AV

Approved Indications:

• Essential Hypertension (Primary Hypertension):
  Indicated for the treatment of high blood pressure in patients whose blood pressure is not adequately controlled with either amlodipine or valsartan monotherapy.
• Initial Therapy for Hypertension:
  Can be used as initial therapy in patients who are likely to require multiple antihypertensive agents to achieve blood pressure goals.

Clinically Accepted Off-label Uses:

• Resistant Hypertension:
  Utilized in patients who require three or more antihypertensives, particularly when blood pressure remains uncontrolled despite monotherapy.
• Hypertension in High Cardiovascular Risk Patients:
  Employed in hypertensive patients with comorbid conditions such as diabetes mellitus, chronic kidney disease, or left ventricular hypertrophy, where tight BP control is essential.

Adults:

• Initial Dose:
  Amlodipine 5 mg + Valsartan 160 mg once daily.
• Titration:
  Dose may be increased after 1–2 weeks based on blood pressure response.
  Maximum dose: Amlodipine 10 mg + Valsartan 320 mg once daily.
• Initial Therapy Option:
  For patients likely to need multiple drugs, therapy may be initiated with the lowest available combination dose.

Elderly Patients:

• Start at the lower end of the dosing range (e.g., Amlodipine 2.5–5 mg) due to the increased sensitivity to hypotensive effects.

Pediatric Use:

• Not recommended in children and adolescents under 18 years due to insufficient safety and efficacy data.

Renal Impairment:

• Mild to Moderate: No dose adjustment required, but monitor renal function regularly.
• Severe Impairment (eGFR <30 mL/min/1.73 m²): Use with caution.

Hepatic Impairment:

• Mild to Moderate: Use with caution.
• Severe: Contraindicated due to reduced hepatic clearance.

Administration:

• Route: Oral
• Frequency: Once daily
• May be taken with or without food
• Tablets should be swallowed whole with water; do not split or chew.

This combination lowers blood pressure via dual complementary mechanisms. Amlodipine Besilate, a dihydropyridine calcium channel blocker, inhibits calcium influx into vascular smooth muscle cells, causing vasodilation and reduced peripheral resistance. Valsartan, an angiotensin II receptor blocker (ARB), selectively blocks the AT1 receptor, thereby inhibiting angiotensin II-induced vasoconstriction, aldosterone secretion, and sodium retention. Together, the agents provide additive antihypertensive effects, improving blood pressure control and reducing the risk of cardiovascular complications.

Amlodipine:

• Absorption: Slowly absorbed; bioavailability ~64–90%
• Time to Peak: 6–12 hours
• Half-life: 30–50 hours
• Metabolism: Extensively hepatic via CYP3A4
• Excretion: Primarily in urine (inactive metabolites)

Valsartan:

• Absorption: Peak plasma concentration in 2–4 hours; bioavailability ~25%
• Protein Binding: >95%
• Half-life: 6 hours
• Metabolism: Minimal; not metabolized by CYP450
• Excretion: Feces (83%), urine (13%)

• Pregnancy:
  Contraindicated during the second and third trimesters. Valsartan can cause fetal injury or death due to its effects on the renin-angiotensin system. If pregnancy is detected, discontinue the drug immediately.
• Breastfeeding:
  Amlodipine is known to be excreted in small amounts into human milk; valsartan excretion in breast milk is unknown. Not recommended during lactation.
• Recommendation:
  Avoid use in pregnant or breastfeeding women; switch to alternatives with better safety profiles.

• Primary Class: Antihypertensive Combination
• Subclasses:
• Amlodipine: Calcium Channel Blocker (Dihydropyridine class)
• Valsartan: Angiotensin II Receptor Blocker (ARB), AT1 subtype selective

• Known hypersensitivity to amlodipine, valsartan, or any excipients
• Pregnancy (especially 2nd and 3rd trimester)
• Severe hepatic impairment or biliary cirrhosis
• Co-administration with aliskiren in patients with diabetes mellitus
• History of angioedema related to previous ARB therapy
• Severe hypotension or shock
• Severe aortic stenosis

• Hypotension Risk: Especially in volume- or salt-depleted individuals; correct imbalances before initiation.
• Renal Impairment: Monitor renal function closely; may worsen existing renal insufficiency.
• Hyperkalemia: Caution in patients taking potassium supplements or potassium-sparing diuretics.
• Heart Failure: Use amlodipine cautiously in patients with heart failure due to risk of worsening edema.
• Liver Dysfunction: Exposure to valsartan may increase in hepatic impairment; avoid in severe cases.
• Monitoring: Blood pressure, renal function, serum electrolytes (especially potassium) should be monitored regularly.

Common (≥1%):

• Cardiovascular: Peripheral edema, hypotension, palpitations
• CNS: Headache, dizziness, fatigue
• Gastrointestinal: Nausea, abdominal pain
• General: Flushing, nasopharyngitis

Less Common or Serious:

• Angioedema
• Hyperkalemia
• Acute renal impairment
• Syncope
• Increased hepatic enzymes
• Gingival hyperplasia (amlodipine-related)

Onset & Severity:

• Most adverse effects occur within the first few weeks of therapy and are generally dose-related.
• Edema is more pronounced with higher doses of amlodipine.

Significant Interactions:

• Potassium-sparing diuretics, potassium supplements: Risk of hyperkalemia
• NSAIDs: May reduce the antihypertensive effect and worsen renal function
• CYP3A4 inhibitors (e.g., ketoconazole, erythromycin): May increase amlodipine levels
• Lithium: Risk of lithium toxicity with valsartan
• Alcohol: May enhance blood pressure-lowering effect, increasing the risk of dizziness or fainting

Enzyme Involvement:

• Amlodipine is metabolized by CYP3A4
• Valsartan is not significantly metabolized by the CYP system

• 2023 AHA/ACC and ESC/ESH Hypertension Guidelines:
  Reaffirmed the use of ARB + CCB combinations as effective first-line therapy, particularly in patients with Stage 2 hypertension or cardiovascular risk.
• FDA Advisory:
  Continues to warn against the use of ARBs like valsartan during pregnancy due to confirmed fetal toxicity risk.
• Clinical Trend:
  Fixed-dose combinations are recommended to improve adherence and enhance blood pressure control.

• Temperature: Store below 30°C
• Humidity: Keep in a dry place; avoid excessive humidity
• Light Protection: Protect from direct light; store in original packaging
• Handling Precautions: Keep out of reach of children; do not use after expiry date
• Reconstitution Needs: Not applicable (oral solid tablet formulation)