Amlodipine-Valsartan-Hctz (amlodipine besylate/valsartan/hydrochlorothiazide)

Dosage of hydrochlorothiazide should be individualized according to the patient's requirements and response. The lowest dosage necessary to produce the desired clinical effect should be used. If hydrochlorothiazide is added to the regimen of a patient stabilized on a potent hypotensive agent, dosage of the hypotensive agent should initially be reduced to avoid the possibility of severe hypotension.

Dosage of amlodipine besylate and amlodipine benzoate is expressed in terms of amlodipine.

Dosage of valsartan must be individualized and adjusted according to blood pressure response. Substantial therapeutic response to valsartan generally occurs within 2 weeks of treatment initiation and maximal reduction is generally achieved after 4 weeks.

Hydrochlorothiazide is administered orally.

Amlodipine is administered orally (as tablets, solution, or suspension) without regard to meals, preferably at the same time each day. Amlodipine is also commercially available in fixed combination with benazepril (e.g., Lotrel(R)), olmesartan medoxomil (e.g., Azor(R)), olmesartan medoxomil and hydrochlorothiazide (e.g., Tribenzor(R)), telmisartan, valsartan (e.g., Exforge(R)), valsartan and hydrochlorothiazide (e.g., Exforge(R) HCT), and atorvastatin (e.g., Caduet(R)). See the full prescribing information for additional administration instructions for each specific combination product.

If a dose of amlodipine is missed, the missed dose may be administered as soon as possible. If the dose is missed for more than 12 hours, do not take the dose and resume treatment with the next scheduled dose.

Amlodipine besylate tablets: Store the tablets at 15-30degreesC; dispense in a tight, light-resistant container.

Amlodipine besylate oral solution (Norliqva(R)): Store the oral solution at 20-25degreesC (excursions permitted to 15-30degreesC). Store and dispense in the original packaging (amber glass bottle).

Amlodipine benzoate oral suspension (Katerzia(R)): Shake the suspension well and measure each dose with a calibrated measuring device; do not use a household teaspoon or tablespoon. Store the oral suspension at 2-8degreesC and protect from light. Avoid freezing and excessive heat.

Valsartan is commercially available as tablets and a solution, administered orally. Although food may decrease the rate and extent (by about 40%) of valsartan absorption, the manufacturers state that the drug can be administered without regard to meals.

Valsartan is also commercially available in fixed-combination tablets containing valsartan and hydrochlorothiazide; valsartan and amlodipine; and valsartan, amlodipine, and hydrochlorothiazide; see the full prescribing information for administration of these combination products.

Store commercially available valsartan solution and tablets at 20degrees-25degreesC; excursions permitted between 15degrees-30degreesC. Protect from moisture.

Valsartan may be administered as an extemporaneously prepared oral suspension in pediatric patients 1--5 years of age, in patients >5 years of age who are unable to swallow tablets, or in pediatric patients for whom the calculated daily dosage does not correspond to the available tablet strengths. The tablets and oral suspension are not substitutable on a milligram-per-milligram basis. Do not combine two dosage forms to achieve the total dosage. The systemic exposure to valsartan is 60% higher with the suspension compared to tablets. When switching between dosage forms, the dosage of valsartan may need to be adjusted.

An extemporaneous suspension containing valsartan 4 mg/mL can be prepared in the following manner. First, add 80 mL of suspending vehicle (e.g., Ora-Plus(R)) to an amber glass bottle containing eight 80-mg tablets of valsartan, and shake the contents for at least 2 minutes. The concentrated suspension should be allowed to stand for at least 1 hour following reconstitution and then should be shaken for at least an additional minute. Dilute the concentrated valsartan suspension with 80 mL of sweetening vehicle (e.g., Ora-Sweet SF(R)), and shake for at least 10 seconds to disperse the contents. Shake bottle for at least 10 seconds before each dose is dispensed. When stored in an amber glass bottle with child-resistant screw-cap closure at a temperature of <30degreesC or at 2-8degreesC, the extemporaneous suspension is stable for up to 30 or up to 75 days, respectively.

Administer a missed dose as soon as possible unless it is almost time for the next dose. Do not double a dose to make up for a missed dose.

No dosing information is available for this tab.

No dosing information is available for this tab.

Amlodipine is a weak inhibitor of cytochrome P-450 (CYP) 3A isoenzymes.

When amlodipine is used in fixed combination with other drugs, interactions associated with the concomitant agent(s) must be considered in addition to those associated with amlodipine.

In vitro studies indicate that valsartan is minimally metabolized by cytochrome P-450 (CYP) 2C9.

In vitro studies indicate that valsartan does not inhibit CYP isoenzymes at therapeutic concentrations. Valsartan is a substrate of the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1 and the hepatic efflux transporter multidrug resistance-associated protein 2 (MRP2).

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

Amlodipine is contraindicated in patients with known hypersensitivity to the drug.

*Known hypersensitivity to valsartan or any ingredient in the formulation.

*Concomitant use of valsartan and aliskiren in patients with diabetes mellitus.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

Adverse effects reported in 1% or more of patients receiving amlodipine include dose-related edema, dizziness, flushing, and palpitations; fatigue, nausea, abdominal pain, and somnolence also reported. Adverse effects reported in the clinical trial in pediatric patients with hypertension were similar to those that have been reported in adults.

Adverse effects occurring patients with hypertension receiving valsartan include headache, dizziness, viral infection, fatigue, and abdominal pain.

Adverse effects occurring in patients with heart failure receiving valsartan include dizziness, hypotension, diarrhea, arthralgia, fatigue, back pain, and hyperkalemia.

In patients receiving valsartan following acute MI, the most common adverse effects resulting in discontinuance of the drug included hypotension, cough, and increased blood creatinine.

There are no severe adverse reactions for this drug.

There are no less severe adverse reactions for this drug.

No enhanced messaging available.

Safety and efficacy of amlodipine in children younger than 6 years of age have not been established. Safety and effectiveness of amlodipine (2.5-5 mg daily) for the treatment of pediatric patients 6-17 years of age with hypertension have been established in a trial of 8 weeks' duration.

Safety and efficacy of amlodipine in fixed combination with atorvastatin, benazepril, olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide) have not been established in pediatric patients.

Safety and efficacy of valsartan tablets have been established in a randomized, double-blind clinical trial in pediatric patients 1-16 years of age with hypertension; adverse effects of the drug in this age group were similar to those observed in adults. In children and adolescents with hypertension where underlying renal abnormalities may be more common, renal function and serum potassium should be closely monitored as clinically indicated.

Valsartan tablet use is not recommended in children less than 1 year of age. Valsartan oral solution is not recommended in children less than 6 years of age. It is not known whether postnatal use of valsartan, before maturation of renal function is complete, has a long-term deleterious effect on the kidney.

Safety and efficacy of valsartan in pediatric patients with a glomerular filtration rate less than 30 mL/minute per 1.73 m2 have not been established.

The manufacturers state that there are limited data on use of amlodipine in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. There is some data indicating that amlodipine crosses the placenta in measurable quantities in the third trimester of pregnancy.

Hypertension in pregnancy is a major cause of maternal, fetal or neonatal morbidity and mortality. Maternal risks include pre-eclampsia, gestational diabetes, premature delivery, placental abruption, delivery complications (e.g., need for cesarean section, postpartum hemorrhage), stroke, pulmonary edema, thromboembolic events, multiple organ failure (liver, kidney) and disseminated intravascular coagulation. Fetal risks include intrauterine growth restriction, prematurity, and intrauterine death. Neonates may require prolonged high-level care and experience morbidity. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Teratogenicity or other embryo-fetal toxicity was not observed when pregnant rats and rabbits were treated orally with a different salt form of amlodipine (amlodipine maleate) at doses up to 10 mg/kg per day (approximately 10 and 20 times the maximum recommended human dose (MRHD) based on body surface area, respectively) during their respective periods of major organogenesis. However, when amlodipine maleate at doses up to 10 mg amlodipine/kg per day was administered to rats for 14 days prior to mating and throughout gestation, litter size decreased approximately 50%, and a 5-fold increase in the number of intrauterine deaths was observed at this dose equivalent to 10 times the MDRD. Amlodipine maleate has also been shown to prolong both the gestation period and the duration of labor in rats at this dose.

Valsartan can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the RAS during the second or third trimester of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Oligohydramnios in pregnant women who use drugs affecting the RAS in the second or third trimester of pregnancy can result in reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and death.

Valsartan should be discontinued as soon as possible when pregnancy is detected. In the unusual case that there is no appropriate alternative to therapy, apprise the mother of the potential risk to the fetus. If valsartan is taken during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate. Discontinue valsartan if oligohydramnios is detected; however, this may not appear until after the fetus has sustained irreversible injury.

The manufacturer states limited available data from a published clinical lactation study reported that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on the breastfed infant have been observed; there is no available information on the effects of amlodipine on milk production.

Valsartan is distributed into milk in rats. It is not known whether valsartan is distributed into human milk or its effects on the breast-fed infant or milk production.

Advise nursing women that breast-feeding is not recommended while taking valsartan due to the potential for adverse reactions in the breast-fed infant.

The elimination of amlodipine may be impaired substantially in geriatric patients, resulting in increased exposure to the drug (AUC increases of 40-60%). For management of hypertension, some manufacturers recommend an initial amlodipine dosage of 2.5 mg once daily for geriatric patients. For management of vasospastic (Prinzmetal variant) angina or chronic stable angina in geriatric patients, an amlodipine dosage of 5 mg daily is recommended; adequate control of angina usually requires a maintenance dosage of 10 mg once daily.

The manufacturer states that no dosage adjustment is necessary in geriatric patients.

In geriatric patients, amlodipine clearance is decreased and AUC is increased by about 40-60%. Therefore, amlodipine dosage should be selected carefully, usually initiating therapy with dosages at the lower end of the recommended range (i.e., 2.5 mg daily). The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.

Clinical studies of amlodipine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients; however, other clinical experience has not revealed age-related differences in response or tolerance.

In the controlled clinical trials of valsartan, 1214 (36.2%) hypertensive patients treated with valsartan were >=65 years of age and 265 (7.9%) were >=75 years of age. No overall difference in the efficacy or safety of valsartan was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out. Exposure (measured by AUC) to valsartan is higher by 70% in geriatric patients than in younger patients; however, no dosage adjustment is necessary.

Of the 2511 patients with heart failure randomized to valsartan in the Valsartan Heart Failure Trial, 45% (1141 patients) were 65 years of age or older. In the VALsartan In Acute myocardial iNfarcTion trial (VALIANT), 53% (2596) of the 4909 patients treated with valsartan and 51% (2515) of the 4885 patients treated with valsartan plus captopril were 65 years of age or older. There were no notable differences in efficacy or safety between older and younger patients in either trial. No substantial differences in safety and efficacy of valsartan in geriatric patients relative to younger adults have been observed, but increased sensitivity cannot be ruled out.