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ANGIOTENSIN II ANTAGONISTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Angiotensin II receptor antagonists selectively bind and, therefore, block the AT(1) receptor subtype. This class of drug blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II on smooth muscle and the adrenal gland.

Specific Substances

    A) GENERAL TERMS
    1) Antagonists, Angiotensin II
    AZILSARTAN (synonym)
    1) TAK-536
    2) CAS 147403-03-0
    LOSARTAN (synonym)
    1) Cozaar(R)
    2) Hyzaar(R)
    3) Lorzaar(R)
    4) DuP 753
    5) MK 954
    6) MRK 717
    7) CAS 114798-26-4
    TASOSARTAN (synonym)
    1) ANA-756
    2) WAY-ANA-756
    VALSARTAN (synonym)
    1) Diovan(R)
    2) CGP-48933
    3) CAS 137862-53-4

    1.2.1) MOLECULAR FORMULA
    1) AZILSARTAN MEDOXOMIL: C30H23KN4O8
    2) CANDESARTAN CILEXETIL: C33H34N6O6
    3) EPROSARTAN MESYLATE: C23H24N2O4S.CH4O3S
    4) IRBESARTAN: C25H28N6O
    5) LOSARTAN POTASSIUM: C22H22CIKN6O
    6) OLMESARTAN MEDOXOMIL: C29H30N6O6
    7) SACUBITRIL/VALSARTAN: C48H55N6O8Na3 2.5 H20
    8) TELMISARTAN: C33H30N4O2
    9) VALSARTAN: C24H29N5O3

Available Forms Sources

    A) FORMS
    1) AZILSARTAN: 40 mg and 80 mg tablets (Prod Info EDARBI(R) oral tablets, 2011).
    2) CANDESARTAN CILEXETIL: 4 mg and 8 mg circular/biconvex-shaped non-film coated tablets (bottles of 30); 16 mg and 32 mg circular/biconvex- shaped non-film coated tablets (bottles of 30, 90, and 100) (Prod Info ATACAND(R) oral tablets, 2005).
    3) EPROSARTAN MESYLATE: film coated 400 mg oval tablets and 600 mg capsule-shaped tablets in bottles of 100 (Prod Info TEVETEN(R) oral tablets, 2005).
    4) IRBESARTAN: available in 75 mg (bottles of 30 and 90), 150 mg (bottles of 30, 90, 500, and unit dose blisters of 100), and 300 mg (bottles of 30, 90, and 500) strength tablets in the United States (Prod Info AVAPRO(R) oral tablets, 2005).
    5) LOSARTAN: 25 mg (bottles of 90, 100 and unit dose 100) film-coated tablets , 50 mg (bottles of 30, 90, 100 and unit dose 100), and 100 mg (bottles of 30 and 90, and unit dose packages of 100) film-coated tablets (Prod Info COZAAR(R) oral tablets, 2005).
    6) LOSARTAN/HYDROCHLOROTHIAZIDE: 50 mg losartan/12.5 mg hydrochlorothiazide (bottles of 30 and 90, and unit dose packages of 100) , 100 mg losartan/12.5 mg hydrochlorothiazide (bottles of 30 and 90, and unit dose packages of 100), and 100 mg losartan/25 mg hydrochlorothiazide (bottles of 30 and 90, and unit dose packages of 100) film-coated tablets (Prod Info HYZAAR(R) oral tablets, 2005).
    7) TELMISARTAN: available in 20 mg round tablets (packed in blister-sealed cartons of 28 tablets) and 40 and 80 mg oblong-shaped tablets (packed in blister-sealed cartons of 30 tablets) (Prod Info MICARDIS(R) oral tablets, 2005).
    8) VALSARTAN: 40 mg (bottles of 30 and unit dose packages of 100), 80 mg (bottles of 90 and unit dose packages of 100), 160 mg (bottles of 90 and unit dose packages of 100), and 320 mg (bottles of 90 and unit dose packages of 100) tablets (Prod Info DIOVAN(R) oral tablets, 2006).
    B) USES
    1) Angiotensin II receptor antagonists are indicated for the treatment of hypertension. These agents may be used alone or in combination with other antihypertensives.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Angiotensin II receptor blockers (ARB) are used for treatment of hypertension.
    B) EPIDEMIOLOGY: Exposures are common, but toxicity is rare and deaths have not been reported following single-substance exposures.
    C) PHARMACOLOGY: Angiotensin II is an endogenous peptide that binds to angiotensin receptors, causing vasoconstriction and stimulation of aldosterone release. Angiotensin receptor blockers are competitive antagonists at these receptors.
    D) TOXICOLOGY: Excessive antagonism of angiotensin receptors causes vasodilation and hypotension.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Common adverse effects include hypotension and dizziness. Angioedema has been reported rarely.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild hypotension and tachycardia, hypokalemia, asymptomatic hypoglycemia, muscle cramps and dizziness have been reported.
    2) SEVERE TOXICITY: Severe toxicity has not been observed with these agents.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Central nervous system effects include headache and dizziness, which have occurred in less than 4% of patients.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Occasional elevations of liver enzymes have occurred in patients treated with angiotensin II receptor antagonists (<0.1%). Infrequent cases of hepatic toxicity have been reported with therapeutic use of losartan.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Infrequent elevations of creatinine and BUN have occurred.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH THERAPEUTIC USE
    1) Hyperkalemia (greater than 20% increase in serum potassium) occurred during clinical trials with valsartan.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Decreases in hemoglobin, hematocrit, and, rarely, microcytic anemia have been reported. Rare reports of thrombocytopenia have been reported with valsartan therapy.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Angioedema has occurred rarely with these agents.
    0.2.18) PSYCHIATRIC
    A) WITH THERAPEUTIC USE
    1) Acute psychosis has been reported in one adult receiving losartan.
    0.2.20) REPRODUCTIVE
    A) Angiotensin II receptor antagonists are contraindicated during pregnancy and should be discontinued as soon as possible when pregnancy is determined. Fetal and neonatal morbidity and death have occurred from the use of ACE inhibitors, drugs that are similar to the ARBs that affect the renin angiotensin system, during any trimester of pregnancy with reports of spontaneous abortion, oligohydramnios, hypotension, neonatal skull hypoplasia, anuria, and newborn renal dysfunction. The occurrence of oligohydramnios is possibly due to decreased fetal renal function. Oligohydramnios was associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported; although, causality to drug therapy has not been established.
    B) CANDESARTAN, EPROSARTAN, IRBESARTAN, OLMESARTAN, and TELMISARTAN are classified as FDA pregnancy category C (first trimester) and D (second and third trimester). AZILSARTAN, LOSARTAN, and VALSARTAN are classified as FDA pregnancy category D (all trimesters).
    0.2.21) CARCINOGENICITY
    A) No evidence of increased carcinogenicity due to angiotensin II antagonists has been found.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes and glucose in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Administer IV fluids for hypotension.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Severe toxicity has not been reported following exposure to these agents. Provide the usual supportive treatment for any symptoms and consider co-ingestion of other medical conditions.
    C) DECONTAMINATION
    1) PREHOSPITAL: Not recommended.
    2) HOSPITAL: Decontamination is unlikely to be necessary as most ingestions remain asymptomatic. Consider activated charcoal after very large recent ingestion or if more toxic co-ingestants are a concern.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be required following overdose. Perform early orotracheal intubation in patients with signs of airway obstruction from angioedema.
    E) ANTIDOTE
    1) There is no antidote for poisoning from these agents.
    F) ENHANCED ELIMINATION
    1) These agents are highly protein bound; hemodialysis is unlikely to be of any benefit.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Healthy children and adults can be managed at home if overdose was inadvertent and no signs or symptoms are present.
    2) OBSERVATION CRITERIA: Any patients with deliberate overdose or more than mild symptoms should be sent to a health care facility for evaluation. Patients with significant cardiovascular disease, those on other cardiodepressant agents (eg beta blocker) and those who have ingested more than 4 pills or 320 mg valsartan should be referred to a healthcare facility.
    3) ADMISSION CRITERIA: Any patient with persistent hypotension should be admitted to the hospital.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in decision making whether or not admission is advisable, managing patients with severe toxicity, or in whom the diagnosis is not clear.
    H) PHARMACOKINETICS
    1) CANDESARTAN: Bioavailability 15%; onset 2 to 4 hours; duration 24 hours, protein binding 99%; volume of distribution 0.13 L/kg, metabolized in the intestinal wall; about one-third by renal excretion and the remaining two-thirds by fecal excretion, and half-life 9 hours.
    2) EPROSARTAN: Bioavailability 13%; protein binding 98%; hepatic metabolism 20%; fecal elimination 90% and half-life 6 hours.
    3) IRBESARTAN: Rapidly absorbed, bioavailability 60% to 80%; onset 2 hours; duration 24 hours; protein binding 90%; volume of distribution 53 to 93 L; hepatic metabolism 50% to 70%; elimination is 20% renal and 65% fecal and half-life 11 to 15 hours.
    4) LOSARTAN: Peak response 6 hours; duration 24 hours; bioavailability 25%; protein binding 99%; volume of distribution 34 L; little hepatic metabolism (14%); elimination is 13% to 35% renal and 50% to 60% biliary; and half-life 1.5 to 2 hours.
    5) TELMISARTAN: Onset 3 hours; duration 24 hours; bioavailability 42%; protein binding 99%; volume of distribution 500 L; eliminated unchanged by biliary excretion in feces; and half-life 24 hours.
    6) VALSARTAN: Onset 2 hours; duration 6 to 8 hours; bioavailability 25%; approximately 95% protein bound; volume of distribution 17 L; 90% biliary excretion into feces and half-life 6 to 9 hours.
    I) DIFFERENTIAL DIAGNOSIS
    1) Mild hypotension is caused by many exposures (eg, angiotensin inhibitors, vasodilators, beta blockers). More severe symptoms should prompt consideration of other diagnoses.

Range Of Toxicity

    A) TOXICITY: Severe toxicity has not been described following isolated overdose from these medications. An adult developed mild toxicity after ingesting 2240 mg valsartan. Azilsartan oral doses up to 320 mg once daily for 7 days were well tolerated in healthy adults during clinical trials.
    B) THERAPEUTIC DOSE: Varies with agent. AZILSARTAN: ADULT: 80 mg orally once daily. CANDESARTAN: ADULT: Total daily dose can range from 8 to 32 mg. EPROSARTAN: ADULT: 400 to 800 mg daily in single or divided doses. IRBESARTAN: ADULT: 150 to 300 mg once daily. LOSARTAN: ADULT: 25 to 100 mg orally daily. TELMISARTAN: ADULT: 20 to 80 mg orally daily. VALSARTAN: ADULT: 80 to 320 mg daily. PEDIATRIC: No dosing information available for these agents.

Clinical Effects

Summary Of Exposure

    A) USES: Angiotensin II receptor blockers (ARB) are used for treatment of hypertension.
    B) EPIDEMIOLOGY: Exposures are common, but toxicity is rare and deaths have not been reported following single-substance exposures.
    C) PHARMACOLOGY: Angiotensin II is an endogenous peptide that binds to angiotensin receptors, causing vasoconstriction and stimulation of aldosterone release. Angiotensin receptor blockers are competitive antagonists at these receptors.
    D) TOXICOLOGY: Excessive antagonism of angiotensin receptors causes vasodilation and hypotension.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Common adverse effects include hypotension and dizziness. Angioedema has been reported rarely.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild hypotension and tachycardia, hypokalemia, asymptomatic hypoglycemia, muscle cramps and dizziness have been reported.
    2) SEVERE TOXICITY: Severe toxicity has not been observed with these agents.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension, with systolic blood pressures below 100 mmHg, is anticipated as an extension of the desired pharmacological response with agents of this class and appears dose-related (Prod Info DIOVAN(R) oral tablets, 2006; Prod Info MICARDIS(R) oral tablets, 2005; Prod Info COZAAR(R) oral tablets, 2005).
    2) WITH POISONING/EXPOSURE
    a) Based on limited data, circulatory collapse, shock and decreased level of consciousness have been reported following overdose with valsartan (Prod Info DIOVAN(R) oral tablets, 2006).
    b) CASE REPORT: A 25-year-old woman developed mild hypotension (90/70) after ingesting an estimated 28 80 mg-valsartan tablets. Blood pressure returned to normal 2 days after ingestion (Kumbasar et al, 2004).
    c) According to a retrospective review of adult valsartan ingestions reported to Texas poison control centers from 2000 to 2005, hypotension occurred in 2 of 185 patients (1.1%) (Forrester, 2007).
    B) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) An increased heart rate is likely to occur during hypotensive episodes in an attempt to achieve cardiovascular homeostasis (Prod Info DIOVAN(R) oral tablets, 2006; Prod Info COZAAR(R) oral tablets, 2005).
    2) WITH POISONING/EXPOSURE
    a) Tachycardia is likely in overdose (Prod Info DIOVAN(R) oral tablets, 2006; Prod Info COZAAR(R) oral tablets, 2005).
    b) CASE REPORT: A 25-year-old woman developed mild tachycardia (118 beats/min) after ingesting 28 80-mg valsartan tablets (Kumbasar et al, 2004).
    c) According to a retrospective review of adult valsartan ingestions reported to Texas poison control centers from 2000 to 2005, tachycardia occurred in 3 of 185 patients (1.6%) (Forrester, 2007).
    C) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) There is a possibility of vagal stimulation (parasympathetic) causing a decrease in the heart rate in overdose (Prod Info DIOVAN(R) oral tablets, 2006; Prod Info COZAAR(R) oral tablets, 2005).
    b) According to a retrospective review of adult valsartan ingestions reported to Texas poison control centers from 2000 to 2005 (n=185), bradycardia occurred in 1 patient (Forrester, 2007).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Central nervous system effects include headache and dizziness, which have occurred in less than 4% of patients.
    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) LOSARTAN: Dizziness 3% (placebo 2%) occurred during clinical studies (Prod Info Cozaar(R), losartan, 1999).
    1) Dizziness and/or light-headedness appear dose dependent with symptoms resolving while supine (Doig et al, 1993a).
    b) VALSARTAN: Although the incidence of headache and dizziness were equivalent to that of controls, these effects were the most common reason for the discontinuation of therapy (Prod Info DIOVAN(R) oral tablets, 2006).
    2) WITH POISONING/EXPOSURE
    a) According to a retrospective review of adult valsartan ingestions reported to Texas poison control centers from 2000 to 2005, dizziness and drowsiness were reported in 5 of 185 patients (2.7%) (Forrester, 2007).
    B) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) According to a retrospective review of adult valsartan ingestions reported to Texas poison control centers from 2000 to 2005, headaches occurred in 3 of 185 patients (1.6%) (Forrester, 2007).
    C) PSYCHOMOTOR AGITATION
    1) WITH POISONING/EXPOSURE
    a) According to a retrospective review of adult valsartan ingestions reported to Texas poison control centers from 2000 to 2005 (n=185), agitation was reported in 1 patient (Forrester, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) According to a retrospective review of adult valsartan ingestions reported to Texas poison control centers from 2000 to 2005 (n=185), nausea and vomiting were each reported in 1 patient (Forrester, 2007).
    B) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) According to a retrospective review of adult valsartan ingestions reported to Texas poison control centers from 2000 to 2005, abdominal pain occurred in 2 of 185 patients (1.1%) (Forrester, 2007).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Occasional elevations of liver enzymes have occurred in patients treated with angiotensin II receptor antagonists (<0.1%). Infrequent cases of hepatic toxicity have been reported with therapeutic use of losartan.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) The incidence of elevated liver enzymes appears to be equivalent between losartan and valsartan, approximately less than 0.1% (Prod Info COZAAR(R) oral tablets, 2005; Prod Info DIOVAN(R) oral tablets, 2006).
    b) One out of 11 salt depleted healthy volunteers developed elevated aminotransferase levels within 24 hours of receiving 100 mg of losartan (Doig et al, 1993).
    B) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Reversible hepatotoxicity has been reported in an adult who developed jaundice, anorexia, weight loss, and elevated liver enzymes after taking losartan 50 mg/day for approximately one month (Bosch, 1997). Rechallenge four months later at a reduced dose of 25 mg/day resulted in similar clinical and laboratory evidence of hepatotoxicity.
    1) An elderly adult developed similar effects, but had inadvertently taken losartan 150 mg/day for 6 weeks instead of 50 mg/day (Andrade et al, 1998). Rechallenge was not conducted.

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Infrequent elevations of creatinine and BUN have occurred.
    3.10.2) CLINICAL EFFECTS
    A) RENAL FUNCTION TESTS ABNORMAL
    1) WITH THERAPEUTIC USE
    a) ANGIOTENSIN II ANTAGONISTS or ACE INHIBITORS: Based on their mechanism of action and previous studies with angiotensin converting enzyme inhibitors and angiotensin receptor antagonists the following effects have occurred or could be anticipated:
    1) Elevations in BUN and creatinine (reported in patients with renal artery stenosis) have occurred (Prod Info DIOVAN(R) oral tablets, 2006; Prod Info COZAAR(R) oral tablets, 2005).
    2) In patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe congestive heart failure), oliguria and/or progressive azotemia and rarely acute renal failure have occurred (Prod Info DIOVAN(R) oral tablets, 2006; Prod Info COZAAR(R) oral tablets, 2005).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Decreases in hemoglobin, hematocrit, and, rarely, microcytic anemia have been reported. Rare reports of thrombocytopenia have been reported with valsartan therapy.
    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) VALSARTAN: Greater than 20% decreases in hemoglobin and hematocrit have occurred in 0.4% and 0.8% of patients versus 0.1% in the placebo group (Prod Info DIOVAN(R) oral tablets, 2006).
    1) Microcytic anemia was reported in one subject requiring termination of drug therapy (Prod Info DIOVAN(R) oral tablets, 2006).
    b) LOSARTAN: Decreases in hemoglobin and hematocrit (mean decrease of approximately 0.11 grams percent and 0.09 volume percent, respectively) occurred frequently (incidence unknown), but rarely was of clinical significance and did not require drug discontinuation (Prod Info COZAAR(R) oral tablets, 2005).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) VALSARTAN: There are rare reports of thrombocytopenia with valsartan therapy (Prod Info DIOVAN(R) oral tablets, 2006).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Angioedema has occurred rarely with these agents.
    3.14.2) CLINICAL EFFECTS
    A) ANGIOEDEMA
    1) WITH THERAPEUTIC USE
    a) Angioedema, involving swelling of the face, lips and/or tongue, has occurred rarely with losartan and valsartan (Prod Info DIOVAN(R) oral tablets, 2006; Prod Info COZAAR(R) oral tablets, 2005).
    2) WITH POISONING/EXPOSURE
    a) According to a retrospective review of adult valsartan ingestions reported to Texas poison control centers from 2000 to 2005 (n=185), edema was reported in 1 patient (Forrester, 2007).
    B) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) According to a retrospective review of adult valsartan ingestions reported to Texas poison control centers from 2000 to 2005 (n=185), pruritus and rash were reported in 1 and 2 patients, respectively (Forrester, 2007).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) CRAMP
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 25-year-old woman developed painful muscle cramps 6 hours after ingesting 28 80-mg valsartan tablets. The cramps became less painful and resolved over 2 days (Kumbasar et al, 2004).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 25-year-old woman developed mild, asymptomatic hypoglycemia (blood glucose 57 mg/dL) after ingesting 28 80-mg valsartan tablets(Kumbasar et al, 2004).

Reproductive

    3.20.1) SUMMARY
    A) Angiotensin II receptor antagonists are contraindicated during pregnancy and should be discontinued as soon as possible when pregnancy is determined. Fetal and neonatal morbidity and death have occurred from the use of ACE inhibitors, drugs that are similar to the ARBs that affect the renin angiotensin system, during any trimester of pregnancy with reports of spontaneous abortion, oligohydramnios, hypotension, neonatal skull hypoplasia, anuria, and newborn renal dysfunction. The occurrence of oligohydramnios is possibly due to decreased fetal renal function. Oligohydramnios was associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported; although, causality to drug therapy has not been established.
    B) CANDESARTAN, EPROSARTAN, IRBESARTAN, OLMESARTAN, and TELMISARTAN are classified as FDA pregnancy category C (first trimester) and D (second and third trimester). AZILSARTAN, LOSARTAN, and VALSARTAN are classified as FDA pregnancy category D (all trimesters).
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) There is no clinical experience with the use of AZILSARTAN, OLMESARTAN, or TELMISARTAN in pregnant women (Prod Info EDARBI oral tablets, 2011; Prod Info BENICAR(R) oral tablets, 2006; Prod Info MICARDIS(R) oral tablets, 2006).
    B) OLIGOHYDRAMNIOS
    1) Drugs acting directly on the renin-angiotensin-aldosterone system are documented to cause fetal harm. Angiotensin II receptor antagonists (ARAs) may cause fetal or neonatal injury or death when used during the second or third trimester of pregnancy. Hypotension, neonatal anemia, hyperkalemia, neonatal skull hypoplasia, anuria, and renal failure have occurred in fetuses and neonates. Oligohydramnios has also occurred, possibly due to decreased fetal renal function, and has been associated with limb contractures, craniofacial deformities, and hypoplastic lung development (Prod Info BENICAR HCT(R) oral tablets, 2016; Prod Info COZAAR(R) oral tablets, 2014a). The relationship between maternal ARA inhibitor use leading to intrauterine growth retardation, prematurity, and patient ductus arteriosus is unclear. Exposure to ARAs limited to the first trimester has not been associated with fetal or neonatal injury (Prod Info EDARBI oral tablets, 2011; Prod Info VALTURNA(R) oral tablets, 2009; Prod Info ATACAND(R) oral tablets, 2009a; Prod Info TEVETEN(R) oral tablets, 2005a; Prod Info AVAPRO(R) oral tablets, 2005a; Prod Info BENICAR(R) oral tablets, 2006; Prod Info MICARDIS(R) oral tablets, 2006; Prod Info DIOVAN(R) oral tablets, 2006).
    2) In rare cases when discontinuation of the drug is not an option, in addition to apprising the mothers of the potential hazards to their fetuses, conduct serial ultrasound examinations to assess the intraamniotic environment. Depending on the week of pregnancy, fetal testing may be considered. If oligohydramnios is noted, discontinue use unless it is considered lifesaving for the mother. It should be noted that oligohydramnios may not be evident until after the fetus has experienced irreversible injury. Closely monitor infants with histories of in utero exposure to an angiotensin II receptor antagonist for hypotension, oliguria, and hyperkalemia (Prod Info BENICAR HCT(R) oral tablets, 2016).
    3) CASE SERIES: Five case reports described 2 healthy infants and 3 infants with adverse events delivered to 5 women treated with either irbesartan or losartan at daily doses of 150 to 300 mg and 50 mg, respectively, initiated at least 3 years prior to conception and discontinued when pregnancy was confirmed. Both healthy infants were delivered at 39 weeks. One was exposed to irbesartan and bisoprolol until week 5 of gestation and the other was exposed to losartan and metoprolol until week 8 of gestation. Among the 3 infants with adverse effects, one was delivered at 40 weeks with one extra digit on the right hand and the left foot after irbesartan exposure through about week 9 of gestation. The other 2 infants were born with oligohydramnios at 29 and 27 weeks of gestation. One was exposed to irbesartan, methyldopa, and lysine acetylsalicylate through week 25 of gestation and the other was exposed to losartan and nifedipine through week 23 of gestation. Both infants were treated for apnea of prematurity and subependymal hemorrhage. The irbesartan-exposed infant was also treated for respiratory distress and pneumothorax and discharged on day 47 of life. The losartan-exposed infant was also treated for transitory decreased renal function and discharged on day 52 of life with a small umbilical hernia and slightly increased muscle tone (Gersak et al, 2009).
    4) CASE REPORT: A 31-year-old female with a history of polyarteritis (periarteritis) nodosa for 6 years developed hypertension at 17 weeks gestation and was prescribed LOSARTAN 50 mg/day during weeks 20 to 31 of pregnancy. Early ultrasounds showed normal fetal growth, but an ultrasound at 31 weeks showed that oligohydramnios was present; losartan was stopped immediately. Several days later the woman delivered a stillborn infant with obvious deformities of the extremities and face observed, which were due to oligohydramnios. Necropsy indicated the presence of pulmonary hypoplasia and fetal hypoplastic skull bones; no apparent renal abnormalities were found. The authors concluded that the pattern of abnormalities and fetal death were caused by losartan (Saji et al, 2001).
    C) NEPHROGENIC DIABETES INSIPIDUS
    1) CASE REPORTS: Salt-losing, nephrogenic diabetes insipidus (NDI) resulting from fetal exposure to candesartan was reported in 2 boys ages 6 yr and 2 yr. The mothers were initiated on candesartan 4 mg/day 1 yr prior to pregnancy and maintained throughout and 2 mg/day from gestational wk 33 through delivery, respectively. The infants were delivered cesarean section due to fetal distress and oligohydramnios at 31 and 37 wk gestation with birth weights of 1384 g and 2438 g, respectively. Both patients had findings consistent with ACE inhibitor/angiotensin II receptor blocker fetopathy, including oligohydramnios, acute renal failure requiring peritoneal dialysis, and hypotension. Both infants, who had mild retardation, recovered from acute neonatal respiratory and renal failure, but developed polyuria and polydipsia. Serum creatinine levels were 0.4 to 0.5 mg/dL and 0.55 mg/dL. After all medications were withdrawn, both were referred for renal function evaluation at ages 6 and 2.2 years. Remarkable salt-losing NDI was present in both patients with daily urine volume levels of 3000 mL and 1500 mL, respectively, and a fractional sodium excretion of greater than 1%. Maximum urine osmolalities of 135 and 379 mOsm/kg, respectively, were revealed after water restriction test and responded very little or not at all to arginine vasopressin (AVP) injections. Serum AVP and urine cyclic AMP levels also increased in both patients. Causes of salt-losing NDI suggested anatomical and functional impairment in the distal nephron, from Loop of Henle to the inner medullary collecting tubes. Abdominal ultrasound showed dysarthria with renal pelvis bilateral mild dilatations, calices, and cortical hyperechogenicity in patient 1 and bilateral mildly hypoplastic kidneys in patient 2 (Miura et al, 2009).
    D) ACUTE RENAL FAILURE
    1) Transient acute renal failure was reported in a male neonate (birth weight, 2.38 kg) during his first days of life after in utero exposure to angiotensin II receptor blockers. The mother was a 33-year-old woman initially treated with methyldopa and amlodipine for hypertension. At week 33 of gestation, telmisartan was started, initially as monotherapy at 40 mg/day and then with hydrochlorothiazide at 80 mg/day, for refractory hypertension. At week 37 of gestation, an emergency cesarean section was performed due to preeclampsia, oligohydramnios, and meconium-stained fluid. The infant did not need resuscitative efforts at birth; Apgar scores were 8, 9, and 9 at 1, 5, and 10 minutes, respectively. After nursery admission, he had transient tachypnea that was treated with free-flow oxygen for 2 hours. On day 2, a normal saline infusion was initiated for persistent anuria and a blood test revealed creatinine at 3.8 mg/dL (normal range, 0.2 to 2 mg/dL) and a BUN level of 27 mg/dL (normal, 3 to 12 mg/dL). Furosemide 4 mg IV bolus and rasburicase 0.1 mg was given with no improvement in the diuresis. Renal parenchymal hyperechogenicity and increased inter-lobal arterial resistance were found on ultrasound. A bladder catheter was inserted, and another furosemide bolus (12 mg IV) and dopamine infusions were given for the anuria. At 72 hours, peritoneal dialysis was started and lasted for 3 days. On day 5, diuresis began with a urine output of 1.6 mL/kg/hr, but blood creatinine and BUN levels peaked at 7.32 and 74 mg/dL, respectively. By day 15, dopamine was discontinued. At his 1-month follow-up, renal function tests were within the normal range and at 12 months, diuresis and renal ultrasound were completely normal (Marchetto et al, 2015).
    E) LACK OF EFFECT
    1) CANDESARTAN: Over 4 or more years of DIRECT (Diabetic Retinopathy and Candesartan Trials) studies, the rate of congenital malformations was no higher in normotensive, normoalbuminuric women with type 1 diabetes exposed to candesartan 32 mg once daily during the first trimester of pregnancy than in placebo-treated pregnant women with the same health profile (n=178). The placebo group reported the only congenital malformation (a ventricular septal defect). DIRECT stopped drug therapy in any subject reporting pregnancy or pregnancy planning; comparisons of dose with menstrual period records showed no exposure to candesartan in any pregnant subject beyond the eighth week. Of the 208 pregnancies, more than half likely received first-trimester candesartan exposure. Delivery outcomes were comparable between the candesartan and placebo groups, including full-term deliveries (51 candesartan, 50 placebo); premature births (21 candesartan, 27 placebo); and spontaneous miscarriages (12 candesartan, 15 placebo). Incidence of stillbirth (2 candesartan, one placebo) and sick infants (2 candesartan, 8 placebo) were also similar in both groups (Porta et al, 2011).
    F) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) CANDESARTAN: In pregnant mice, there were no adverse effects on fetal development at oral candesartan doses of 138 times the maximum recommended daily human dose (MRHD) (Prod Info ATACAND(R) oral tablets, 2009a).
    b) EPROSARTAN: In pregnant rabbits, no maternal or fetal adverse effects were observed at oral eprosartan doses of 0.8 times the maximum recommended human dose (MRHD). In pregnant rats, there were no adverse effects in utero or in postnatal development of offspring at doses of 0.6 times the MRHD (Prod Info TEVETEN(R) oral tablets, 2005a).
    c) OLMESARTAN: In rats and rabbits, no teratogenic effects were noted at oral olmesartan doses 240 times the maximum recommended human dose (MRHD) on the basis of surface area and half the MRHD, respectively. In rabbits, this was the highest dose that could be evaluated because higher doses were lethal to the fetus. In rats, the no observed effect dose for developmental toxicity was 0.3 mg/kg/day (about 1/10 the MRHD). In rats, delays in separation of ear auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) were noted at maternal olmesartan doses of 1.6 mg/kg/day or greater. A dose-dependent increased incidence of renal pelvis dilation in rats was observed at olmesartan doses of 8 mg/kg/day or greater (Prod Info BENICAR(R) oral tablets, 2006).
    d) TELMISARTAN: In pregnant rats and rabbits, no teratogenic effects were reported at oral telmisartan doses of up to 50 mg/kg/day and 45 mg/kg/day, respectively. The no observed effect doses for developmental toxicity in rats and rabbits were about 0.64 and 3.7 times the maximum recommended human dose (Prod Info MICARDIS(R) oral tablets, 2006).
    e) VALSARTAN: The "no fetal adverse effect" level for valsartan in mice, rats, and rabbits was 600, 200 and 2 mg/kg/day, respectively (9, 6 and 0.1 times, respectively, the MRHD) (Prod Info VALTURNA(R) oral tablets, 2009; Prod Info DIOVAN(R) oral tablets, 2006).
    2) FETAL/NEONATAL INJURY
    a) Hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, decreased body weight, delayed physical and behavioral development and death have been reported in animals treated with angiotensin II antagonists (Prod Info ENTRESTO(TM) oral tablets, 2015; Prod Info VALTURNA(R) oral tablets, 2009; Prod Info ATACAND(R) oral tablets, 2009a; Prod Info TEVETEN(R) oral tablets, 2005a; Prod Info AVAPRO(R) oral tablets, 2005a; Prod Info COZAAR(R) oral tablets, 2014a; Prod Info BENICAR(R) oral tablets, 2006; Prod Info MICARDIS(R) oral tablets, 2006).
    b) CANDESARTAN: In pregnant rats, oral candesartan cilexetil doses of 2.8 times the maximum recommended daily human dose (MRHD) during late gestation were associated with reduced survival and an increased incidence of trophoneurosis in offspring (Prod Info ATACAND(R) oral tablets, 2009a).
    c) EPROSARTAN: In pregnant rabbits, oral doses as low as 10 mg eprosartan/kg/day resulted in fetal mortality, resorptions, abortions, and litter loss (Prod Info TEVETEN(R) oral tablets, 2005a).
    d) IRBESARTAN: In pregnant rats, irbesartan doses equivalent to the maximum recommended human dose (MRHD) from day 0 to day 20 of gestation resulted in increased incidences of renal pelvic cavitation, hydroureter, and/or absence of renal papilla and doses about 4 times the MRHD resulted in subcutaneous edema in fetuses. However, these adverse events were not observed in rats at similar irbesartan doses from gestation days 6 to 15, suggesting potentially late gestational effects of the drug (Prod Info AVAPRO(R) oral tablets, 2005a).
    e) LOSARTAN: In rats, delayed physical and behavioral development, mortality and renal toxicity were observed at doses exceeding 25 mg/kg/day (approximately 3 times the maximum recommended human dose of 100 mg on a mg/m2 basis) and decreased neonatal weight was observed at doses as low as 10 mg/kg/day. These effects were attributed to drug exposure during late gestation and during lactation. Losartan and its active metabolite were observed in rat fetal plasma at significant levels during late gestation (Prod Info COZAAR(R) oral tablets, 2014a).
    f) NEBIVOLOL/VALSARTAN
    1) The nebivolol/valsartan combination has not been tested in reproductive animal toxicity studies, but the individual agents have been tested. Embryofetal and perinatal lethality were observed after the administration of nebivolol to pregnant rats during organogenesis at doses 1.2 times the maximum recommended human dose (MRHD) on a body surface area basis. No adverse effects on embryofetal morphology, sex, viability or weight were noted after the administration of nebivolol to pregnant rabbits at doses 10 times the MRHD. The administration of valsartan to rats and rabbits at maternally toxic doses (approximately 9 times the MRHD) during organogenesis or late gestation resulted in decreased fetal and birth weights as well as decreased pup survival rates and slight developmental delays (Prod Info BYVALSON(TM) oral tablets, 2016).
    2) After the administration of nebivolol at maternally toxic doses (5 and 10 times the maximum recommended human dose) to pregnant rats during organogenesis, reduced fetal weights and reversible sternal and thoracic ossification delays occurred (Prod Info BYVALSON(TM) oral tablets, 2016).
    g) OLMESARTAN: In rats, significantly decreased pup birth weight and weight gain were reported at olmesartan doses of 1.6 mg/kg/day or greater (Prod Info BENICAR(R) oral tablets, 2006).
    h) TELMISARTAN: In pregnant rabbits, embryolethality associated with maternal toxicity was noted at 12 times the maximum recommended human dose (MRHD). In rats, adverse neonatal effects associated with maternal toxicity, including reduced viability, low birth weight, delayed maturation, and decreased weight gain, were reported at oral telmisartan doses of 1.9 times the MRHD administered during late gestation and lactation. Telmisartan has been reported to be present in rat fetuses during late gestation (Prod Info MICARDIS(R) oral tablets, 2006).
    i) VALSARTAN: In rats, fetal and neonatal toxicities were observed at valsartan doses of 600 mg/kg/day. In rabbits, maternal toxicities were observed at 5 and 10 mg/kg/day (Prod Info VALTURNA(R) oral tablets, 2009; Prod Info DIOVAN(R) oral tablets, 2006).
    j) VALSARTAN/SACUBITRIL: During animal studies, embryo-fetal lethality was reported with sacubitril and valsartan at doses up to 4-fold the maximum recommended human dose (MRHD). Teratogenic effects, including fetal hydrocephaly, were also reported. Offspring development and survival were affected during pre- and postnatal development studies with administration of sacubitril at doses 4.5-fold the MRHD and valsartan at doses 0.86-fold the MRHD during organogenesis, gestation, and lactation (Prod Info ENTRESTO(TM) oral tablets, 2015).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The following have been classified as FDA pregnancy category D:
    1) AMLODIPINE/HYDROCHLOROTHIAZIDE/VALSARTAN (Prod Info Exforge HCT(R) oral tablets, 2009)
    2) AZILSARTAN (Prod Info EDARBI oral tablets, 2011)
    3) AZILSARTAN MEDOXOMIL/CHLORTHALIDONE (Prod Info EDARBYCLOR oral tablets, 2011)
    4) LOSARTAN (Prod Info COZAAR(R) oral tablets, 2014a)
    5) OLMESARTAN MEDOXOMIL/HYDROCHLOROTHIAZIDE (Prod Info BENICAR HCT(R) oral tablets, 2016).
    6) VALSARTAN (Prod Info DIOVAN(R) oral tablets, 2007)
    2) The following have been classified as FDA pregnancy category C (first trimester) and D (second and third trimester):
    1) AMLODIPINE/TELMISARTAN (Prod Info TWYNSTA(R) oral tablets, 2009)
    2) CANDESARTAN (Prod Info ATACAND(R) oral tablets, 2009a)
    3) EPROSARTAN (Prod Info TEVETEN(R) oral tablets, 2005a)
    4) IRBESARTAN (Prod Info AVAPRO(R) oral tablets, 2005a)
    5) OLMESARTAN (Prod Info BENICAR(R) oral tablets, 2006)
    6) OLMESARTAN/AMLODIPINE/HYDROCHLOROTHIAZIDE (Prod Info TRIBENZOR(R) oral tablets, 2010)
    7) TELMISARTAN (Prod Info MICARDIS(R) oral tablets, 2006)
    3) NEBIVOLOL/VALSARTAN: The use of nebivolol/valsartan and other drugs that act on the renal-angiotensin system during pregnancy can reduce fetal renal function and increase fetal morbidity and mortality rates (Prod Info BYVALSON(TM) oral tablets, 2016).
    B) CONTRAINDICATIONS
    1) Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death. When pregnancy is detected, angiotensin II receptor antagonists should be DISCONTINUED as soon as possible (Prod Info EDARBI oral tablets, 2011; Prod Info ATACAND(R) oral tablets, 2009a; Prod Info TEVETEN(R) oral tablets, 2005a; Prod Info AVAPRO(R) oral tablets, 2005a; Prod Info COZAAR(R) oral tablets, 2014a; Prod Info BENICAR(R) oral tablets, 2006; Prod Info MICARDIS(R) oral tablets, 2006).
    C) FETAL INJURY
    1) CANDESARTAN
    a) In one reported case, a 35-year-old woman was taking 16 mg/day of candesartan, an angiotensin II antagonist, combined with pramipexole, and amitriptyline as preventative treatment for migraines, as well as zolmitriptan and metoclopramide during attacks, throughout her pregnancy. At 33 weeks gestation it was determined that candesartan is a fetotoxic medication and the medication was discontinued. At birth, the baby had hyaline membranes of the lungs, hypoplasia of the lungs and skull, and renal tubular dysgenesis and died as a result (Haaland, 2010).
    b) A 39-year-old woman was treated with candesartan for essential hypertension throughout pregnancy. The infant was born at 31 weeks gestation with limb contractures, skull hypoplasia, microcephaly, moderately underdeveloped calvarial bones. He then developed hypotension and oliguria with increased urinary protein to creatinine ratio. At two weeks he had mild hypertension. At 34 months of age, he had moderately impaired cognitive function, normal calvarial bones, normal creatinine, slightly increased urinary protein to creatinine ratio, and on ultrasound, kidneys were small and hyperechogenic with loss of corticomedullary differentiation (Simonetti et al, 2006).
    2) LOSARTAN
    a) A 22-year-old woman with congenital heart disease was treated with losartan, digoxin, and furosemide throughout pregnancy. She delivered at 35 weeks. The infant had large anterior and posterior fontanelles with wide open metopic, sagittal and squamoparietal sutures without hydrocephalus, and hypoplasia of the skull (Nayar et al, 2003).
    3) VALSARTAN
    a) A woman with hypertension treated with prazosin, valsartan, and hydrochlorothiazide became pregnant. At 24 weeks gestation, ultrasound revealed severe anhydramnios; the fetus had hyperechoic kidneys and valsartan was discontinued. At 27 weeks gestation, beta microglobulin levels were elevated in fetal cord blood, indicating severe renal insufficiency. At delivery, there was decreased amniotic fluid volume. The infant had wide cranial sutures and varus deformity of the right foot. Ultrasound showed enlarged, hyperechoic kidneys and elevated serum creatinine. The child had persistent mild renal insufficiency at 30 months with otherwise normal growth and development (Bos-Thompson et al, 2005).
    D) OLIGOHYDRAMNIOS
    1) Drugs acting directly on the renin-angiotensin-aldosterone system are documented to cause fetal harm. Angiotensin II receptor antagonists (ARAs) may cause fetal or neonatal injury or death when used during the second or third trimester of pregnancy. Hypotension, hyperkalemia, neonatal skull hypoplasia, anuria, and renal failure have occurred in fetuses and neonates. Oligohydramnios has also occurred, possibly due to decreased fetal renal function, and has been associated with limb contractures, craniofacial deformities, and hypoplastic lung development (Prod Info BENICAR HCT(R) oral tablets, 2016; Prod Info COZAAR(R) oral tablets, 2014a). The relationship between maternal ARA inhibitor use leading to intrauterine growth retardation, prematurity, and patient ductus arteriosus is unclear. Exposure to ARAs limited to the first trimester has not been associated with fetal or neonatal injury (Prod Info EDARBI oral tablets, 2011; Prod Info ATACAND(TM) oral tablets, 2005; Prod Info TEVETEN(R) oral tablets, 2005a; Prod Info AVAPRO(R) oral tablets, 2005a; Prod Info BENICAR(R) oral tablets, 2006; Prod Info MICARDIS(R) oral tablets, 2006; Prod Info DIOVAN(R) oral tablets, 2006).
    2) In rare cases when discontinuation of the drug is not an option, in addition to apprising the mothers of the potential hazards to their fetuses, conduct serial ultrasound examinations to assess the intraamniotic environment. Depending on the week of pregnancy, fetal testing may be considered. If oligohydramnios is noted, discontinue use unless it is considered lifesaving for the mother. It should be noted that oligohydramnios may not be evident until after the fetus has experienced irreversible injury. Closely monitor infants with histories of in utero exposure to an angiotensin II receptor antagonist for hypotension, oliguria, and hyperkalemia (Prod Info BENICAR HCT(R) oral tablets, 2016).
    3) CASE SERIES: Five case reports described 2 healthy infants and 3 infants with adverse events delivered to 5 women treated with either irbesartan or losartan at daily doses of 150 to 300 mg and 50 mg, respectively, initiated at least 3 years prior to conception and discontinued when pregnancy was confirmed. Both healthy infants were delivered at 39 weeks. One was exposed to irbesartan and bisoprolol until week 5 of gestation and the other was exposed to losartan and metoprolol until week 8 of gestation. Among the 3 infants with adverse effects, one was delivered at 40 weeks with one extra digit on the right hand and the left foot after irbesartan exposure through about week 9 of gestation. The other 2 infants were born with oligohydramnios at 29 and 27 weeks of gestation. One was exposed to irbesartan, methyldopa, and lysine acetylsalicylate through week 25 of gestation and the other was exposed to losartan and nifedipine through week 23 of gestation. Both infants were treated for apnea of prematurity and subependymal hemorrhage. The irbesartan-exposed infant was also treated for respiratory distress and pneumothorax and discharged on day 47 of life. The losartan-exposed infant was also treated for transitory decreased renal function and discharged on day 52 of life with a small umbilical hernia and slightly increased muscle tone (Gersak et al, 2009).
    4) CASE REPORT: A 31-year-old female with a history of polyarteritis (periarteritis) nodosa for 6 years developed hypertension at 17 weeks gestation and was prescribed LOSARTAN 50 mg/day during weeks 20 to 31 of pregnancy. Early ultrasounds showed normal fetal growth, but an ultrasound at 31 weeks showed that oligohydramnios was present; losartan was stopped immediately. Several days later the woman delivered a stillborn infant with obvious deformities of the extremities and face observed, which were due to oligohydramnios. Necropsy indicated the presence of pulmonary hypoplasia and fetal hypoplastic skull bones; no apparent renal abnormalities were found. The authors concluded that the pattern of abnormalities and fetal death were caused by losartan (Saji et al, 2001).
    5) REVERSIBLE EFFECTS: A 43-year-old pregnant woman with chronic hypertension was treated with VALSARTAN until gestation week 20 when a complete anhydramnios was detected. Six days after valsartan discontinuation at gestation week 23.5, amniotic fluid reappeared and reached a normal level. At 38.5 gestation week, a healthy infant was delivered. At 6-month follow-up, the plasmatic creatinine level was 38 micromoles/L (normal 20 to 50 micromoles/L) and the renal ultrasound examination was normal (Berkane et al, 2004).
    E) SPONTANEOUS ABORTION
    1) LOSARTAN: Four pregnancies were reported in a losartan postmarketing safety surveillance study (n=14,522). Losartan was stopped at 8 weeks of gestation in two pregnancies. One baby was delivered by Caesarean section at 29 weeks with growth retardation and died at day 9, and one fetus spontaneously aborted at 6 to 8 weeks gestation. The third pregnancy resulted in premature birth by Caesarean section at 30 weeks due to preeclampsia and breech presentation with no major problems with the baby; losartan was stopped approximately 6 weeks after the last menstrual period. The fourth pregnancy ended in a spontaneous abortion at 6 weeks of gestation, even though losartan was stopped 2 months before the pregnancy (Mann et al, 1999).
    F) LACK OF EFFECT
    1) CANDESARTAN: Over 4 or more years of DIRECT (Diabetic Retinopathy and Candesartan Trials) studies, the rate of congenital malformations was no higher in normotensive, normoalbuminuric women with type 1 diabetes exposed to candesartan 32 mg once daily during the first trimester of pregnancy than in placebo-treated pregnant women with the same health profile (n=178). The placebo group reported the only congenital malformation (a ventricular septal defect). DIRECT stopped drug therapy in any subject reporting pregnancy or pregnancy planning; comparisons of dose with menstrual period records showed no exposure to candesartan in any pregnant subject beyond the eighth week. Of the 208 pregnancies, more than half likely received first-trimester candesartan exposure. Delivery outcomes were comparable between the candesartan and placebo groups, including full-term deliveries (51 candesartan, 50 placebo); premature births (21 candesartan, 27 placebo); and spontaneous miscarriages (12 candesartan, 15 placebo). Incidence of stillbirth (2 candesartan, one placebo) and sick infants (2 candesartan, 8 placebo) were also similar in both groups (Porta et al, 2011).
    G) ANIMAL STUDIES
    1) MATERNAL TOXICITY
    a) CANDESARTAN: In pregnant rabbits, oral candesartan cilexetil doses of 2.8 times the maximum recommended daily human dose (MRHD) during late gestation led to maternal toxicity (decreased body weight and mortality), but in surviving dams, there were no adverse effects on fetal survival, fetal weight, or external, visceral, or skeletal development (Prod Info ATACAND(R) oral tablets, 2009a).
    b) EPROSARTAN: In pregnant rabbits, oral eprosartan doses as low as 10 mg/kg/day resulted in maternal toxicity (mortality and low maternal body weight and food consumption) (Prod Info TEVETEN(R) HCT oral tablets, 2006).
    c) IRBESARTAN: In pregnant rabbits, oral irbesartan doses of 1.5 times the MRHD on a body surface area basis were associated with maternal mortality and abortion. Among surviving females receiving this dose, there was a slight increase in early resorptions and a decrease in live fetuses. In rats and rabbits, irbesartan was shown to cross the placental barrier (Prod Info AVAPRO(R) oral tablets, 2005a).
    d) NEBIVOLOL/VALSARTAN: After the administration of nebivolol at maternally toxic doses (5 and 10 times the maximum recommended human dose) to pregnant rats during organogenesis, reduced fetal weights and reversible sternal and thoracic ossification delays occurred (Prod Info BYVALSON(TM) oral tablets, 2016).
    e) TELMISARTAN: In pregnant rabbits and rats, maternal toxicity (reduced body weight gain and food consumption) was reported at oral telmisartan doses of 12 times and 1.9 times the maximum recommended human dose (MRHD), respectively (Prod Info MICARDIS(R) oral tablets, 2006).
    f) VALSARTAN: In rats, maternal toxicities were observed at valsartan doses of 600 mg/kg/day. In rabbits, fetotoxicity associated with maternal toxicity (mortality) was observed at 5 and 10 mg/kg/day (Prod Info DIOVAN(R) oral tablets, 2006).
    2) LACK OF EFFECT
    a) CANDESARTAN: Maternal toxicity and fetal development were not affected when pregnant mice were treated with oral candesartan cilexetil doses of 138 times the maximum recommended daily human dose (MRHD) (Prod Info ATACAND(R) oral tablets, 2009a).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to nebivolol/valsartan during lactation in humans (Prod Info BYVALSON(TM) oral tablets, 2016).
    B) BREAST MILK
    1) Overall, it is not known whether angiotensin II antagonist parent drugs or active metabolites are excreted in human milk; however, active drug or metabolites have been detected in rat milk (Prod Info EDARBI oral tablets, 2011; Prod Info VALTURNA(R) oral tablets, 2009; Prod Info ATACAND(R) oral tablets, 2009a; Prod Info TEVETEN(R) oral tablets, 2005a; Prod Info AVAPRO(R) oral tablets, 2005a; Prod Info COZAAR(R) oral tablets, 2014a; Prod Info BENICAR(R) oral tablets, 2006; Prod Info MICARDIS(R) oral tablets, 2006; Prod Info DIOVAN(R) oral tablets, 2006).
    C) OLMESARTAN MEDOXOMIL/HYDROCHLOROTHIAZIDE
    1) Thiazides are known to appear in human milk and olmesartan was excreted into the milk of lactating animals at low concentrations (Prod Info BENICAR HCT(R) oral tablets, 2016).
    2) Discontinue treatment or discontinue nursing, taking into account the importance of the drug to the mother (Prod Info BENICAR HCT(R) oral tablets, 2016).
    D) VALSARTAN/SACUBITRIL
    1) Do not breastfeed while taking sacubitril/valsartan (Prod Info ENTRESTO(TM) oral tablets, 2015).
    E) ANIMAL STUDIES
    1) NEBIVOLOL/VALSARTAN
    a) Nebivolol was detected in the milk of lactating rats and levels peaked at 4 hours after single and repeat doses of 2.5 mg/kg/day. Rat pups were exposed to a daily dose of 0.3% of the administered dose. Fifteen minutes after the administration of valsartan 3 mg/kg to pregnant female rats, the drug was detected in the milk (Prod Info BYVALSON(TM) oral tablets, 2016).
    2) VALSARTAN/SACUBITRIL
    a) Oral administration of sacubitril/valsartan in lactating animals resulted in transfer of both LBQ657 (the active metabolite of sacubitril) and valsartan into the animal's milk (Prod Info ENTRESTO(TM) oral tablets, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) AZILSARTAN: In male and female rats, no effects on fertility were noted with the administration of azilsartan medoxomil at oral doses of up to 1000 mg/kg/day (approximately 122 times the maximum daily human dose (MRHD) on a mg/m(2) basis) or with azilsartan's major metabolite (M-II) at doses up to 3000 mg/kg/day (Prod Info EDARBI oral tablets, 2011).
    b) CANDESARTAN: In male and female rats, candesartan at doses 83 times the maximum daily human dose (MRHD) did not affect fertility or reproductive performance (Prod Info ATACAND(R) oral tablets, 2009a).
    c) EPROSARTAN: In male and female rats, eprosartan at doses 0.6 times the MRHD did not affect reproductive performance (Prod Info TEVETEN(R) oral tablets, 2005a).
    d) IRBESARTAN: In male and female rats, irbesartan at doses 5 times the MRHD did not affect fertility or mating (Prod Info AVAPRO(R) oral tablets, 2005a).
    e) LOSARTAN: In male rats, losartan at doses up to 150 mg/kg/day did not affect fertility or mating (Prod Info COZAAR(R) oral tablets, 2014a).
    f) NEBIVOLOL/VALSARTAN: The administration of nebivolol to male rats and mice at doses 10 and 5 times the maximum recommended human dose (MRHD), respectively, had irreversible and partially reversible effects on spermatogenesis, respectively. However, valsartan had no adverse reproductive effects when administered at oral doses up to 6 times the MRHD on a body surface area basis (Prod Info BYVALSON(TM) oral tablets, 2016).
    g) OLMESARTAN: In male rats and female rats dosed at 9 weeks and 2 weeks prior to mating, respectively, olmesartan at doses up to 240 times the MRHD did not affect fertility or mating (Prod Info BENICAR(R) oral tablets, 2006).
    h) TELMISARTAN: In male and female rats, telmisartan at doses up to 13 times the MRHD did not affect fertility or mating (Prod Info MICARDIS(R) oral tablets, 2006).
    i) VALSARTAN: In male and female rats, valsartan at doses up to 6 times the MRHD did not affect fertility or mating (Prod Info DIOVAN(R) oral tablets, 2006).
    j) VALSARTAN/SACUBITRIL: There was no evidence of impaired fertility in animals administered sacubitril or valsartan up to 1-fold and 0.18-fold, respectively, the maximum recommended human dose (Prod Info ENTRESTO(TM) oral tablets, 2015).
    2) FERTILITY DECREASED: FEMALE
    a) LOSARTAN: In female rats, the administration of toxic dose levels of losartan (300/200 mg/kg/day) was associated with a statistically significant decrease in the number of corpora lutea, implants and live fetuses at C-section (Prod Info COZAAR(R) oral tablets, 2014a).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) No evidence of increased carcinogenicity due to angiotensin II antagonists has been found.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) AZILSARTAN/MEDOXOMIL/CHLORTHALIDONE
    a) At the time of this review, carcinogenicity studies have not been conducted (Prod Info EDARBYCLOR oral tablets, 2011).
    2) VALSARTAN/SACUBITRIL
    a) At the time of this review, specific human carcinogenicity studies with sacubitril/valsartan have not been conducted (Prod Info ENTRESTO(TM) oral tablets, 2015).
    B) LOSARTAN
    1) In a 105 week study, at the maximally tolerated dose (270 mg/kg/day) no significant increase in the incidence of carcinogenicity was observed compared to controls (Prod Info Cozaar(R), losartan, 1999).
    a) Females at this high dose did appear to have a slightly higher incidence of pancreatic acinar adenoma (Prod Info Cozaar(R), losartan, 1999).
    C) VALSARTAN
    1) No carcinogenic potential was found after the administration of doses up to 160 and 200 mg/kg/day in mice and rats for up to 2 years, respectively (equivalent to 2.6 and 6 times the human dose respectively), based on a mg/M(2) basis (Prod Info Diovan(R), valsartan, 2000).
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) AZILSARTAN MEDOXOMIL/CHLORTHALIDONE
    a) At the time of this review, carcinogenicity studies have not been conducted (Prod Info EDARBYCLOR oral tablets, 2011).
    B) LACK OF EFFECT
    1) AZILSARTAN MEDOXOMIL
    a) Carcinogenicity studies of azilsartan medoxomil in transgenic mice and rats administered up to 450 mg/kg/day and 600 mg/kg/day, respectively, produced no carcinogenic effects. The mice and rats produced exposures of 12 and 27 times the average human exposure based on the 80 mg/day maximum recommended human dose, respectively. M-II, the major metabolite of azilsartan medoxomil, was also found to be noncarcinogenic following administration of doses up to 8000 mg/kg/day and 11,000 mg/kg/day in male and female mice, respectively. Male and female rats administered M-II doses up to 1000 mg/kg/day and 3000 mg/kg/day, respectively, also showed no signs of carcinogenicity (Prod Info EDARBYCLOR oral tablets, 2011).
    2) VALSARTAN/SACUBITRIL
    a) There was no evidence of carcinogenic potential following administration of sacubitril at doses up to 16 times the maximum recommended human dose (MRHD) and valsartan at doses up to 10 times the MRHD (Prod Info ENTRESTO(TM) oral tablets, 2015).

Genotoxicity

    A) AZILSARTAN MEDOXOMIL
    1) There was no evidence of genotoxicity or mutagenicity in azilsartan medoxomil, azilsartan, and the major metabolite, M-II, in the following tests: Ames reverse mutation assay, in vitro Chinese Hamster Ovary Cell forward mutation assay, in vitro mouse lymphoma gene mutation test, ex vivo unscheduled DNA synthesis test, and in vivo mouse and/or rat bone marrow micronucleus assay (Prod Info EDARBYCLOR oral tablets, 2011).
    2) Azilsartan medoxomil, azilsartan, and the major metabolite, M-II, tested positive for structural aberrations, with or without metabolic activation, using the Chinese Hamster Lung Cytogenic Assay (Prod Info EDARBYCLOR oral tablets, 2011).
    B) VALSARTAN/SACUBITRIL
    1) There was no evidence of mutagenicity or clastogenicity at the gene or chromosome level (Prod Info ENTRESTO(TM) oral tablets, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes and glucose in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor renal function, liver enzymes and serum electrolytes in symptomatic patients or asymptomatic patients with significant overdoses.
    2) Monitor blood glucose in symptomatic patients.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor blood pressure and heart rate frequently following any significant ingestion.
    b) Obtain baseline ECG and institute continuous cardiac monitoring after any significant overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Any patient with persistent hypotension should be admitted to the hospital.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Healthy children and adults can be managed at home if overdose was inadvertent and no signs or symptoms are present.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in decision making whether or not admission is advisable, managing patients with severe toxicity, or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patients with deliberate overdose or more than mild symptoms should be sent to a health care facility for evaluation. Patients with significant cardiovascular disease, those on other cardiodepressant agents (eg beta blocker) and those who have ingested more than 4 pills or 320 mg valsartan should be referred to a healthcare facility.
    B) Observe patients with careful blood pressure monitoring for 4 to 6 hours after overdose.
    C) According to a retrospective study involving ADULT valsartan ingestions reported to Texas poison control centers from 2000 to 2005 (Forrester, 2007), the patient should be referred to a health care facility if:
    1) the overdose ingestion is intentional
    2) the patient is symptomatic at the time of the first call
    3) the patient has significant underlying cardiovascular disease, or if the patient is also taking a beta-blocker or other cardiodepressant agent
    4) the maximum amount of valsartan ingested is either greater than 320 mg or greater than 4 tablets (if dose is unknown), or
    5) the patient is unable to estimate the maximum amount ingested

Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes and glucose in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is not recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) HYPOTENSIVE EPISODE
    1) Monitor blood pressure frequently.
    2) Based on limited data, circulatory collapse, shock and decreased level of consciousness have been reported following overdose with valsartan (Prod Info DIOVAN(R) oral tablets, 2006).
    3) Initially, administer 10 to 20 mL/kg of isotonic intravenous fluids and place the patient supine. If the patient is unresponsive to these measures, administer dopamine or norepinephrine.
    4) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    5) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status. Monitor serum electrolytes and glucose in symptomatic patients.
    C) ANAPHYLAXIS
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) EXTRACORPOREAL ELIMINATION
    1) CANDESARTAN CILEXETIL: Based on the high degree of protein binding (99%), hemodialysis would not be effective (Prod Info ATACAND(R) oral tablets, 2005). Theoretically, based on the volume of distribution (0.13), hemoperfusion would be expected to removed a substantial drug burden. However, this has not been evaluated in clinical practice.
    2) IRBESARTAN: It cannot be removed by hemodialysis; protein binding is 90% (Prod Info AVAPRO(R) oral tablets, 2005).
    3) LOSARTAN: Losartan and its active metabolites are not removed by dialysis (Prod Info COZAAR(R) oral tablets, 2005). Theoretically, based on the volume of distribution (0.68), charcoal hemoperfusion would be expected to remove a substantial drug burden. However, this has not been evaluated in clinical practice.
    4) TELMISARTAN: It cannot be removed by hemodialysis, due to the high degree of protein binding (99.5%). Similarly, charcoal hemoperfusion would not have any impact on the total drug burden because of the large volume of distribution (10.0) (Prod Info MICARDIS(R) oral tablets, 2005).
    5) VALSARTAN: Hemodialysis is not able to remove valsartan from the plasma (Prod Info DIOVAN(R) oral tablets, 2006). Theoretically, based on the volume of distribution (0.34), charcoal hemoperfusion would be expected to remove a substantial drug burden. However, this has not been evaluated in clinical practice.

Range Of Toxicity

Summary

    A) TOXICITY: Severe toxicity has not been described following isolated overdose from these medications. An adult developed mild toxicity after ingesting 2240 mg valsartan. Azilsartan oral doses up to 320 mg once daily for 7 days were well tolerated in healthy adults during clinical trials.
    B) THERAPEUTIC DOSE: Varies with agent. AZILSARTAN: ADULT: 80 mg orally once daily. CANDESARTAN: ADULT: Total daily dose can range from 8 to 32 mg. EPROSARTAN: ADULT: 400 to 800 mg daily in single or divided doses. IRBESARTAN: ADULT: 150 to 300 mg once daily. LOSARTAN: ADULT: 25 to 100 mg orally daily. TELMISARTAN: ADULT: 20 to 80 mg orally daily. VALSARTAN: ADULT: 80 to 320 mg daily. PEDIATRIC: No dosing information available for these agents.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) AZILSARTAN MEDOXOMIL
    a) The recommended dose is 80 mg ORALLY once daily. In patients who are treated with high doses of diuretics, consider a starting dose of 40 mg ORALLY once daily (Prod Info EDARBI(R) oral tablets, 2011).
    2) AZILSARTAN MEDOXOMIL/CHLORTHALIDONE
    a) The recommended initial dose of azilsartan medoxomil 40 mg/chlorthalidone is 12.5 mg ORALLY once daily. May increase to azilsartan medoxomil 40 mg/chlorthalidone 25 mg ORALLY once daily after 2 to 4 weeks. MAXIMUM: azilsartan medoxomil 40 mg/chlorthalidone 25 mg ORALLY once daily (Prod Info EDARBYCLOR oral tablets, 2011).
    3) CANDESARTAN CILEXETIL
    a) INITIAL DOSE: The usual starting dose is 16 mg once daily when used as a monotherapy in patients who are not volume depleted. Daily total dose range is 8 to 32 mg. At present, there is little experience and not a greater response (lower blood pressure) observed with larger doses (Prod Info ATACAND(R) oral tablets, 2009).
    b) HEART FAILURE: The recommended initial dose is 4 mg once daily, doubling the dose at approximately 2-week intervals up to a target dose of 32 mg (Prod Info ATACAND(R) oral tablets, 2009).
    4) EPROSARTAN MESYLATE
    a) Usual starting dose is 600 mg once daily when used as a monotherapy in individuals who are not volume depleted; maintenance dosing ranges from 400 to 800 mg daily in single or divided doses. Limited experience with dosing beyond 800 mg daily (Prod Info TEVETEN(R) oral tablets, 2005).
    b) Eprosartan mesylate can be combined with other antihypertensives; discontinuation does not appear to lead to rebound of increased blood pressure (Prod Info TEVETEN(R) oral tablets, 2005).
    5) IRBESARTAN
    a) Usual starting dose is 150 mg once daily; maintenance dosing ranges from 150 to 300 mg once daily (Prod Info AVAPRO(R) oral tablets, 2005).
    6) LOSARTAN
    a) INITIAL DOSE: The usual starting dose is 50 mg once daily. May be administered once or twice daily with total daily doses ranging from 25 to 100 mg (Prod Info COZAAR(R) oral tablets, 2010).
    7) NEBIVOLOL/VALSARTAN
    a) The recommended dose is one tablet (nebivololol 5 mg/valsartan 80 mg) orally once daily (Prod Info BYVALSON(TM) oral tablets, 2016).
    8) OLMESARTAN
    a) The recommended starting dose is 20 mg once daily. Maintenance doses range from 20 to 40 mg once daily (Prod Info BENICAR(R) oral tablets, 2012).
    9) OLMESARTAN MEDOXOMIL/HYDROCHLOROTHIAZIDE
    a) The recommended starting dose is olmesartan medoxomil 20 or 40 mg and hydrochlorothiazide 12.5 mg once daily. May be titrated up to olmesartan medoxomil 40 mg/hydrochlorothiazide 25 mg if necessary (Prod Info BENICAR HCT(R) oral tablets, 2016).
    10) TELMISARTAN
    a) INITIAL DOSE: The usual starting dose is 40 mg once daily. Maintenance dosing ranges from 20 to 80 mg once daily (Prod Info MICARDIS(R) oral tablets, 2009).
    11) TELMISARTAN/HYDROCHLOROTHIAZIDE
    a) The usual starting dose is telmisartan 80 mg/hydrochlorothiazide 12.5 mg once daily. Titrate up to doses of telmisartan 160 mg/hydrochlorothiazide 25 mg if necessary (Prod Info MICARDIS(R) HCT oral tablets, 2016).
    12) VALSARTAN
    a) INITIAL DOSE: The recommended starting dose is 80 mg or 160 mg once daily when used as a monotherapy. Maintenance dosing ranges from 80 to 320 mg once daily. MAXIMUM dose, 320 mg once daily (Prod Info Diovan oral tablets, 2010).
    13) VALSARTAN/SACUBITRIL
    a) Initial dose (not currently taking ACE inhibitor or angiotensin receptor blocker, or taking low doses): Sacubitril 24 mg/valsartan 26 mg orally twice daily (Prod Info ENTRESTO(TM) oral tablets, 2015)
    b) Initial dose (switching from an ACE inhibitor or angiotensin receptor blocker at a standard dosage): Sacubitril 49 mg/valsartan 51 mg orally twice daily (Prod Info ENTRESTO(TM) oral tablets, 2015)
    c) Maintenance dose: Double the dose every 2 to 4 weeks to a target dosage of sacubitril 97 mg/valsartan 103 mg twice daily, as tolerated (Prod Info ENTRESTO(TM) oral tablets, 2015)
    7.2.2) PEDIATRIC
    A) AZILSARTAN MEDOXOMIL
    1) Safety and efficacy have not been established in pediatric patients (Prod Info EDARBI(R) oral tablets, 2011).
    B) AZILSARTAN MEDOXOMIL/CHLORTHALIDONE
    1) Safety and efficacy have not been established in pediatric patients (Prod Info EDARBYCLOR oral tablets, 2011).
    C) CANDESARTAN CILEXETIL
    1) LESS THAN 1 YEAR OF AGE: Use is NOT recommended (Prod Info ATACAND(R) oral tablets, 2009).
    2) 1 TO LESS THAN 6 YEARS OF AGE: The recommended starting dose of oral suspension is 0.2 mg/kg/day. The dose range is 0.05 to 0.4 mg/kg/day (Prod Info ATACAND(R) oral tablets, 2009).
    3) 6 TO LESS THAN 17 YEARS OF AGE: The recommended starting dose is 4 to 8 mg/day (range of 2 to 16 mg/day) for patients weighing less than 50 kg. The recommended starting dose is 8 to 16 mg/day (range of 4 to 32 mg/day) for patients weighing more than 50 kg (Prod Info ATACAND(R) oral tablets, 2009).
    D) EPROSARTAN MESYLATE
    1) Safety and efficacy have not been established in pediatric patients (Prod Info TEVETEN(R) oral tablets, 2011).
    E) IRBESARTAN
    1) LESS THAN 6 YEARS OF AGE: Safety and efficacy have not been established (Prod Info AVAPRO(R) oral tablets, 2005).
    2) 6 TO 16 YEARS OF AGE: Doses up to 4.5 mg/kg/day once daily were not effective in reducing blood pressure (Prod Info AVAPRO(R) oral tablets, 2005).
    F) LOSARTAN
    1) LESS THAN 6 YEARS OF AGE: Safety and efficacy have not been established and use is NOT recommended (Prod Info COZAAR(R) oral tablets, 2010).
    2) 6 TO 18 YEARS OF AGE: The usual recommended starting dose is 0.7 mg/kg once daily (up to 50 mg total). Doses above 1.4 mg/kg (or greater than 100 mg) daily have not been studied (Prod Info COZAAR(R) oral tablets, 2010).
    G) NEBIVOLOL/VALSARTAN
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info BYVALSON(TM) oral tablets, 2016)
    H) OLMESARTAN
    1) INFANTS LESS THAN 1 YEAR OF AGE: Olmesartan should NOT be administered to hypertensive patients younger than 1 year of age due to the potential for adverse effects on renal development (Prod Info BENICAR(R) oral tablets, 2012).
    2) LESS THAN 6 YEARS OF AGE: Efficacy has not been demonstrated (Prod Info BENICAR(R) oral tablets, 2012).
    3) 6 TO 16 YEARS OF AGE:
    a) WEIGHING 20 TO LESS THAN 35 KG: The recommended starting dose is 10 mg once daily. Maintenance doses range from 10 to 20 mg once daily. MAXIMUM DOSE: 20 MG (Prod Info BENICAR(R) oral tablets, 2012).
    b) WEIGHING 35 KG OR GREATER: The recommended starting dose is 20 mg once daily. Maintenance doses range from 20 to 40 mg once daily. MAXIMUM DOSE: 40 MG (Prod Info BENICAR(R) oral tablets, 2012).
    I) OLMESARTAN MEDOXOMIL/HYDROCHLOROTHIAZIDE
    1) Safety and efficacy in the pediatric population have not been established (Prod Info BENICAR HCT(R) oral tablets, 2016).
    J) TELMISARTAN
    1) Safety and efficacy have not been established in pediatric patients (Prod Info MICARDIS(R) oral tablets, 2009).
    K) TELMISARTAN/HYDROCHLOROTHIAZIDE
    1) Safety and efficacy in the pediatric population have not been established (Prod Info MICARDIS(R) HCT oral tablets, 2016).
    L) VALSARTAN
    1) LESS THAN 6 YEARS OF AGE: Use is NOT recommended (Prod Info Diovan oral tablets, 2010).
    2) 6 TO 16 YEARS OF AGE: The usual recommended starting dose is 1.3 mg/kg once daily (up to 40 mg total). Doses higher than 2.7 mg/kg (up to 160 mg) once daily have not been studied (Prod Info Diovan oral tablets, 2010).
    M) VALSARTAN/SACUBITRIL
    1) Safety and efficacy have not been established in pediatric patients (Prod Info ENTRESTO(TM) oral tablets, 2015).

Minimum Lethal Exposure

    A) SPECIFIC SUBSTANCE
    1) LOSARTAN
    a) HUMAN: No information is available on overdose in humans.
    b) ANIMAL DATA: Significant lethality was observed in mice and rats after oral administration of 1,000 and 2,000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m(2) basis (Prod Info COZAAR(R) oral tablets, 2005).
    2) VALSARTAN
    a) HUMAN: No information is available on lethal overdose in humans.
    b) ANIMAL DATA: Single oral doses up to 2000 mg/kg in rats produced salivation and diarrhea in the rat, and doses up to 1000 mg/kg in marmosets produced vomiting at the highest dose levels. The highest dose levels corresponded to 60 and 31 times, respectively, the maximum recommended human dose on a mg/m(2) basis (Prod Info DIOVAN(R) oral tablets, 2006).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) AZILSARTAN
    a) During clinical trials, azilsartan doses up to 320 mg orally once daily for 7 days were well tolerated in healthy subjects (Prod Info EDARBI(R) oral tablets, 2011).
    2) VALSARTAN
    a) Doses up to 320 mg were tolerated during clinical trials (Prod Info DIOVAN(R) oral tablets, 2006).
    b) CASE REPORT: A healthy adult developed mild hypotension and tachycardia, mild hypokalemia, asymptomatic hypoglycemia and painful muscle cramps after ingesting 2240 mg. She recovered with supportive care (Kumbasar et al, 2004).

Physicochemical

Physical Characteristics

    A) AZILSARTAN MEDOXOMIL is a white to nearly white powder that is freely soluble in methanol and practically insoluble in water (Prod Info Edarbi oral tablets, 2014).
    B) CANDESARTAN CILEXETIL is a white to off-white powder that is sparingly soluble in methanol and practically insoluble in water (Prod Info ATACAND(R) oral tablets, 2015).
    C) EPROSARTAN MESYLATE is a white to off-white free-flowing crystalline powder that is freely soluble in ethanol and insoluble in water. Eprosartan mesylate melts between 248 and 250 degrees C (Prod Info TEVETEN(R) oral tablets, 2014).
    D) IRBESARTAN is a white to off-white crystalline powder that is practically insoluble in water and slightly soluble in alcohol and methylene chloride. Irbesartan is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at a pH of 7.4 (Prod Info AVAPRO(R) oral tablets, 2014).
    E) LOSARTAN POTASSIUM is a white to off-white free-flowing crystalline powder that is slightly soluble in common organic solvents (ie, acetonitrile, methyl ethyl ketone), soluble in alcohols, and freely soluble in water (Prod Info COZAAR(R) oral tablets, 2014).
    F) OLMESARTAN MEDOXOMIL is a white to light yellowish-white powder or crystalline powder that is sparingly soluble in methanol and practically insoluble in water (Prod Info BENICAR(R) oral tablets, 2014).
    G) TELMISARTAN is a white to slightly yellowish solid that is practically insoluble in water. When in a pH range of 3 to 9, telmisartan is soluble in a strong base and sparingly soluble in a strong acid with the exception of hydrochloric acid (insoluble) (Prod Info MICARDIS(R) oral tablets, 2014).
    H) VALSARTAN is a white to practically white fine powder that is slightly soluble in water and soluble in methanol and ethanol (Prod Info Diovan(R) oral capsules, 2014).

Molecular Weight

    A) AZILSARTAN MEDOXOMIL: 606.62 (Prod Info Edarbi oral tablets, 2014)
    B) CANDESARTAN CILEXETIL: 610.67 (Prod Info ATACAND(R) oral tablets, 2015)
    C) EPROSARTAN MESYLATE: 520.625 (Prod Info TEVETEN(R) oral tablets, 2014)
    D) IRBESARTAN: 428.5 (Prod Info AVAPRO(R) oral tablets, 2014)
    E) LOSARTAN POTASSIUM: 461.01 (Prod Info COZAAR(R) oral tablets, 2014)
    F) OLMESARTAN MEDOXOMIL: 558.59 (Prod Info BENICAR(R) oral tablets, 2014)
    G) SACUBITRIL/VALSARTAN: 957.99 (complex structure) (Prod Info ENTRESTO(TM) oral tablets, 2015)
    H) TELMISARTAN: 514.63 (Prod Info MICARDIS(R) oral tablets, 2014)
    I) VALSARTAN: 435.5 (Prod Info Diovan(R) oral capsules, 2014)

References

General Bibliography

    1) Ahmad S: Losartan and reversible psychosis (letter). Cardiology 1996; 87:569-570.
    2) Andrade RJ, Lucena MI, & Santalla F: Hepatic injury associated with losartan (letter). Annal Pharmacother 1998; 32:1371-1372.
    3) Berkane N, Carlier P, Verstraete L, et al: Fetal toxicity of valsartan and possible reversible adverse side effects. Birth Defects Research 2004; 70:547-549.
    4) Bos-Thompson MA, Hillaire-Buys D, Muller F, et al: Fetal toxic effects of angiotensin II receptor antagonists: case report and follow-up after birth. Ann Pharmacother 2005; 39:157-161.
    5) Bosch X: Losartan-induced hepatotoxicity (letter). JAMA 1997; 278:1572.
    6) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    7) Doig JK, MacFadyen RJ, & Sweet CS: Dose-ranging study of the angiotensin Type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man. J Cardio Pharmacol 1993a; 21:732-738.
    8) Doig JK, MacFadyen RJ, Sweet CS, et al: Dose-ranging study of the angiotensin type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man. J Carciovas Pharmacol 1993; 21:732-738.
    9) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    10) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    11) Forrester MB: Valsartan ingestions among adults reported to Texas poison control centers, 2000 to 2005. J Med Toxicol 2007; 3(4):157-163.
    12) Gersak K, Cvijic M, & Cerar LK: Angiotensin II receptor blockers in pregnancy: a report of five cases. Reprod Toxicol 2009; 28(1):109-112.
    13) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    14) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    15) Haaland K: Angiotensin II receptor antagonists against migraine in pregnancy: fatal outcome. J Headache Pain 2010; epub:epub-.
    16) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    17) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    18) Kumbasar B, Atlibatur Akbas F, Serez K, et al: High-dose exposure to valsartan with suicidal intention. Int J Clin Pharmacol Therapeutics 2004; 42:328-329.
    19) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    20) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    21) Mann RD, Mackay F, Pearce G, et al: Losartan: a study of pharmacovigilance data on 14522 patients. J Hum Hypertens 1999; 13:551-557.
    22) Marchetto L, Sordino D, De Bernardo G, et al: Postnatal acute renal failure after fetal exposure to angiotensin receptor blockers. BMJ Case Rep 2015; 2015:1.
    23) Miura K, Sekine T, Iida A, et al: Salt-losing nephrogenic diabetes insipidus caused by fetal exposure to angiotensin receptor blocker. Pediatr Nephrol 2009; 24(6):1235-1238.
    24) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    25) Nayar B, Singhal A, Aggarwal R, et al: Losartan induced fetal toxicity. Indian J Pediatr 2003; 70(11):923-924.
    26) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    27) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    28) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    29) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    30) Porta M, Hainer JW, Jansson SO, et al: Exposure to candesartan during the first trimester of pregnancy in type 1 diabetes: experience from the placebo-controlled DIabetic REtinopathy Candesartan Trials. Diabetologia 2011; 54(6):1298-1303.
    31) Product Information: MICARDIS(R) HCT oral tablets, telmisartan hydrochlorothiazide oral tablets. Boehringer Ingelheim Pharmaceuticals, Inc. (per Manufacturer), Ridgefield, CT, 2016.
    32) Product Information: ATACAND(R) oral tablets, candesartan cilexetil oral tablets. AstraZeneca LP, Wilmington, DE, 2005.
    33) Product Information: ATACAND(R) oral tablets, candesartan cilexetil oral tablets. AstraZeneca LP (per FDA), Wilmington, DE, 2015.
    34) Product Information: ATACAND(R) oral tablets, candesartan cilexetil oral tablets. AstraZeneca LP, Wilmington, DE, 2009.
    35) Product Information: ATACAND(R) oral tablets, candesartan cilexetil oral tablets. AstraZeneca LP, Wilmington, DE, 2009a.
    36) Product Information: ATACAND(TM) oral tablets, candesartan cilexetil oral tablets. AstraZeneca,LP, Wilmington, DE, 2005.
    37) Product Information: ATACAND(TM) oral tablets, candesartan cilexetil oral tablets. AstraZeneca LP (per FDA), Wilmington, DE, 2011.
    38) Product Information: AVAPRO(R) oral tablets, irbesartan oral tablets. Bristol-Myers Squibb / Sanofi-Synthelabo Partnership, New York, NY, 2005a.
    39) Product Information: AVAPRO(R) oral tablets, irbesartan oral tablets. Bristol-Myers Squibb Company, New York, NY, 2005.
    40) Product Information: AVAPRO(R) oral tablets, irbesartan oral tablets. Bristol-Myers Squibb Sanofi-Synthelabo Partnership (per FDA), New York, NY, 2011.
    41) Product Information: AVAPRO(R) oral tablets, irbesartan oral tablets. Sanofi-Aventis U.S. LLC (per FDA), Bridgewater, NJ, 2014.
    42) Product Information: BENICAR HCT(R) oral tablets, olmesartan medoxomil hydrochlorothiazide oral tablets. Daiichi Sankyo, Inc (per FDA), Parsippany, NJ, 2016.
    43) Product Information: BENICAR(R) oral tablets, olmesartan medoxomil oral tablets. Sankyo Pharma,Inc, Parsippany, NJ, 2006.
    44) Product Information: BENICAR(R) oral tablets, olmesartan medoxomil oral tablets. Daiichi Sankyo, Inc (Per FDA), Parsippany, NJ, 2012.
    45) Product Information: BENICAR(R) oral tablets, olmesartan medoxomil oral tablets. Daiichi Sankyo, Inc. (per FDA), Parsippany, NJ, 2014.
    46) Product Information: BYVALSON(TM) oral tablets, nebivolol, valsartan oral tablets. Allergan USA Inc (per manufacturer), Irvine, CA, 2016.
    47) Product Information: COZAAR(R) oral tablets, losartan potassium oral tablets. Merck & Co.,Inc., Whitehouse Station, NJ, 2005.
    48) Product Information: COZAAR(R) oral tablets, losartan potassium oral tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2014.
    49) Product Information: COZAAR(R) oral tablets, losartan potassium oral tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2014a.
    50) Product Information: COZAAR(R) oral tablets, losartan potassium oral tablets. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, 2010.
    51) Product Information: Cozaar(R), losartan. Merck & Co, Inc, West Point, PA, 1999.
    52) Product Information: DIOVAN(R) oral tablets, valsartan oral tablets. Novartis Pharmaceuticals Corp, East Hanover, NJ, 2007.
    53) Product Information: DIOVAN(R) oral tablets, valsartan oral tablets. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2006.
    54) Product Information: Diovan oral tablets, valsartan oral tablets. Novartis Pharmaceuticals Corp. (per manufacturer), East Hanover, NJ, 2011.
    55) Product Information: Diovan oral tablets, valsartan oral tablets. Novartis Pharmaceuticals Corp., East Hanover, NJ, 2010.
    56) Product Information: Diovan(R) oral capsules, valsartan oral capsules. Novartis Pharmaceuticals Corp. (per FDA), East Hanover, NJ, 2014.
    57) Product Information: Diovan(R), valsartan. Novartis Pharmaceuticals Corp, East Hanover, NJ, 2000.
    58) Product Information: EDARBI oral tablets, azilsartan medoxomil oral tablets. Takeda Pharmaceuticals America, Inc. (per FDA), Deerfield, IL, 2011.
    59) Product Information: EDARBI(R) oral tablets, azilsartan medoxomil oral tablets. Takeda Pharmaceuticals America, Inc, Deerfield, IL, 2011.
    60) Product Information: EDARBYCLOR oral tablets, azilsartan medoxomil and chlorthalidone oral tablets. Takeda Pharmaceuticals America, Inc (Per Manufacturer), Deerfield, IL, 2011.
    61) Product Information: ENTRESTO(TM) oral tablets, sacubitril valsartan oral tablets. Novartis Pharmaceuticals Corporation (per Manufacturer), East Hanover, NJ, 2015.
    62) Product Information: Edarbi oral tablets, azilsartan medoxomil oral tablets. Arbor Pharmaceuticals, LLC (per FDA), Atlanta, GA, 2014.
    63) Product Information: Exforge HCT(R) oral tablets, amlodipine, valsartan, hydrochlorothiazide oral tablets. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2009.
    64) Product Information: HYZAAR(R) oral tablets, losartan postassium, hydrochlorothiazide oral tablets. Merck & Co,Inc, Whitehouse Station, NJ, 2005.
    65) Product Information: MICARDIS(R) oral tablets, telmisartan oral tablets. Boehringer Ingelheim Pharmaceuticals,Inc, Ridgefield, CT, 2006.
    66) Product Information: MICARDIS(R) oral tablets, telmisartan oral tablets. Boehringer Ingleheim, Ridgefield, CT, 2005.
    67) Product Information: MICARDIS(R) oral tablets, telmisartan oral tablets. Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, 2009.
    68) Product Information: MICARDIS(R) oral tablets, telmisartan oral tablets. Boehringer Ingelheim Pharmaceuticals, Inc. (per FDA), Ridgefield, CT, 2014.
    69) Product Information: MICARDIS(R) oral tablets, telmisartan oral tablets. Boehringer Ingelheim Pharmaceuticals, Inc. (per manufacturer), Ridgefield, CT, 2011.
    70) Product Information: TEVETEN(R) HCT oral tablets, eprosartan mesylate, hydrochlorothiazide oral tablets. Kos Pharmaceuticals,Inc, Cranbury, NJ, 2006.
    71) Product Information: TEVETEN(R) oral tablets, eprosartan mesylate oral tablets. Kos Pharmaceuticals, Cranbury, NJ, 2005.
    72) Product Information: TEVETEN(R) oral tablets, eprosartan mesylate oral tablets. Kos Pharmaceuticals,Inc, Cranbury, NJ, 2005a.
    73) Product Information: TEVETEN(R) oral tablets, eprosartan mesylate oral tablets. AbbVie Inc. (per FDA), North Chicago, IL, 2014.
    74) Product Information: TEVETEN(R) oral tablets, eprosartan mesylate oral tablets. Abbott Laboratories (per manufacturer), North Chicago, IL, 2011.
    75) Product Information: TRIBENZOR(R) oral tablets, olmesartan medoxomil amlodipine hydrochlorothiazide oral tablets. Daiichi Sankyo, Inc, Parsippany, NJ, 2010.
    76) Product Information: TWYNSTA(R) oral tablets, telmisartan amlodipine oral tablets. Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, 2009.
    77) Product Information: VALTURNA(R) oral tablets, aliskiren and valsartan oral tablets. Novartis Pharmaceuticals Corporation, 2009.
    78) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    79) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    80) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    81) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    82) Saji H, Yamanaka M, & Hagiwara A: Losartan and fetal toxic effects (letter). Lancet 2001; 357:363.
    83) Siegl PKS: Discovery of losartan, the first specific non-peptide angiotensin II receptor antagonist. J Hypertens 1993; 11(Suppl 3):S19-S22.
    84) Simonetti GD, Baumann T, Pachlopnik JM, et al: Non-lethal fetal toxicity of the angiotensin receptor blocker candesartan. Pediatr Nephrol 2006; 21(9):1329-1330.
    85) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.