AMLODIPINE BESYLATE, VALSARTAN AND HYDROCHLOROTHIAZIDE
Clinical safety rating: avoid
NSAIDs may diminish the antihypertensive effect Lithium levels may be increased Use in pregnancy can cause injury and death to the developing fetus.
Amlodipine is a dihydropyridine calcium channel blocker that inhibits calcium ion influx across cardiac and vascular smooth muscle cells, causing vasodilation and reduced peripheral resistance. Valsartan is an angiotensin II receptor blocker (ARB) that selectively blocks AT1 receptors, inhibiting vasoconstriction and aldosterone release. Hydrochlorothiazide is a thiazide diuretic that inhibits the Na+/Cl- symporter in the distal convoluted tubule, increasing sodium and water excretion.
| Metabolism | Amlodipine is extensively metabolized in the liver via CYP3A4 to inactive metabolites. Valsartan is primarily eliminated unchanged via biliary excretion (83%) and renal (13%); minimal hepatic metabolism via CYP2C9. Hydrochlorothiazide is not metabolized; excreted unchanged by the kidneys. |
| Excretion | Amlodipine: 60% renal, 20-25% biliary/fecal; Valsartan: 83% fecal via bile, 13% renal; Hydrochlorothiazide: ≥95% renal as unchanged drug. |
| Half-life | Amlodipine: 30-50 hours (terminal, allows once-daily dosing); Valsartan: 6 hours; Hydrochlorothiazide: 6-15 hours (prolonged in renal impairment). |
| Protein binding | Amlodipine: 93-98% bound to plasma proteins; Valsartan: 95-97% bound (primarily albumin); Hydrochlorothiazide: 40-68% bound (albumin). |
| Volume of Distribution | Amlodipine: 21 L/kg (extensive tissue distribution); Valsartan: 17 L (not weight-based, indicates moderate distribution); Hydrochlorothiazide: 0.83 L/kg (primarily extracellular fluid). |
| Bioavailability | Oral: Amlodipine 64-90%; Valsartan 23% (with food reduces AUC by 40%); Hydrochlorothiazide 65-75%. |
| Onset of Action | Oral: Amlodipine 2-8 h (antianginal), 24-48 h (antihypertensive); Valsartan 2 weeks (full effect); Hydrochlorothiazide 2 hours (diuresis), 3-4 weeks (antihypertensive). |
| Duration of Action | Amlodipine: 24 hours (sustained BP reduction); Valsartan: 24 hours; Hydrochlorothiazide: 6-12 hours (diuresis), 24 hours (antihypertensive). |
| Molecular Weight | Amlodipine besylate: 567.05 Da; Valsartan: 435.5 Da; Hydrochlorothiazide: 297.74 Da |
One tablet orally once daily. Available strengths: amlodipine 5 mg/valsartan 160 mg/HCTZ 12.5 mg, amlodipine 5 mg/valsartan 160 mg/HCTZ 25 mg, amlodipine 10 mg/valsartan 160 mg/HCTZ 12.5 mg, amlodipine 10 mg/valsartan 160 mg/HCTZ 25 mg, amlodipine 10 mg/valsartan 320 mg/HCTZ 25 mg. Titrate based on response, max dose: amlodipine 10 mg/valsartan 320 mg/HCTZ 25 mg daily.
| Dosage form | TABLET |
| Renal impairment | Contraindicated if eGFR <30 mL/min/1.73m² due to HCTZ component. For eGFR 30-60 mL/min/1.73m²: No dose adjustment needed; monitor renal function and electrolytes. For eGFR <30 mL/min/1.73m²: Not recommended; alternative therapy preferred. |
| Liver impairment | Child-Pugh Class A or B: Initiate amlodipine at 2.5 mg daily; use lowest available combination strength (amlodipine 5 mg/valsartan 160 mg/HCTZ 12.5 mg) and titrate cautiously. Child-Pugh Class C: Contraindicated due to amlodipine and valsartan accumulation. |
| Pediatric use | Safety and efficacy not established in pediatric patients <18 years. |
| Geriatric use | Initiate at lowest available strength (amlodipine 5 mg/valsartan 160 mg/HCTZ 12.5 mg) once daily. Titrate slowly due to increased risk of hypotension, electrolyte disturbances, and renal impairment. Monitor orthostatic blood pressure, serum electrolytes, and renal function frequently. |
| 1st trimester | Avoid in first trimester due to potential teratogenicity associated with angiotensin receptor blockers (ARBs) and hydrochlorothiazide. Limited data; use only if benefit outweighs risk. |
| 2nd trimester | Contraindicated in second trimester due to risk of fetal renal dysfunction, oligohydramnios, and skull ossification defects from ARB component. Hydrochlorothiazide may cause electrolyte imbalances. |
| 3rd trimester | Contraindicated in third trimester due to risk of fetal and neonatal hypotension, renal failure, and hyperkalemia from ARB; hydrochlorothiazide may cause neonatal thrombocytopenia. |
Clinical note
NSAIDs may diminish the antihypertensive effect Lithium levels may be increased Use in pregnancy can cause injury and death to the developing fetus.
| FDA category | Contraindicated |
| Placental transfer | Amlodipine crosses placenta; valsartan and hydrochlorothiazide are known to cross. ARBs have documented fetal toxicity. |
■ FDA Black Box Warning
None. No FDA boxed warning for this combination product.
| Common Effects | heart failure |
| Serious Effects |
AnuriaHypersensitivity to any componentHistory of angioedema with ARBsSevere hepatic impairmentConcomitant aliskiren in patients with diabetes
| Precautions | Fetal toxicity: Discontinue as soon as pregnancy is detected; drugs acting directly on the renin-angiotensin system can cause fetal morbidity and death, Hypotension: Symptomatic hypotension may occur in patients with severe volume or salt depletion, Impaired renal function: Monitor serum creatinine and potassium; avoid use in patients with severe renal impairment (CrCl <30 mL/min), Electrolyte imbalances: May cause hypokalemia, hyponatremia, and hypercalcemia; monitor electrolytes, Exacerbation of angina or myocardial infarction: Rarely, calcium channel blockers may increase frequency or severity of angina, Hepatic impairment: Use with caution; amlodipine clearance is decreased in severe hepatic impairment |
Loading safety data…
| Breastfeeding | Amlodipine is excreted in breast milk in small amounts; limited data on valsartan and hydrochlorothiazide. Use caution, especially in preterm infants. Monitor for hypotension and electrolyte disturbances. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Limited data, but angiotensin II receptor antagonists (valsartan) and ACE inhibitors are associated with increased risk of congenital malformations (renal, cardiac, CNS) if used in second and third trimesters. Hydrochlorothiazide is generally considered low risk but may cause electrolyte disturbances in mother and fetus. Second and third trimesters: Valsartan is contraindicated due to risk of fetal renal dysfunction, oligohydramnios, skull hypoplasia, and neonatal renal failure. Amlodipine may cause reduced uteroplacental perfusion. Hydrochlorothiazide can cause fetal thrombocytopenia, jaundice, and electrolyte imbalances. Overall: Avoid in pregnancy, especially second and third trimesters. |
| Fetal Monitoring | Monitor maternal blood pressure, renal function (serum creatinine, BUN), electrolytes (potassium, sodium, chloride, bicarbonate), and uric acid. Fetal monitoring: serial ultrasound for fetal growth, amniotic fluid volume, and anatomy if exposed in second/third trimester. Consider fetal echocardiography if valsartan exposure occurred during organogenesis. Neonatal monitoring: blood pressure, renal function, and electrolytes in newborns exposed in utero, especially if maternal use continued near term. |
| Fertility Effects | No significant adverse effects on fertility reported in animal studies or human data for any component. Amlodipine, valsartan, and hydrochlorothiazide do not impair fertility. However, antihypertensive therapy may be necessary during pregnancy for maternal health. |
| Food/Dietary | Avoid grapefruit and grapefruit juice (may increase amlodipine levels). Limit high-potassium foods (e.g., bananas, oranges, spinach) due to valsartan. Avoid excessive salt intake. May need to avoid alcohol due to additive hypotensive effect. |
| Clinical Pearls | This triple combination is used when blood pressure is not controlled on dual therapy. Maximum antihypertensive effect occurs within 2-4 weeks. Do not use as initial therapy. Avoid in patients with anuria, sulfonamide allergy (HCTZ component), or severe renal impairment (CrCl <30 mL/min). Monitor serum potassium: risk of hypokalemia (HCTZ) and hyperkalemia (valsartan). Dose adjustment needed in hepatic impairment (amlodipine). |
| Patient Advice | Take exactly as prescribed; do not stop suddenly. · Do not use potassium supplements or salt substitutes with potassium without consulting your doctor. · May cause dizziness; avoid driving until you know how medication affects you. · Report swelling of feet/ankles, persistent cough, or muscle cramps. · Avoid excessive alcohol consumption. · Use caution in hot weather or during exercise; risk of dehydration. · Store at room temperature away from moisture and heat. |