Olmesartan Medoxomil 5 Mg Oral Tablet

For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate olmesartan medoxomil under close medical supervision and give consideration to use of a lower starting dose [see Warnings and Precautions (5.3)].

Use of olmesartan medoxomil tablets in children <1 year of age is not recommended [see Warnings and Precautions ( 5.2) and Use in Specific Populations (8.4)].

For children who cannot swallow tablets, the same dose can be given using an extemporaneous suspension as described below [see Clinical Pharmacology (12.3)].

Follow the suspension preparation instructions below to administer olmesartan medoxomil 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 medoxomil 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.

Olmesartan medoxomil can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system (RAS) 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 medoxomil as soon as possible [see Use in specific Populations (8.1)].

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 medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.

Adult Hypertension

Olmesartan medoxomil 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.

Events generally were mild, transient and had no relationship to the dose of olmesartan medoxomil.

Analysis of gender, age and race groups demonstrated no differences between olmesartan medoxomil 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 medoxomil 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 medoxomil and at a higher incidence versus placebo was dizziness (3% vs. 1%).

Facial edema was reported in five patients receiving olmesartan medoxomil. Angioedema has been reported with angiotensin II antagonists.

Pediatric Hypertension

No relevant differences were identified between the adverse experience profile for pediatric patients aged 1 to 16 years and that previously reported for adult patients.

Body as a Whole: Asthenia, angioedema, anaphylactic reactions

Gastrointestinal: Vomiting, sprue-like enteropathy [see Warnings and Precautions(5.5)]

Metabolic and Nutritional Disorders: Hyperkalemia

Musculoskeletal: Rhabdomyolysis

Urogenital System: Acute renal failure, increased blood creatinine levels

Skin and Appendages: Alopecia, pruritus, urticaria

Data from one controlled trial and an epidemiologic study have suggested that high-dose  olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive. The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo in patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease. The trial met its primary endpoint, delayed onset of microalbuminuria, but olmesartan had no beneficial effect on decline in glomerular filtration rate (GFR). There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization death) in the olmesartan group compared to the placebo group (15 olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18).

The epidemiologic study included patients 65 years and older with overall exposure of > 300,000 patient-years. In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of death (HR 2.0, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin receptor blockers. In contrast, high-dose olmesartan use in non-diabetic patients appeared to be associated with a decreased risk of death (HR 0.46, 95% CI 0.24, 0.86) compared to similar patients taking other angiotensin receptor blockers. No differences were observed between the groups receiving lower doses of olmesartan compared to other angiotensin blockers or those receiving therapy for < 6 months.

Overall, these data raise a concern of a possible increased CV risk associated with the use of high-dose olmesartan in diabetic patients. There are, however, concerns with the credibility of the finding of increased CV risk, notably the observation in the large epidemiologic study for a survival benefit in non-diabetics of a magnitude similar to the adverse finding in diabetics.

The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil may be attenuated by NSAIDs including selective COX-2 inhibitors.

Do not co-administer aliskiren with olmesartan medoxomil in patients with diabetes [see Contraindications (4)]. Avoid use of aliskiren with olmesartan medoxomil in patients with renal impairment (GFR <60 ml/min).

concomitant administration of lithium with angiotensin II receptor antagonists, including

olmesartan medoxomil. Monitor serum lithium levels during concomitant use.

Olmesartan medoxomil can cause fetal harm when administered to a pregnant woman. 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. 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. In animal reproduction studies, olmesartan medoxomil treatment during organogenesis resulted in increased embryofetal toxicity in rats at doses lower than maternally toxic doses.

When pregnancy is detected, discontinue olmesartan medoxomil as soon as possible. Consider alternative antihypertensive therapy during pregnancy.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions

Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death. In patients taking olmesartan medoxomil during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. 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 medoxomil for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to olmesartan medoxomil, if oliguria or hypotension occurs, utilize measures to maintain adequate blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and supporting renal function.

Data

Animal Data

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) on a mg/m²basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m²basis; 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.

There is no information regarding the presence of olmesartan in human milk, the effects on the breastfed infant, or the effects on milk production. Olmesartan is secreted at low concentration in the milk of lactating rats (see Data). 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.

Data Presence of olmesartan in milk was observed after a single oral administration of 5 mg/kg [¹⁴C] olmesartan medoxomil to lactating rats.

Olmesartan medoxomil has not been shown to be effective for hypertension in children <6 years of age.

Use of olmesartan medoxomil tablets in children <1 year of age is not recommended. [see Warnings and Precautions (5.2)]. 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.

receptor blockers.

An AT₂ receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT₁ receptor than for the AT₂ receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan medoxomil does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.

Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of olmesartan medoxomil to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels and no effect on serum potassium.

Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract.

Olmesartan medoxomil tablets and the suspension formulation prepared from olmesartan medoxomil tablets are bioequivalent [see Dosage and Administration (2.2)].

The absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (C_max) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan. Olmesartan medoxomil tablets may be administered with or without food.

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.

Specific Populations

Geriatric Patients

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; AUC_ss, _τ  was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CL_R [see Dosage and Administration (2.1) and Use in Specific Populations (8.5)].

Pediatric Patients

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 [see Use in Specific Populations (8.4)].

Olmesartan pharmacokinetics have not been investigated in pediatric patients less than 1 year of age [see Warnings and Precautions (5.2) and Use in Specific Populations (8.4)].

Male and Female Patients

Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men. AUC and C_max were 10-15% higher in women than in men.

Patient with Hepatic Impairment

Increases in AUC_0-∞ and C_max were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60% [see Dosage and Administration (2.1) and Use in Specific Populations (8.6)].

Patient with Renal Impairment 

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 [see Dosage and Administration (2.1), Warnings and Precautions (5.4) and Use in Specific Populations (8.7)].

Drug Interaction Studies

Bile Acid Sequestering Agent Colesevelam

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in C_max and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in C_max and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride [see Drug Interactions (7.5)].

Other Studies

No significant drug interactions were reported in studies in which olmesartan medoxomil 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.

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.

Olmesartan medoxomil tablets Dose Response Placebo-Adjusted Reduction in Blood Pressure (mmHg)

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 medoxomil 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 medoxomil tablets once daily for three weeks in an open label phase and then were randomized to receiving olmesartan medoxomil tablets 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 medoxomil; this difference in blood pressure was not statistically significant (95% C.I. -2 to 7/-1 to 7).