with diabetes.
Warnings
|
WARNING: FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
*When pregnancy is detected, discontinue Olmesartan as soon as possible.
|
Fetal Toxicity
Pregnancy Category D
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Olmesartan as soon as possible.
Morbidity in Infants
- Children <1 year of age must not receive Olmesartan for hypertension. Drugs that act directly on the renin-angiotensin aldosterone system (RAAS) can have effects on the development of immature kidneys.
Hypotension in Volume- or Salt-Depleted Patients
- In patients with an activated renin-angiotensin aldosterone system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with Olmesartan. Initiate treatment under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give 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.
Impaired Renal Function
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with Olmesartan. In patients whose renal function may depend upon the activity of the renin angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. Similar results may be anticipated in patients treated with Olmesartan.
- In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of Olmesartan in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.
Sprue-like Enteropathy
- Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of Olmesartan in cases where no other etiology is identified.
Adverse Reactions
Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Adult Hypertension
- Olmesartan has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 for at least 1 year. Treatment with Olmesartan was well tolerated, with an incidence of adverse reactions similar to placebo. Events generally were mild, transient and had no relationship to the dose of Olmesartan.
- The overall frequency of adverse reactions was not dose-related. Analysis of gender, age and race groups demonstrated no differences between Olmesartan and placebo-treated patients. The rate of withdrawals due to adverse reactions in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with Olmesartan and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse reaction that occurred in more than 1% of patients treated with Olmesartan and at a higher incidence versus placebo was dizziness (3% vs. 1%).
- The following adverse reactions occurred in placebo-controlled clinical trials at an incidence of more than 1% of patients treated with Olmesartan, but also occurred at about the same or greater incidence in patients receiving placebo: back pain, bronchitis, increased creatine phosphokinase , diarrhea, headache, hematuria, hyperglycemia, hypertriglyceridemia, influenza-like symptoms, pharyngitis, rhinitis and sinusitis.
- The incidence of cough was similar in placebo (0.7%) and Olmesartan (0.9%) patients.
- Other potentially important adverse reactions that have been reported with an incidence of greater than 0.5%, whether or not attributed to treatment, in the more than 3100 hypertensive patients treated with Olmesartan monotherapy in controlled or open-label trials are listed below.
Body as a Whole: chest pain, peripheral edema Central and Peripheral Nervous System: vertigo Gastrointestinal: abdominal pain, dyspepsia, gastroenteritis, nausea Heart Rate and Rhythm Disorders: tachycardia Metabolic and Nutritional Disorders: hypercholesterolemia, hyperlipemia, hyperuricemia Musculoskeletal: arthralgia, arthritis, myalgia Skin and Appendages: rash
- Facial edema was reported in five patients receiving Olmesartan. Angioedema has been reported with angiotensin II antagonists.
Laboratory Test Findings: In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Olmesartan. Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g/dL and 0.3 volume percent, respectively) were observed.
Liver Function Tests: Elevations of liver enzymes and/or serum bilirubin were observed infrequently. Five patients (0.1%) assigned to Olmesartan and one patient (0.2%) assigned to placebo in clinical trials were withdrawn because of abnormal liver chemistries (transaminases or total bilirubin). Of the five Olmesartan patients, three had elevated transaminases, which were attributed to alcohol use, and one had a single elevated bilirubin value, which normalized while treatment continued.
Pediatric Hypertension
- No relevant differences were identified between the adverse experience profile for pediatric patients aged 1 to16 years and that previously reported for adult patients.
Postmarketing Experience
The following adverse reactions have been reported in post-marketing experience. 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.
Body as a Whole: Asthenia, angioedema, anaphylactic reactions Gastrointestinal: Vomiting, sprue-like enteropathy Metabolic and Nutritional Disorders: Hyperkalemia Musculoskeletal: Rhabdomyolysis Urogenital System: Acute renal failure, increased blood creatinine levels Skin and Appendages: Alopecia, pruritus, urticaria
Drug Interactions
- No significant drug interactions were reported in studies in which Olmesartan was co-administered with digoxin or warfarin in healthy volunteers.
- The bioavailability of olmesartan was not significantly altered by the co-administration of antacids [Al(OH)3/Mg(OH)2].
- Olmesartan medoxomil is not metabolized by 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.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including olmesartan medoxomil, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving olmesartan medoxomil and NSAID therapy.
- The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil may be attenuated by NSAIDs including selective COX-2 inhibitors.
Dual Blockade of the Renin-Angiotensin System (RAS)
- Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Olmesartan and other agents that affect the RAS.
- Do not co-administer aliskiren with Olmesartan in patients with diabetes. Avoid use of aliskiren with Olmesartan in patients with renal impairment (GFR <60 ml/min).
Colesevelam hydrochloride
- Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan. Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose.
Use in Specific Populations
Pregnancy
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Olmesartan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramniosis observed, discontinue Olmesartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Olmesartan for hypotension, oliguria , and hyperkalemia .
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Olmesartan in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Olmesartan during labor and delivery.
Nursing Mothers
- It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
- Neonates with a history of in utero exposure to Olmesartan:
- If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
- The antihypertensive effects of Olmesartan were evaluated in one randomized, double-blind clinical study in pediatric patients 1 to 16 years of age. The pharmacokinetics of Olmesartan were evaluated in pediatric patients 1 to 16 years of age. Olmesartan was generally well tolerated in pediatric patients, and the adverse experience profile was similar to that described for adults.
- Olmesartan has not been shown to be effective for hypertensionin children <6 years of age.
- Children <1 year of age must not receive Olmesartan for hypertension . The renin-angiotensin aldosterone system (RAAS) plays a critical role in kidney development. RAAS blockade has been shown to lead to abnormal kidney development in very young mice. Administering drugs that act directly on the renin- angiotensin aldosterone system (RAAS) can alter normal renal development.
Geriatic Use
- Of the total number of hypertensive patients receiving Olmesartan in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. No overall differences in effectiveness or safety were observed between elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Gender
There is no FDA guidance on the use of Olmesartan with respect to specific gender populations.
Race
There is no FDA guidance on the use of Olmesartan with respect to specific racial populations.
Renal Impairment
- Patients with renal insufficiency have elevated serum concentrations of olmesartan compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min).
Hepatic Impairment
- Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%. No initial dosage adjustment is recommended for patients with moderate to marked hepatic dysfunction.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Olmesartan in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Olmesartan in patients who are immunocompromised.
Black patient
- The antihypertensive effect of Olmesartan was smaller in black patients (usually a low renin population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor blockers.
Administration and Monitoring
Administration
Oral
Monitoring
FDA Package Insert for Olmesartan contains no information regarding drug monitoring.
IV Compatibility
There is limited information about the IV Compatibility.
Overdosage
- Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If symptomatic hypotensionoccurs, initiate supportive treatment. The dialyzability of olmesartan is unknown.
Pharmacology
Mechanism of Action
There is limited information regarding Olmesartan Mechanism of Action in the drug label.
Structure
- Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist.
- Olmesartan medoxomil is described chemically as 2,3-dihydroxy-2-butenyl 4-(1 hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5 carboxylate, cyclic 2,3-carbonate.
- Its empirical formula is C29H30N6O6 and its structural formula is:
Pharmacodynamics
- Olmesartan doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of Olmesartan >40 mg giving >90% inhibition at 24 hours.
- Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of Olmesartan to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg Olmesartan had minimal influence on aldosterone levels and no effect on serum potassium.
Pharmacokinetics
Absorption
- Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract.
- Olmesartan tablets and the suspension formulation prepared from Olmesartan tablets are bioequivalent.
- The absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (Cmax) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan.
Distribution
- The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses.
- In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats.
Metabolism and Excretion
- Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile.
- Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing.
Geriatric
- The pharmacokinetics of olmesartan were studied in the elderly (≥65 years). Overall, maximum plasma concentrations of olmesartan were similar in young adults and the elderly. Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUCss, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CLR.
Pediatric
- The pharmacokinetics of olmesartan were studied in pediatric hypertensive patients aged 1 to16 years. The clearance of olmesartan in pediatric patients was similar to that in adult patients when adjusted by the body weight.
- Olmesartan pharmacokinetics have not been investigated in pediatric patients less than 1 year of age.
Gender
- Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men. AUC and Cmax were 10-15% higher in women than in men.
Hepatic Insufficiency
- Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%.
Renal Insufficiency
- In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). The pharmacokinetics of olmesartan in patients undergoing hemodialysis has not been studied.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Olmesartan medoxomil was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m2 basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan medoxomil.
- Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested).
- Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating.
Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
- No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose [MRHD] of olmesartan medoxomil 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 doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricula, 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 renal pelvis were observed at doses ≥8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.
Clinical Studies
Adult Hypertension
- The antihypertensive effects of Olmesartan have been demonstrated in seven placebo controlled studies at doses ranging from 2.5 mg to 80 mg for 6 to 12 weeks, each showing statistically significant reductions in peak and trough blood pressure. A total of 2693 patients (2145 Olmesartan; 548 placebo) with essential hypertensionwere studied. Olmesartan once daily lowered diastolic and systolic blood pressure. The response was dose-related, as shown in the following graph. A Olmesartan dose of 20 mg daily produces a trough sitting BP reduction over placebo of about 10/6 mmHg and a dose of 40 mg daily produces a trough sitting BP reduction over placebo of about 12/7 mmHg. Olmesartan doses greater than 40 mg had little additional effect. The onset of the antihypertensive effect occurred within 1 week and was largely manifest after 2 weeks.
- Data above are from seven placebo-controlled studies (2145 Olmesartan patients, 548 placebo patients). The blood pressure lowering effect was maintained throughout the 24-hour period with Olmesartan once daily, with trough-to-peak ratios for systolic and diastolic response between 60 and 80%.
- The blood pressure lowering effect of Olmesartan, with and without hydrochlorothiazide, was maintained in patients treated for up to 1 year. There was no evidence of tachyphylaxisduring long-term treatment with Olmesartan or rebound effect following abrupt withdrawal of olmesartan medoxomil after 1 year of treatment.
- The antihypertensive effect of Olmesartan was similar in men and women and in patients older and younger than 65 years. The effect was smaller in black patients (usually a low renin population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor blockers. Olmesartan had an additional blood pressure lowering effect when added to hydrochlorothiazide.
- There are no trials of Olmesartan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.
Pediatric Hypertension
- The antihypertensive effects of Olmesartan in the pediatric population were evaluated in a randomized, double-blind study involving 302 hypertensive patients aged 6 to 16 years. The study population consisted of an all black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks. The etiology of the hypertensionwas predominantly essential hypertension(87% of the black cohort and 67% of the mixed cohort). Patients who weighed 20 to <35 kg were randomized to 2.5 or 20 mg of Olmesartan once daily and patients who weighed ≥35 kg were randomized to 5 or 40 mg of Olmesartan once daily. At the end of 3 weeks, patients were re-randomized to continuing Olmesartan or to taking placebo for up to 2 weeks. During the initial dose-response phase, Olmesartan significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner. Overall, the two dose levels of Olmesartan (low and high) significantly reduced systolic blood pressure by 6.6 and 11.9 mmHg from the baseline, respectively. These reductions in systolic blood pressure included both drug and placebo effect. During the randomized withdrawal to placebo phase, mean systolic blood pressure at trough was 3.2 mmHg lower and mean diastolic blood pressure at trough was 2.8 mmHg lower in patients continuing Olmesartan than in patients withdrawn to placebo. These differences were statistically different. As observed in adult populations, the blood pressure reductions were smaller in black patients.
- In the same study, 59 patients aged 1 to 5 years who weighed ≥5 kg received 0.3 mg/kg of Olmesartan once daily for three weeks in an open label phase and then were randomized to receiving Olmesartan or placebo in a double-blind phase. At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mmHg lower in the group randomized to Olmesartan; this difference in blood pressure was not statistically significant (95% C.I. -2 to 7/-1 to 7).
How Supplied
- Olmesartan is supplied as yellow, round, film-coated, non-scored tablets containing 5 mg of olmesartan medoxomil, as white, round, film-coated, non-scored tablets containing 20 mg of olmesartan medoxomil, and as white, oval-shaped, film-coated, non-scored tablets containing 40 mg of olmesartan medoxomil. Tablets are debossed with Sankyo on one side and C12, C14, or C15 on the other side of the 5, 20, and 40 mg tablets, respectively.
Tablets are supplied as follows:
Storage
- Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature].
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Olmesartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
Precautions with Alcohol
Of the five Olmesartan patients, three had elevated transaminases, which were attributed to alcohol use, and one had a single elevated bilirubin value, which normalized while treatment continued.
Brand Names
- Benicar ®[1]
Look-Alike Drug Names
Olmesartan - Mevacor[2]
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
- ↑ "BENICAR- olmesartan medoxomil tablet".
- ↑ "https://www.ismp.org". External link in
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{{#subobject:
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