Professional Drug Information > Valsartan

Valsartan (Systemic)

VA CLASSIFICATION
Primary: CV805
Secondary: CV409

Commonly used brand name(s): Diovan.

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



Category:


Antihypertensive—

Indications

Accepted

Hypertension (treatment)—Valsartan is indicated for the treatment of hypertension ^{01}{14}. It may be used alone or in combination with other antihypertensive medications ^{01}{14}. Valsartan is normally used in those patients in whom treatment with a diuretic or beta-blocker was ineffective or associated with unacceptable side effects. Valsartan may be used as an initial agent in those patients in whom the use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious side effects ^{14}.
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    435.5 ^{01}{14}

Mechanism of action/Effect:

Valsartan is a nonpeptide angiotensin II antagonist that selectively blocks the binding of angiotensin II to the AT ₁ receptors in tissues such as vascular smooth muscle and the adrenal gland ^{01}. In the renin-angiotensin system, angiotensin I is converted by angiotensin-converting enzyme (ACE) to form angiotensin II ^{01}. Angiotensin II stimulates the adrenal cortex to synthesize and secrete aldosterone, which decreases the excretion of sodium and increases the excretion of potassium ^{01}. Angiotensin II also acts as a vasoconstrictor in vascular smooth muscle ^{01}. Valsartan, by blocking the binding of angiotensin II to the AT ₁ receptors, promotes vasodilation and decreases the effects of aldosterone ^{01}. The negative feedback regulation of angiotensin II on renin secretion also is inhibited, resulting in a rise in plasma renin concentrations and a consequent rise in angiotensin II plasma concentrations; however, these effects do not counteract the blood pressure–lowering effect that occurs ^{01}.

Absorption:

Absolute bioavailability for the capsule formulation is approximately 25% (range, 10 to 35%) ^{01}{14}.

Food decreases the area under the plasma concentration–time curve (AUC) and peak plasma concentration (C _max) by approximately 40 and 50%, respectively ^{01}.

Distribution:

Vol _D—Steady-state: 17 L ^{01}{14}.

Protein binding:

Very high (95%), mainly to albumin ^{01}{14}.

Biotransformation:

The enzymes responsible for the metabolism of valsartan have not been identified; however, valsartan is not believed to be metabolized by cytochrome P450 isozymes ^{01}{14}. The primary metabolite, valeryl 4-hydroxy valsartan, is inactive, with an affinity for the AT ₁ receptor of about one-two hundredth that of valsartan itself ^{01}. About 20% of a dose of valsartan is eliminated as metabolites ^{01}.

Half-life:


Elimination:

Approximately 6 hours ^{01}

6.6 hours in patients with renal failure.^{02}


Onset of action:

Hypertension, oral: 2 hours.^{03}{14}

Time to peak concentration:

2 to 4 hours ^{01}.

3.5 to 4 hours in patients with mild to moderate liver disease.^{05}

2 to 3 hours in patients with mild to severe renal disease.^{06}

Peak serum concentration:

3.3 mg/L following a single 160-mg dose in healthy volunteers.^{05}

3.9 to 5.9 mg/L following a single 160-mg dose in patients with mild to moderate liver disease^{05}

0.8 to 1.6 mg/L following a single 80-mg dose in 12 patients with mild to severe renal disease.^{06}

Duration of action:

Hypertension, oral: 24 hours.^{{01}{04}{12}{13}{14}}

Elimination:
    Renal—13% ^{01}{14}.
    Fecal—83% ^{01}{14}.


In dialysis—
        Valsartan is not removed from the plasma by hemodialysis.^{11}{12}{14}



Precautions to Consider

Carcinogenicity

No evidence of carcinogenicity was found in mice or rats given valsartan for up to 2 years in dietary doses of up to 160 and 200 mg per kg of body weight (mg/kg) per day, respectively ^{01}{14}. These doses represent 2.6 and 6 times the maximum recommended human dose (MRHD), respectively, on a mg per square meter of body surface area (mg/m ²) basis, assuming an oral dose of 320 mg per day and a 60-kg patient ^{01}.

Mutagenicity

Mutagenicity was not detected at either the gene or chromosome level in bacterial mutagenicity tests with Salmonella (Ames test) and E. coli , a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells, or a rat micronucleus test ^{01}{14}.

Pregnancy/Reproduction
Fertility—
No impairment of reproductive performance was found in male or female rats given oral doses of up to 200 mg/kg per day ^{01}. This dose represents six times the MRHD on a mg/m ² basis, assuming an oral dose of 320 mg per day and a 60-kg patient ^{01}.

Pregnancy—
Medications that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and mortality when administered to pregnant women during the second and third trimesters ^{01}{14}. Valsartan should be discontinued as soon as possible when pregnancy is detected, unless no alternative therapy can be used ^{01}{14}. In the latter instance, serial ultrasound examinations should be performed to assess the intra-amniotic environment ^{01}{14}. If oligohydramnios is observed, valsartan should be discontinued unless it is considered lifesaving for the mother ^{01}{14}. Perinatal diagnostic tests, such as contraction-stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) also may be appropriate during the applicable week of pregnancy ^{01}{14}. Oligohydramnios may not appear until after the fetus has sustained irreversible damage ^{01}{14}.

Fetal exposure to drugs that act directly on the renin-angiotensin system during the second and third trimesters can cause hypotension, reversible or irreversible renal failure, anuria, neonatal skull hypoplasia, and death in the fetus or neonate ^{01}{14}. Maternal oligohydramnios, which may result from decreased fetal renal function, has been reported, and is associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development ^{01}{14}. Other adverse effects that have been reported are prematurity, intrauterine growth retardation, and patent ductus arteriosus, although it is not clear how these effects are related to drug exposure ^{01}{14}. When limited to the first trimester, exposure to this medication does not appear to be associated with these adverse effects ^{01}{14}.

Infants exposed in utero to angiotensin II receptor antagonists should be closely observed for hypotension, oliguria, and hyperkalemia ^{01}{14}. Oliguria should be treated with support of blood pressure and renal perfusion ^{01}{14}. Dialysis or exchange transfusion may be necessary to reverse hypotension and/or substitute for disordered renal function ^{01}{14}.

Teratogenic effects were not observed in pregnant mice or rats given oral doses of up to 600 mg/kg per day or to pregnant rabbits given oral doses of up to 10 mg/kg per day ^{01}{14}. Studies in rats given oral, maternally toxic (based on a reduction in body weight gain and food consumption) doses of 600 mg/kg per day of valsartan during organogenesis or late gestation and lactation periods resulted in significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones ^{01}{14}. Studies in rabbits given maternally toxic (associated with mortality) doses of 5 and 10 mg/kg per day of valsartan resulted in fetotoxic effects, such as fetal resorptions, litter loss, abortions, and low body weight in pups ^{01}{14}. No adverse effects were observed in mice, rats, and rabbits given 600, 200, and 2 mg/kg per day, respectively, of valsartan ^{01}. This represents 9, 6, and 0.1 times, respectively, the MRHD on a mg/m ² basis, assuming an oral dose of 320 mg/day and a 60-kg patient ^{01}.

FDA Pregnancy Category C (first trimester) ^{01}.

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

Breast-feeding

It is not known whether valsartan is distributed into breast milk ^{01}{14}. However, valsartan is distributed into the milk of lactating rats ^{01}{14}. Because of the potential for adverse effects, it is recommended that valsartan not be administered to nursing mothers ^{01}.

Pediatrics

No information is available on the relationship of age to the effects of valsartan in pediatric patients. Safety and efficacy have not been established ^{01}{14}.


Geriatrics


Use of valsartan in patients 65 years of age and older (36.2% of patients in clinical studies) has not demonstrated geriatrics-specific problems that would limit the usefulness of valsartan in the elderly ^{01}. However, the area under the plasma concentration–time curve (AUC) and elimination half-life increased by 70 and 35%, respectively, when compared with those in younger patients ^{01}. Elderly patients may also experience greater sensitivity to the effects of valsartan ^{01}{14}.

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


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

» Diuretics    (concurrent use with valsartan may have additive hypotensive effects ^{01}{14})


Lithium salts    (concurrent use with valsartan may reduce lithium clearance; monitor serum lithium levels^{14})


» Potassium-sparing drugs, potassium supplements, or potassium-containing salt substitutes    (concurrent use with valsartan may increase serum potassium ^{14})


Warfarin    (concurrent use with valsartan may cause an increase (12%) in prothrombin time (PT); activated partial thromboplastin time (APTT) is unaffected ^{14})



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

With physiology/laboratory test values
Creatinine, serum ^{01}    (minor increases in concentrations may occur ^{01}{14})


Hematocrit ^{01} and
Hemoglobin ^{01}    (in clinical studies, decreases of greater than 20% occurred in 0.8 and 0.4% of hematocrit and hemoglobin values, respectively, compared with 0.1% and 0.1% in placebo-treated patients.^{{01}{11}{12}{14}} Valsartan therapy was discontinued in one patient because of microcytic anemia ^{01}{14})


Liver function tests    (in clinical studies, occasional elevations of greater than 150% have occurred in valsartan-treated patients ^{01}; three patients (< 0.1%) discontinued valsartan because of elevated liver enzyme values ^{01}{11}{12})


Leukocyte counts ^{01}    (in clinical studies, neutropenia occurred in 1.9% of patients who were taking valsartan and in 0.8% of patients treated with placebo ^{{01}{11}{12}{14}})


Potassium, serum ^{01}    (in clinical studies, increases in concentration of greater than 20% were observed in 4.4% of patients treated with valsartan compared to 2.9% of placebo-treated patients; however, this did not require discontinuation of valsartan therapy ^{01}{12}{14})


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


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to valsartan
Risk-benefit should be considered when the following medical problems exist
Dehydration (sodium or volume depletion, due to excessive perspiration, vomiting, diarrhea, prolonged diuretic therapy, dialysis, or dietary salt restriction ^{01} )    (a reduction in salt or fluid volume may increase the risk of symptomatic hypotension ^{01}{14})


Hepatic function impairment, mild to moderate, including biliary obstructive disorders ^{01}{05}{14} or
Hepatic function impairment, severe    (in patients with mild to moderate chronic liver disease, decreased biliary elimination of valsartan may result in an increase in the AUC and peak serum concentration ^{01}{05}{11}; the AUC in patients with mild to moderate chronic liver disease may be doubled, as compared with healthy volunteers ^{01}{05}{11}; no information is available on the use of valsartan in patients with severe hepatic function impairment)


Renal artery stenosis, unilateral or bilateral ^{01}{14} or
Renal function impairment ^{01}{14}    (increases in serum creatinine or blood urea nitrogen [BUN]^{01} and small increases in elimination half-life^{02} may occur; therapy with angiotensin receptor–antagonists in patients susceptible to changes in the renin-angiotensin-aldosterone system, such as patients with severe congestive heart failure, has been associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death ^{{01}{11}{12}{14}})



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

» Blood pressure measurements ^{01}{14}    (periodic monitoring is necessary for titration of dose according to the patient's response ^{01}{14})


Renal function ^{14}    (use of valsartan should include assessment of renal function ^{14})




Side/Adverse Effects

Note: Elevated liver enzymes and very rare occurrences of hepatitis have been reported in post-marketing experiences.^{11}

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

Those indicating need for medical attention
Incidence rare
    
Angioedema^{11} (sudden trouble in swallowing or breathing; swelling of face, mouth, hands, or feet; hoarseness )
    
hypotension ^{01} (dizziness, lightheadedness, or fainting)—usually seen in volume- or salt-depleted patients receiving high doses of a diuretic ^{01}
    
neutropenia ^{01} (chills; fever; sore throat )—incidence 1.9% ^{01}



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Abdominal pain ^{01}
    
arthralgia ^{14}(pain, swelling, or redness in joints; muscle pain or stiffness; difficulty in moving)
    
back pain ^{14}
    
coughing ^{14}
    
diarrhea ^{01}
    
dizziness ^{01}
    
fatigue ^{01}
    
headache ^{01}
    
upper respiratory tract infection ^{14}(cough; fever; sneezing; sore throat)
    
viral infection ^{01}


Note: In clinical trials, the side effects that most often resulted in the discontinuation of therapy were headache and dizziness, which occurred in 2.3% of patients taking valsartan and in 2% of patients taking placebo.^{01}{11}{12}





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

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
    
Bradycardia ^{01} ( slow heartbeat)—as a result of parasympathetic (vagal) stimulation ^{01}
    
hypotension ^{01}{14} (dizziness, lightheadedness, or fainting)
    
tachycardia ^{01}{14} ( fast heartbeat)


Treatment of overdose
Treatment should be symptomatic and supportive ^{01}{14}.

Valsartan is not removed from plasma by dialysis ^{14}.

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


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Valsartan (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to valsartan

Pregnancy—Fetal and neonatal hypotension, skull hypoplasia, renal failure, and death have been reported in humans; valsartan should be discontinued as soon as possible when pregnancy is detected





Breast-feeding—Valsartan is distributed into milk of lactating rats; not recommended in nursing mothers





Use in the elderly—Area under the plasma concentration–time curve (AUC) and half-life may be increased; may experience greater sensitivity to the medication's effects
Other medications, especially diuretics, potassium-sparing drugs, potassium supplements, and potassium-containing salt substitutes

Proper use of this medication
» Compliance with therapy; taking medication at the same time each day to maintain the antihypertensive effect

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

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress

Notifying physician immediately if pregnancy is suspected

Not taking other medications without consulting the physician

Caution when driving or doing other things requiring alertness because of possible dizziness

To prevent dehydration and hypotension, checking with physician if severe nausea, vomiting, or diarrhea occurs and continues

Caution when exercising or during exposure to hot weather because of the risk of dehydration and hypotension due to reduced fluid volume


Side/adverse effects
Signs of potential side effects, especially angioedema, hypotension, and neutropenia


General Dosing Information
Dosage must be adjusted, on the basis of clinical response, to meet the individual requirements of each patient.

Studies using valsartan in patients with severe renal function impairment or in patients undergoing dialysis have not been done ^{01}. Caution should be used when using valsartan in the treatment of these patients and in patients with hepatic function impairment ^{01}{14}.

The antihypertensive effect is considerable after 2 weeks of valsartan therapy ^{01}{14}. The maximum antihypertensive effect is usually attained after 4 weeks of therapy ^{01}{14}.

Diet/Nutrition
Valsartan may be taken with or without food ^{01}{14}.

For treatment of adverse effects
Recommended treatment consists of the following:    • Treatment of symptomatic hypotension involves placing the patient in a supine position and, if needed, administering normal saline intravenously ^{01}.



Oral Dosage Forms

VALSARTAN CAPSULES

Usual adult dose
Antihypertensive
Oral, initially 80 mg once a day, when used as single therapy in patients who are not volume-depleted ^{01}{14}.

Note: For additional antihypertensive effect, the dosage may be increased to 160 or 320 mg, or a diuretic may be added ^{01}{14}. The added effect of a diuretic will be greater than that of dose increases above 80 mg ^{01}.
Initial doses of 40 mg have been used in clinical trials in patients with creatinine clearance between 20 to 30 mL/min/1.73 m ², titrating to 80 mg after 4 weeks if needed.^{02}



Usual adult prescribing limits
320 mg per day ^{01}.

Usual pediatric dose
Safety and efficacy have not been established ^{01}{14}.

Strength(s) usually available
U.S.—


80 mg (Rx) [Diovan]


160 mg (Rx) [Diovan]

Canada—


80 mg (Rx) [Diovan (magnesium stearate) (microcrystalline cellulose) (povidone compounds) (sodium lauryl sulfate) (gelatin) (black iron oxide) (red iron oxide) (titanium dioxide )]^{14}


160 mg (Rx) [Diovan (magnesium stearate) (microcrystalline cellulose) (povidone compounds) (sodium lauryl sulfate) (gelatin) (black iron oxide) (red iron oxide) (titanium dioxide )]^{14}

Packaging and storage:
Store below 30 ºC (86 ºF) ^{01}. Protect from moisture and heat ^{14}{01}. Store in tight container ^{01}.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice.
   • May cause dizziness.

Developed: 10/31/1997
Revised: 09/06/2000

References

1. Valsartan package insert (Ciba—US), Rev 12/96, Rec 4/97.
   

2. Perico N, Spormann D, Peruzzi E et al: Efficacy and tolerability of valsartan compared with lisinopril in patients with hypertension and renal insufficiency. Clin Drug Invest 1997; 14:252–259.
   

3. Mueller P, Cohen P, de Gasparo M et al: Angiotensin II receptor blockade with single doses of valsartan in healthy, normotensive subjects. Eur J Clin Pharmacol 1994; 47: 231–245.
   

4. Neutel J, Weber M, Pool J et al: Valsartan, a new angiotensin II antagonist: antihypertensive effects over 24 hours. Clin Ther 1997; 19:447–458.
   

5. Brookman LJ, Rolan PE, Benjamin IS et al: Pharmacokinetics of valsartan in patients with liver disease. Clin Pharmacol Ther 1997; 62:272–278.
   

6. Prasad P, Mangat S, Choi L et al: Effect of renal function on the pharmacokinetics of valsartan. Clin Drug Invest 1997; 13:207–214.
   

7. Stroedter D, Zeissig I, Heath R et al: Angiotension-II-Antagonist cGP 48933 (Valsartan) — Ergebnisse einer doppelblinden, plazebo-kontrollierten Multicenter-Studie. Nieren- und Hochdruckkrankheiten 1994; 23:217–220.
   

8. Mazayev VP, Fomina IG, Kazakov EN et al: Valsartan in heart failure patients previously untreated with an ACE inhibitor. Int J Cardiol 1998; 65:239–246.
   

9. Faulhaber H-D, Mann JF, Stein G et al: Effect of Valsartan on renal function in patients with hypertension and stable renal insufficiency. Curr Ther Res 1999; 60(3):170–183.
   

10. Plum J, Bunten B, Nemeth R et al: Effects of the angiotensin II antagonist valsartan on blood pressure, proteinuria, and renal hemodynamics in patients with chronic renal failure and hypertension. J Am Soc Nephrol 1998; 9:2223–2234.
    

11. Product information: Diovan, valsartan. Novartis, East Hanover, NJ, 12/98.
    

12. Manufacturer comment 3/07/00, Associate Drug Information Specialist, Novartis.
    

13. Panel comment, 3/01/00
    

14. Product information: Diovan, valsartan. Novartis, Dorval, Quebec, Canada, (PI revised 10/30/1997) reviewed 08/2000.
    

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