Olmesartan Medoxomil

FETAL TOXICITY When pregnancy is detected, discontinue olmesartan medoxomil as soon as possible (5.1, 8.1). Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1, 8.1).

Do not co-administer aliskiren with olmesartan medoxomil tablets in patients with diabetes [see DRUG INTERACTIONS (7.3)].

• 5.1 Fetal Toxicity 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)].
• 5.2 Morbidity in Infants Use of olmesartan medoxomil in children <1 year of age is not recommended.
• Drugs that act directly on the renin-angiotensin-aldosterone system (RAAS) can have effects on the development of immature kidneys [see USE IN SPECIFIC POPULATIONS (8.4)].
• 5.3 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 medoxomil.
• Initiate treatment under close medical supervision and consider starting at a lower dose.
• If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline [see DOSAGE AND ADMINISTRATION (2.1)].
• A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
• 5.4 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 medoxomil.
• 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 medoxomil [see DOSAGE AND ADMINISTRATION (2.1), DRUG INTERACTIONS (7.3), USE IN SPECIFIC POPULATIONS (8.7) and CLINICAL PHARMACOLOGY (12.3)].
• 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.
• 5.5 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 alternative antihypertensive therapy in cases where no other etiology is identified.
• 5.6 Hyperkalemia Serum potassium should be monitored in patients receiving olmesartan medoxomil.
• Drugs that inhibit the renin angiotensin system can cause hyperkalemia.
• Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes [see DRUG INTERACTIONS (7.3)].

• Risk Summary 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% to 4% and 15% to 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/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.
• 8.2 Lactation Risk Summary 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.
• 8.4 Pediatric Use The antihypertensive effects of olmesartan medoxomil were evaluated in one randomized, double-blind clinical study in pediatric patients 1 to 16 years of age [see CLINICAL STUDIES (14.2)].
• The pharmacokinetics of olmesartan medoxomil were evaluated in pediatric patients 1 to 16 years of age [see CLINICAL PHARMACOLOGY (12.3)].
• Olmesartan medoxomil was generally well tolerated in pediatric patients, and the adverse experience profile was similar to that described for
• adults.
• Olmesartan medoxomil has not been shown to be effective for hypertension in children <6 years of age.
• Use of olmesartan medoxomil 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.
• 8.5 Geriatric Use Of the total number of hypertensive patients receiving olmesartan medoxomil 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 [see CLINICAL PHARMACOLOGY (12.3)].
• 8.6 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 [see CLINICAL PHARMACOLOGY (12.3)].
• 8.7 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) [see DOSAGE AND ADMINISTRATION (2.1), WARNINGS AND PRECAUTIONS (5.4) and CLINICAL PHARMACOLOGY (12.3)].
• 8.8 Black Patients The antihypertensive effect of olmesartan medoxomil was smaller in black patients (usually a low-renin population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor blockers.

• 7.1 Agents Increasing Serum Potassium Concomitant use of olmesartan with other agents that block the renin-angiotensin system, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium.
• If co-medication is considered necessary, monitoring of serum potassium is advisable.
• 7.2 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.
• 7.3 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.
• Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy.
• In general, avoid combined use of RAS inhibitors.
• Closely monitor blood pressure, renal function and electrolytes in patients on olmesartan medoxomil and other agents that affect the RAS.
• 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).
• 7.4 Lithium Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including olmesartan medoxomil.
• Monitor serum lithium levels during concomitant use.
• 7.5 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 [see CLINICAL PHARMACOLOGY (12.3)].

• 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 hypotension occurs, initiate supportive treatment.
• The dialyzability of olmesartan is unknown.