Olmesartan (Systemic)


VA CLASSIFICATION
Primary: CV805

Commonly used brand name(s): Benicar.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antihypertensive—

Indications

Accepted

Hypertension (treatment)—Olmesartan is indicated for treatment of hypertension and may be used alone or in combination with other antihypertensive agents.{01}
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Olmesartan medoxomil: 558.59 {01}

Solubility
    Olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol.{01}

Mechanism of action/Effect:

Antihypertensive—Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan's action is independent of the pathways for angiotensin II synthesis. An AT2 receptor is also found 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 AT 1 rather than the AT2 receptor. 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.{01}


Other actions/effects:

In addition to to inhibiting the biosynthesis of angiotensin II from angiotensin I, ACE inhibitors also inhibit the degradation of of bradykinin, a reaction also catalyzed by ACE. Because olmesartan does not inhibit ACE (kininase II), it does not affect the response of bradykinin. It is unknown whether this difference has clinical relevance.{01}

Absorption:

Absolute bioavailability of olmesartan from the administered prodrug, olmesartan medoxomil, is approximately 26%. Food does not affect the bioavailability of olmesartan.{01}

Distribution:

Volume of distribution (Vol D)—approximately 17 liters{01}

Protein binding:

Very high (99%) to plasma proteins and does not penetrate red blood cells{01}

The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses.{01}

Biotransformation:

Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. There is virtually no further metabolism of olmesartan.{01}

Elimination

Approximately 13 hours{01}

Time to peak plasma concentration

1 to 2 hours{01}

Steady state concentration

Olmesartan shows linear pharmacokinetics with steady-state levels being achieved within 3 to 5 days and no accumulation in plasma occurring following once-daily dosing. {01}

Elimination:
    Total plasma clearance—1.3 L/hour{01}
    Renal clearance—0.6 L/hour{01}
    Renal—Approximately 35 to 50%{01}
    Fecal (biliary)—Approximately 50 to 65%{01}
    In dialysis—The pharmacokinetics of olmesartan in patients undergoing hemodialysis has not been studied.{01}

Pharmacodynamics

Olmesartan medoxomil doses of 2.5 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 medoxomil >40 mg giving >90% inhibition at 24 hours.{01}

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.{01}


Precautions to Consider

Carcinogenicity

Olmesartan was not carcinogenic when administered by dietary administration to rats for up to 2 years. Additionally, 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, revealed no evidence of a carcinogenic effect of olmesartan.{01}

Mutagenicity

Olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames test for bacterial mutagenicity. However, olmesartan was shown to induce chromosomal aberrations in cultured cells in vitro. It also tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. At oral doses of up to 2000 mg per kg of body weight, olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney, for DNA damage in the rat kidney (comet assay) and for clastogenicity in mouse bone marrow (micronucleus test).{01}

Pregnancy/Reproduction
Fertility—
Fertility of rats was unaffected by the administration of olmesartan medoxomil at high dose levels of 1000 mg per kg of body weight per day (240 times the maximum recommended human dose) when the starting dose was given 2 weeks (female) or 9 weeks (male) prior to mating.{01}

Pregnancy—
When pregnancy is detected, olmesartan should be discontinued as soon as possible. On rare occasions (less often than once in every thousand pregnancies), no alternative therapy can be found. In these cases, the patient should be apprised of the potential hazards and serial ultrasound examinations should be performed to assess the intra-amniotic environment.{01}

Because olmesartan acts directly on the renin-angiotensin system, it can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature of patients who were taking angiotensin converting enzyme (ACE) inhibitors.{01}

Fetal exposure to drugs that act directly on the renin-angiotensin system during the second and third trimesters has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, possibly resulting from decreased fetal function, and may cause fetal limb contractures, craniofacial deformation and hypoplastic lung development. If oligohydramnios is observed, olmesartan should be discontinued unless it is considered life-saving for the mother. Oligohydramnios may not appear until after the fetus has sustained irreversible damage. In addition, prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. When limited to the first trimester, exposure to olmesartan does not appear to be associated with these adverse effects. However, mothers who were exposed to this drug during the first trimester should be informed.{01}

Infants exposed in utero to angiotensin II receptor antagonists should be observed closely for hypotension, oliguria, and hyperkalemia. Oliguria should be treated with support of blood pressure and renal perfusion. Dialysis or exchange transfusion may be necessary to reverse hypotension and/or substitute for disordered renal function.{01}

No clinical experience with the use of olmesartan in pregnant women is available. When olmesartan was administered orally at high doses to pregnant rats or pregnant rabbits, no teratogenic effects were observed. However, in rats, significant decreases in pup birth weight and weight gain were observed at doses ³1.6 mg per kg of body weight per day, and delays in developmental milestones and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ³8 mg per kg of body weight per day. The no observed effect dose for developmental toxicity in rats is 0.3 mg per kg of body weight per day, about one-tenth the maximum recommended human dose (MRHD) of 40 mg per day.{01}

FDA Pregnancy Category C (first trimester){01}

FDA Pregnancy Category D (second and third trimesters){01}

Breast-feeding

It is not known whether olmesartan is distributed into breast milk. However, olmesartan is distributed 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.{01}

Pediatrics

Safety and effectiveness in pediatric patients have not been established. The pharmacokinetics of olmesartan have not been studied in patients younger than 18 years of age. Infants exposed in utero to angiotensin II receptor antagonists should be observed closely for hypotension, oliguria, and hyperkalemia. Oliguria should be treated with support of blood pressure and renal perfusion. Dialysis or exchange transfusion may be necessary to reverse hypotension and/or substitute for disordered renal function. See Pregnancy section.{01}


Geriatrics


In pharmacokinetics studies of olmesartan in the patients 65 years of age and older, 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 was 33% higher in elderly patients and there was a reduction in renal clearance (CLR) of approximately 30%. No overall differences in safety or effectiveness were observed between elderly patients and younger patients. However, greater sensitivity in older patients cannot be ruled out.{01}


Pharmacogenetics

Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men with AUC and Cmax being 10 to 15% higher in women than in men. The antihypertensive effect of olmesartan was similar in men and women. However, black patients showed a smaller response to the antihypertensive effect of olmesartan, as has been seen with other ACE inhibitors, angiotensin receptor blockers and beta-blockers.{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Clinically significant medication interactions are not expected between olmesartan and digoxin, warfarin, antacids [Al(OH) 3/Mg(OH)2], or drugs that inhibit, induce, or are metabolized by cytochrome P450 enzymes. {01}


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Diuretics    (concurrent use with olmesartan may have additive hypotensive effects, especially in volume-depleted and/or salt-depleted patients {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Bilirubin, serum and
Liver enzymes    (may elevate serum bilirubin and liver enzymes {01})


Blood urea nitrogen (BUN) and
Creatinine, serum    (increases in BUN and serum creatinine, including creatinine phosphokinase, have been reported in patients with unilateral or bilateral renal artery stenosis who were treated with angiotensin-converting enzyme (ACE) inhibitors, there has been no long-term use of olmesartan and patients with this condition, but similar results may be expected {01})


Hematocrit and hemoglobin levels    (small decreases of 0.3 volume percent and 0.3 g per dL, respectively, were observed {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to olmesartan {01}
Risk-benefit should be considered when the following medical problems exist
» Congestive heart failure, severe    (treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria, azotemia, acute renal failure and/or death {01})


Hepatic impairment, moderate    (may increase Cmax of olmesartan; may increase AUC of olmesartan by about 60% {01})


Renal artery stenosis, unilateral or bilateral or
» Renal function impairment    (increases in serum creatinine or BUN concentrations in patients with renal artery stenosis who were treated with ACE inhibitors and similar results may be anticipated with olmesartan; may elevate serum concentrations of olmesartan with the AUC approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL per min); changes in renal function as a result of inhibiting the renin-angiotensin-aldosterone system have been associated with oliguria, progressive azotemia, acute renal failure and/or death in susceptible patients {01})


Salt depletion or
Volume depletion    (may increase the risk of symptomatic hypotension; close medical supervision recommended; lower starting dose consideration should be given {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure measurements    (periodic monitoring to individualize dose to the patient's response {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Bronchitis (cough producing mucus; difficulty breathing; shortness of breath; tightness in chest; wheezing)
    
hematuria (blood in urine)
    
upper respiratory tract infection (ear congestion; nasal congestion; chills; cough, fever, sneezing, or sore throat; body aches or pain; headache; loss of voice; runny nose; unusual tiredness or weakness; difficulty in breathing)

{01}Incidence rare
    
Hyperlipemia (large amount of fat in the blood)
    
hyperuricemia (joint pain, stiffness, or swelling; lower back, side, or stomach pain; swelling of feet or lower legs)
    
tachycardia (fast, pounding, or irregular heartbeat or pulse )
    
urinary tract infection (bladder pain; bloody or cloudy urine; difficult, burning, or painful urination; frequent urge to urinate; lower back or side pain)
{01}
Frequency unknown
    
Hypotension (blurred vision; confusion; dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly; sweating; unusual tiredness or weakness)
{01}


Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Back pain
    
diarrhea
    
dizziness
    
headache
    
hyperglycemia (abdominal pain; blurred vision; dry mouth; fatigue; flushed, dry skin; fruit-like breath odor; increased hunger; increased thirst; increased urination; nausea; sweating; troubled breathing; unexplained weight loss; vomiting)
    
hypertriglyceridemia
    
influenza-like symptoms (chills; cough; diarrhea; fever; general feeling of discomfort or illness; headache; joint pain; loss of appetite; muscle aches and pains; nausea; runny nose; shivering; sore throat; sweating; trouble sleeping; unusual tiredness or weakness; vomiting)
    
pharyngitis (body aches or pain; congestion; cough; dryness or soreness of throat; fever; hoarseness; runny nose; tender, swollen glands in neck; trouble in swallowing; voice changes)
    
rhinitis (stuffy nose; runny nose; sneezing)
    
sinusitis (pain or tenderness around eyes and cheekbones; fever; stuffy or runny nose; headache; cough; shortness of breath or troubled breathing; tightness of chest or wheezing)
{01}
Incidence rare
    
Abdominal pain (stomach pain)
    
arthralgia (pain in joints; muscle pain or stiffness; difficulty in moving), chest pain
    
arthritis (pain, swelling, or redness in joints; muscle pain or stiffness; difficulty in moving)
    
cough
    
dyspepsia ( acid or sour stomach; belching; heartburn; indigestion; stomach discomfort, upset, or pain)
    
facial edema ( swelling or puffiness of face)
    
fatigue (unusual tiredness or weakness)
    
gastroenteritis (abdominal or stomach pain; diarrhea; loss of appetite; nausea; weakness )
    
hypercholesterolemia
    
insomnia ( sleeplessness; trouble sleeping; unable to sleep)
    
myalgia (joint pain; swollen joints; muscle aching or cramping; muscle pains or stiffness; difficulty in moving)
    
nausea
    
pain
    
peripheral edema (bloating or swelling of face, arms, hands, lower legs, or feet; rapid weight gain; tingling of hands or feet; unusual weight gain or loss)
    
rash
    
skeletal pain
    
vertigo (dizziness or lightheadedness; feeling of constant movement of self or surroundings; sensation of spinning)
{01}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Bradycardia (chest pain or discomfort; lightheadedness; dizziness or fainting; shortness of breath; slow or irregular heartbeat; unusual tiredness)—could be encountered if parasympathetic (vagal) stimulation occurs
    
hypotension (blurred vision; confusion; dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly; sweating; unusual tiredness or weakness )
    
tachycardia (fast, pounding, or irregular heartbeat or pulse)
{01}

Treatment of overdose
There is no specific antidote to olmesartan. Treatment is generally symptomatic and supportive.


To enhance elimination:
The dialyzability of olmesartan is unknown. {01}

Dialysis is not expected to be effective because of the high degree of protein binding (99%). {01}



Monitoring:
Monitor blood pressure.



Supportive care:
Treatment should be symptomatic and supportive.

Correct symptomatic hypotension.

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Olmesartan (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Fetal exposure to drugs that act directly on the renin-angiotensin system during the second and third trimesters has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. When pregnancy is detected, olmesartan should be discontinued as soon as possible.





Breast-feeding—Because of the potential for adverse effects on the nursing infant, olmesartan is not recommended for nursing mothers.





Use in the elderly—Elderly patients may experience greater sensitivity to the effects of olmesartan.
Pharmacogenetics—The antihypertensive effect of olmesartan was similar in men and women. However, black patients showed a smaller response to the antihypertensive effect of olmesartan, as has been seen with other ACE inhibitors, angiotensin receptor blockers and beta-blockers.
Other medications, especially diuretics
Other medical problems, especially renal function impairment and severe congestive heart failure

Proper use of this medication

» Proper dosing
Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

Proper storage

Precautions while using this medication
» Notifying physician immediately if pregnancy is suspected because of possibility of fetal or neonatal injury and/or death

Regular visits to physician to check progress and monitor blood pressure

Not taking other medications without consulting the physician


Side/adverse effects
Signs of potential side effects, especially bronchitis, hematuria, upper respiratory tract infection, hyperlipemia, hyperuricemia, tachycardia, urinary tract infection, and hypotension


General Dosing Information
If blood pressure is not controlled by olmesartan alone, a diuretic may be added. Olmesartan may be administered with other antihypertensive agents.{01}

Diet/Nutrition
Olmesartan may be administered with or without food.{01}

For treatment of adverse effects
Treatment of symptomatic hypotension—placing patient in the supine position and, if necessary, administering an intravenous infusion of normal saline{01}


Oral Dosage Forms

OLMESARTAN MEDOXOMILTABLETS

Usual Adult Dose
Hypertension
Oral, initially 20 mg once daily, prescribed and monitored by a physician. For patients requiring a further reduction in blood pressure after two weeks of therapy, the dose may be increased to the maximum of 40 mg once daily. Twice-daily dosing offers no advantage over the same total dose given once daily{01}


Usual adult prescribing limits
40 mg{01}

Usual Pediatric Dose
Safety and efficacy have not been established.{01}

Usual Geriatric Dose
See Usual adult dose.

Usual geriatric prescribing limits
See Usual adult prescribing limits.

Strength(s) usually available
U.S.—


5 mg (Rx) [Benicar (hydroxypropylcellulose ) (lactose) (low-substituted hydroxypropylcellulose) (magnesium stearate) (microcrystalline cellulose) (talc ) (titanium dioxide) ( yellow iron oxide)]


20 mg (Rx) [Benicar (hydroxypropylcellulose ) (lactose) (low-substituted hydroxypropylcellulose) (magnesium stearate) (microcrystalline cellulose) (talc ) (titanium dioxide)]


40 mg (Rx) [Benicar (hydroxypropylcellulose ) (lactose) (low-substituted hydroxypropylcellulose) (magnesium stearate ) (microcrystalline cellulose) ( talc) (titanium dioxide)]
{01}
Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F){01}



Developed: 12/26/2002



References
  1. Product Information: Benicar™, olmesartan medoxomil. Sankyo Pharma, New York, New York (PI revised 04/2002) reviewed 08/2002
Hide
(web3)