Amlodipine And Olmesartan Medoxomil

• When pregnancy is detected, discontinue amlodipine and olmesartan medoxomil as soon as possible 

  5.1 Fetal Toxicity

  Amlodipine and 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. 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 as soon as possible

  [see Use in Specific Populations (8.1)].

   

  8.1 Pregnancy

  Risk Summary

  Amlodipine and 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

  [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 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/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 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/m²basis) 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.

  .
• Drugs that act directly on the renin-angiotensin system (RAS) can cause injury and death to the developing fetus 

  5.1 Fetal Toxicity

  Amlodipine and 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. 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 as soon as possible

  [see Use in Specific Populations (8.1)].

   

  8.1 Pregnancy

  Risk Summary

  Amlodipine and 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

  [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 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/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 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/m²basis) 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.

  .

Amlodipine and olmesartan medoxomil tablets are indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with amlodipine and olmesartan medoxomil tablets.



Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).



Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.



Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.



Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.



Amlodipine and olmesartan medoxomil tablets may also be used as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals.



Patients with moderate or severe hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk.



Data from an 8-week, placebo-controlled, parallel-group factorial study

The figures above provide an approximation of the likelihood of reaching a targeted blood pressure goal (e.g., Week 8 SBP <140 mmHg or <130 mmHg or a DBP <90 mmHg or <80 mmHg) for the high-dose treatment groups evaluated in the study. Amlodipine and olmesartan medoxomil tablets 5 mg/20 mg, the lowest dose combination treatment group, increases the probability of reaching blood pressure goal compared with the highest dose monotherapies, amlodipine 10 mg and olmesartan medoxomil 40 mg.



For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 48% likelihood of achieving a goal of <140 mmHg (systolic) and a 51% likelihood of achieving a goal of <90 mmHg (diastolic) on monotherapy with olmesartan medoxomil 40 mg, and about a 46% likelihood of achieving a goal of <140 mmHg (systolic) and a 60% likelihood of achieving a goal of <90 mmHg (diastolic) on monotherapy with amlodipine 10 mg. The likelihood of achieving these same goals increases to 63% (systolic) and 71% (diastolic) on amlodipine and olmesartan medoxomil tablets 5 mg/20 mg, and to 68% (systolic) and 85% (diastolic) on amlodipine and olmesartan medoxomil tablets 10 mg/40 mg.

The usual starting dose of amlodipine and olmesartan medoxomil tablets is 5 mg/20 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum dose of one 10 mg/40 mg tablet once daily as needed to control blood pressure

Amlodipine and olmesartan medoxomil tablets USP are formulated for oral administration in the following strength combinations:

•  Lactation: Breastfeeding is not recommended (
  8.2 Lactation

  Risk Summary

  
  
  

  There is limited information regarding the presence of amlodipine and olmesartan medoxomil 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.

  
  
  

  Data

  
  
  

  Presence of olmesartan in milk was observed after a single oral administration of 5 mg/kg [¹⁴C] olmesartan medoxomil to lactating rats.
  ).
• Geriatric: Not recommended for initial therapy in patients ≥75 years old (
  8.5 Geriatric Use

  Of the total number of subjects in the double-blind clinical study of amlodipine and olmesartan medoxomil, 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 is 5/20 mg; therefore, initial therapy with amlodipine and olmesartan medoxomil 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.
  ).
• Hepatic Impairment: Not recommended for initial therapy (
  8.6 Hepatic Impairment

  There are no studies of amlodipine and olmesartan medoxomil 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.

  
  
  

  Amlodipine.

  Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) 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%.
  ).