Amlodipine and Olmesartan Medoxomil

• FETAL TOXICITY When pregnancy is detected, discontinue amlodipine and olmesartan medoxomil tablets as soon as possible ( 5.1 , 8.1 ).
• Drugs that act directly on the renin-angiotensin system (RAS) can cause injury and death to the developing fetus ( 5.1 , 8.1 ).
• WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning.
• When pregnancy is detected, discontinue amlodipine and olmesartan medoxomil tablets 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 amlodipine and olmesartan medoxomil tablets in patients with diabetes [ See Drug Interactions (7.2) ]. Do not co-administer aliskiren with amlodipine and olmesartan medoxomil tablets in patients with diabetes (4) .

• Anticipate hypotension in volume-or salt-depleted patients with treatment initiation.
• Start treatment under close supervision ( 5.2 ).
• Increased angina or myocardial infarction may occur upon dosage initiation or increase ( 5.3 ).
• Impaired renal function: changes in renal function may occur ( 5.4 ).
• Sprue-like enteropathy has been reported.
• Consider discontinuation of amlodipine and olmesartan medoxomil tablets in cases where no other etiology is found ( 5.6 ).
• 5.1 Fetal Toxicity Amlodipine and olmesartan medoxomil tablets can cause fetal harm when administered to a pregnant woman.
• 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 amlodipine and olmesartan medoxomil tablets as soon as possible [see Use in Specific Populations (8.1) ] .
• 5.2 Hypotension in Volume- or Salt-Depleted Patients Olmesartan medoxomil.
• In 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) symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil.
• Initiate treatment with amlodipine and olmesartan medoxomil tablets 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.
• Amlodipine.
• Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis.Because of the gradual onset of action, acute hypotension is unlikely.
• 5.3 Increased Angina or Myocardial Infarction Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase.
• The mechanism of this effect has not been elucidated.
• 5.4 Impaired Renal Function Changes in renal function may be anticipated in susceptible individuals treated with 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 congestive heart failure), treatment with angiotensin converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death.
• Similar effects may occur in patients treated with amlodipine and olmesartan medoxomil tablets because of the olmesartan medoxomil component[ see Drug Interactions (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 effects would be expected with olmesartan medoxomil and amlodipine and olmesartan medoxomil tablets.
• 5.5 Patients with Hepatic Impairment Patients with hepatic impairment have decreased clearance of amlodipine.
• Starting amlodipine or adding amlodipine at 2.5 mg in hepatically impaired patients is recommended.
• The lowest dose of amlodipine and olmesartan medoxomil tablets is 5/20 mg; therefore, initial therapy with amlodipine and olmesartan medoxomil tablets is not recommended in hepatically impaired patients [see Use in Specific Populations (8.6) ].
• Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2 ) is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment.
• 5.6 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 amlodipine and olmesartan medoxomil tablets in cases where no other etiology is identified.
• 5.7 Electrolyte Imbalances Amlodipine and olmesartan medoxomil tablets contain olmesartan, a drug that inhibits the renin-angiotensin system (RAS).
• Drugs that inhibit the RAS can cause hyperkalemia.Monitor serum electrolytes periodically.

• Risk Summary Amlodipine and olmesartan medoxomil tablets 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 [see Clinical Considerations] .
• 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.
• When pregnancy is detected, discontinue amlodipine and olmesartan medoxomil tablets 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 Olmesartan medoxomil 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.
• 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 for hypotension, oliguria, and hyperkalemia.
• In neonates with a history of in utero exposure to olmesartan, if oliguria or hypotension occur, 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 [see Use in Specific Populations (8.4) ] .
• Data Animal Data No reproductive studies have been conducted with the combination of olmesartan medoxomil, and amlodipine.
• However, these studies have been conducted for olmesartan medoxomil and amlodipine alone.
• Olmesartan medoxomil 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/m 2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m 2 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 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 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.
• Amlodipine No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits 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/m 2 basis) during their respective periods of major organogenesis (Calculations based on a patient weight of 60 kg).
• However, litter size was significantly decreased (by about 50%), and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation.
• Amlodipine maleate has been shown to prolong both the gestational period and the duration of labor in rats at this dose.
• IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended ( 8.2 ).
• Geriatric:
• Not recommended for initial therapy in patients ≥75 years old ( 8.5 ) Hepatic Impairment:
• Not recommended for initial therapy ( 8.6 )
• 8.1 Pregnancy Risk Summary Amlodipine and olmesartan medoxomil tablets 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 [see Clinical Considerations] .
• 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.
• When pregnancy is detected, discontinue amlodipine and olmesartan medoxomil tablets 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 Olmesartan medoxomil 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.
• 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 for hypotension, oliguria, and hyperkalemia.
• In neonates with a history of in utero exposure to olmesartan, if oliguria or hypotension occur, 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 [see Use in Specific Populations (8.4) ] .
• Data Animal Data No reproductive studies have been conducted with the combination of olmesartan medoxomil, and amlodipine.
• However, these studies have been conducted for olmesartan medoxomil and amlodipine alone.
• Olmesartan medoxomil 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/m 2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m 2 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 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 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.
• Amlodipine No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits 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/m 2 basis) during their respective periods of major organogenesis (Calculations based on a patient weight of 60 kg).
• However, litter size was significantly decreased (by about 50%), and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation.
• Amlodipine maleate has been shown to prolong both the gestational period and the duration of labor in rats at this dose.
• 8.2 Lactation Risk Summary There is limited information regarding the presence of amlodipine and olmesartan medoxomil tablets in human milk, the effects on the breastfed infant, or the effects on milk production.
• Amlodipine is present in human milk.
• Olmesartan is present in rat milk [see Data] .
• Because of the potential for adverse effects on the nursing infant, advise a nursing woman that breastfeeding is not recommended during treatment with amlodipine and olmesartan medoxomil tablets.
• Data Presence of olmesartan in milk was observed after a single oral administration of 5 mg/kg [ 14 C] olmesartan medoxomil to lactating rats.
• 8.4 Pediatric Use The safety and effectiveness of amlodipine and olmesartan medoxomil tablets in pediatric patients have not been established.
• 8.5 Geriatric Use Of the total number of subjects in the double-blind clinical study of amlodipine and olmesartan medoxomil tablets, 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.
• Elderly patients have decreased clearance of amlodipine.
• Starting amlodipine or adding amlodipine at 2.5 mg in patients ≥ 75 years old is recommended.
• The lowest dose of amlodipine and olmesartan medoxomil tablets is 5/20 mg; therefore, initial therapy with amlodipine and olmesartan medoxomil tablets is not recommended in patients ≥ 75 years old.
• Amlodipine.
• Reported clinical experience has not identified differences in responses between the elderly and younger patients.
• In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
• 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.
• Olmesartan medoxomil.
• 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.
• 8.6 Hepatic Impairment There are no studies of amlodipine and olmesartan medoxomil tablets in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with hepatic impairment.
• The recommended initial dose of amlodipine in patients with severe hepatic impairment is 2.5 mg, a dose not available with amlodipine and olmesartan medoxomil tablets.
• Amlodipine.
• Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½ ) is 56 hours in patients with severely impaired hepatic function [see Warnings and Precautions (5.5) ] .
• Olmesartan medoxomil .
• Increases in AUC 0-∞ and peak plasma concentration (C max ) for olmesartan were observed with moderate hepatic impairment compared to those in matched controls with an increase in AUC of about 60%.
• 8.7 Renal Impairment There are no studies of amlodipine and olmesartan medoxomil tablets in patients with renal impairment.
• Amlodipine.
• The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.
• Patients with renal failure may therefore receive the usual initial dose.
• Olmesartan medoxomil.
• Patients with renal insufficiency have elevated serum concentrations of olmesartan compared with patients with normal renal function.
• After repeated dosing, 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).
• 8.8 Black Patients Of the total number of subjects in the double-blind clinical study of amlodipine and olmesartan medoxomil tablets, 25% (481/1940) were black patients.
• Amlodipine and olmesartan medoxomil tablets were 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.

• Amlodipine ( 7.1 ):
• If simvastatin is co-administered with amlodipine,
• do not exceed 20 mg daily of simvastatin.
• Increased exposure of cyclosporine and tacrolimus.
• Increased exposure of amlodipine when coadministered with CYP3A inhibitors.
• Olmesartan medoxomil ( 7.2 ):
• Nonsteroidal anti-inflammatory drugs (NSAIDS) may lead to increased risk of renal impairment and loss of antihypertensive effect.
• Dual inhibition of the renin-angiotensin system:
• Increased risk of renal impairment, hypotension, and hyperkalemia.
• Colesevelam hydrochloride:
• Consider administering olmesartan at least 4 hours before colesevelam hydrochloride dose.
• Lithium: Increases in serum lithium concentrations and lithium toxicity.
• 7.1 Drug Interactions with Amlodipine Simvastatin:
• Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin.
• Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology (12.3) ].
• Immunosuppressants:
• Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered.
• Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology (12.3) ].
• CYP3A Inhibitors :
• Co-administration of amlodipine with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction.
• Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment.
• CYP3A Inducers:
• No information is available on the quantitative effects of CYP3A inducers on amlodipine.
• Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.
• 7.2 Drug Interactions with Olmesartan Medoxomil 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.
• 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 amlodipine and olmesartan medoxomil tablets and other agents that affect the RAS.
• Do not co-administer aliskiren with amlodipine and olmesartan medoxomil tablets in patients with diabetes [ see Contraindications (4) ].
• Avoid use of aliskiren with amlodipine and olmesartan medoxomil tablets in patients with renal impairment (GFR <60 ml/min).
• Use with 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) ] .
• Lithium:
• Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including amlodipine and olmesartan medoxomil tablets.
• Monitor serum lithium levels during concomitant use.

• There is no information on overdosage with amlodipine and olmesartan medoxomil tablets in humans.
• Amlodipine.
• Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths.
• Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m 2 basis) caused a marked peripheral vasodilation and hypotension.
• Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia.
• In humans, experience with intentional overdosage of amlodipine is limited.
• If massive overdose should occur, active cardiac and respiratory monitoring should be instituted.
• Frequent blood pressure measurements are essential.
• Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated.
• If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output.
• Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade.
• As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
• Olmesartan medoxomil.
• 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 should occur, supportive treatment should be initiated.
• The dialyzability of olmesartan is unknown.