AMLODIPINE BESYLATE AND VALSARTAN
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 the influx of calcium ions into vascular smooth muscle and cardiac muscle, causing vasodilation and reduced peripheral vascular resistance. Valsartan is an angiotensin II receptor blocker that selectively blocks the binding of angiotensin II to AT1 receptors, resulting in vasodilation and reduced aldosterone secretion.
| Metabolism | Amlodipine is extensively metabolized in the liver via cytochrome P450 3A4 (CYP3A4). Valsartan is minimally metabolized; about 20% is metabolized to a glucuronide conjugate via UDP-glucuronosyltransferase (UGT) 2B7, and it is not metabolized by CYP450 enzymes. |
| Excretion | Amlodipine: ~60% renal (10% as unchanged drug), ~20-25% biliary/fecal. Valsartan: ~83% fecal via biliary, ~13% renal (mainly unchanged). |
| Half-life | Amlodipine: 30-50 hours (terminal); Valsartan: 6-9 hours. Amlodipine's long half-life allows once-daily dosing; steady state achieved after 7-10 days. |
| Protein binding | Amlodipine: ~93% bound to plasma proteins; Valsartan: ~95% bound (mainly albumin). |
| Volume of Distribution | Amlodipine: ~21 L/kg (large Vd indicating extensive tissue distribution); Valsartan: ~17 L (not per kg; approx 0.24 L/kg assuming 70 kg). |
| Bioavailability | Amlodipine: ~64-90% after oral administration; Valsartan: ~25% (oral), high variability. |
| Onset of Action | Amlodipine: 2-4 hours after oral dose (gradual onset); Valsartan: ~2 hours (peak effect). |
| Duration of Action | Amlodipine: 24 hours (allows once-daily); Valsartan: 24 hours (once-daily dosing). Both maintain effect over 24-hour interval. |
| Molecular Weight | 567.05 Da |
Adults: initial combination therapy 5/160 mg (amlodipine/valsartan) orally once daily; titrate based on response, maximum 10/320 mg once daily.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min. Not recommended for GFR <30 mL/min due to limited data. |
| Liver impairment | Child-Pugh A: no dose adjustment. Child-Pugh B: initial amlodipine dose 2.5 mg; combination product not recommended due to fixed doses. Child-Pugh C: contraindicated. |
| Pediatric use | Not established for patients <6 years. Age 6-16 years: initial 2.5/80 mg (amlodipine/valsartan) orally once daily; titrate based on response, maximum 5/320 mg once daily (weight ≥50 kg) or 5/160 mg once daily (weight <50 kg). |
| Geriatric use | Start at lowest available dose (e.g., 2.5/160 mg) due to higher incidence of hypotension; cautious titration. No specific dose adjustment per se, but sensitivity to antihypertensives is increased. |
| 1st trimester | Use is not recommended due to risk of fetal toxicity. Drugs acting on the renin-angiotensin system can cause fetal renal dysfunction, oligohydramnios, and skull ossification defects when used in the second and third trimesters, but first trimester exposure has also been associated with increased risk of congenital malformations. |
| 2nd trimester | Contraindicated in the second and third trimesters. Exposure during the second and third trimesters is associated with oligohydramnios, fetal renal dysfunction, skull ossification defects, and neonatal hypotension, hyperkalemia, and renal failure. |
| 3rd trimester | Contraindicated in the second and third trimesters. Same risks as second trimester, with additional concerns for neonatal morbidity. |
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 |
■ FDA Black Box Warning
Warning: Fetal toxicity. Drugs acting directly on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.
| Common Effects | heart failure |
| Serious Effects |
Hypersensitivity to amlodipine, valsartan, or any component of the formulationConcomitant use with aliskiren in patients with diabetes mellitusHistory of angioedema with ARBsPregnancy (second and third trimesters)Severe hepatic impairment (Child-Pugh class C)Biliary cirrhosis or cholestasisAnuria (with valsartan component)
| Precautions | Avoid use in pregnancy; discontinue if pregnancy occurs, Symptomatic hypotension, especially in patients with severe aortic stenosis or intravascular volume depletion, Worsening angina or myocardial infarction (rare, with calcium channel blockers), Impaired renal function: monitor serum potassium and creatinine, Peripheral edema (common with amlodipine) |
Loading safety data…
| Both amlodipine and valsartan cross the placenta. Valsartan is known to cross the human placenta and has been detected in cord blood and amniotic fluid. Amlodipine crosses the placenta in animal studies; human data are limited but transfer is expected. |
| Breastfeeding | Amlodipine is excreted into breast milk in low concentrations (relative infant dose <4%). Valsartan is excreted into breast milk in animal studies, but no human data are available. Caution is advised; monitor the breastfed infant for hypotension, hyperkalemia, and renal impairment. Use only if potential benefit outweighs risk. |
| Lactation Rating | L3 (Moderately Safe) for amlodipine component; L4 (Possibly Hazardous) for valsartan component due to insufficient data on ARB transfer. Overall rating: L4 (Possibly Hazardous). |
| Teratogenic Risk | First trimester: Limited human data; animal studies show no teratogenicity at clinically relevant doses. Second and third trimesters: Fetal toxicity including oligohydramnios, fetal renal dysfunction, skull ossification defects, and neonatal hypotension, hyperkalemia, and renal failure. Risk increases with prolonged exposure. |
| Fetal Monitoring | Monitor maternal blood pressure, renal function, serum electrolytes, and urine output. Fetal monitoring including ultrasound for amniotic fluid volume (oligohydramnios) and fetal growth. Neonatal monitoring for hypotension, hyperkalemia, and renal function. |
| Fertility Effects | No formal studies; animal studies do not suggest impaired fertility. Based on mechanism, angiotensin II receptor blockers may theoretically affect reproductive function but no human evidence of significant impact. |
| Food/Dietary |
| Avoid grapefruit and grapefruit juice; they can increase amlodipine serum concentrations and potentiate hypotensive effects. No significant food interactions with valsartan, but advise a low-salt diet as part of hypertension management. Alcohol may exacerbate hypotension; limit intake. |
| Clinical Pearls | Amlodipine/amlodipine besylate is a dihydropyridine calcium channel blocker; valsartan is an angiotensin II receptor blocker. This combination is indicated for hypertension not adequately controlled on monotherapy. The fixed-dose combination may improve compliance. Amlodipine can cause peripheral edema, which may be more common at higher doses and in older patients; adding valsartan may reduce the incidence of edema. Avoid use in pregnancy (due to valsartan) and in patients with bilateral renal artery stenosis. Monitor serum potassium and renal function periodically, especially in patients with renal impairment or on potassium-sparing diuretics. The maximum recommended dose is 10 mg/320 mg once daily. |
| Patient Advice | Take exactly as prescribed, usually once daily. Do not crush or chew tablets. · Do not use if pregnant or planning to become pregnant; stop and inform your doctor immediately if you become pregnant. · Avoid potassium supplements and salt substitutes containing potassium unless approved by your doctor. · Common side effects include swelling in ankles or feet, dizziness, flushing, and headache. Notify your doctor if swelling or dizziness is bothersome. · Do not stop taking this medication suddenly without consulting your doctor. · If you miss a dose, take it as soon as you remember unless it is near the time for your next dose. Do not double up. · Avoid grapefruit and grapefruit juice as they may increase amlodipine levels. |