Cardovan Plus

Approved Indications:

• Hypertension (Essential or Primary):
  Indicated for the treatment of hypertension in patients not adequately controlled with monotherapy of either valsartan or hydrochlorothiazide alone.
• Combination Therapy:
  Used in patients who require multiple antihypertensive agents to achieve target blood pressure, especially when initial monotherapy proves insufficient.
• Edema (secondary to hypertension):
  May assist with reduction of fluid retention in hypertensive patients with mild to moderate edema.

Off-label/Clinically Accepted Uses:

• Left Ventricular Hypertrophy (LVH):
  May be used as part of a combination therapy for blood pressure control in patients with LVH to reduce associated cardiovascular risk.
• Post-Myocardial Infarction Hypertension:
  In select cases, used in the management of post-MI patients to control blood pressure when monotherapy is inadequate.

General Recommendations:

• Initial Dose (Adults):
  One tablet once daily, usually starting with valsartan 80 mg + hydrochlorothiazide 12.5 mg.
• Maintenance Dose:
  May be increased after 1–2 weeks to maximum of valsartan 320 mg + hydrochlorothiazide 25 mg once daily, based on response.

Special Populations:

• Elderly:
  No initial dosage adjustment necessary; however, monitor closely for hypotension or renal function decline.
• Renal Impairment:
  Avoid in patients with severe renal impairment (CrCl <30 mL/min). Use with caution in moderate impairment.
• Hepatic Impairment:
  Not recommended in patients with severe hepatic dysfunction. Use cautiously in mild-to-moderate liver disease without cholestasis.

Pediatric Use:
Not recommended in children under 18 years due to insufficient data.

Administration Route:
Oral; may be taken with or without food. Tablets should be swallowed whole with water.

Valsartan is an angiotensin II receptor blocker (ARB) that selectively inhibits the AT1 receptor, preventing angiotensin II-mediated vasoconstriction and aldosterone secretion, leading to decreased blood pressure. Hydrochlorothiazide is a thiazide diuretic that inhibits sodium reabsorption in the distal tubules of the kidney, promoting diuresis and reducing plasma volume, thereby lowering blood pressure. The combination provides additive antihypertensive effects through complementary mechanisms: one reducing vascular resistance and the other decreasing intravascular volume.

Valsartan:

• Absorption: Oral bioavailability ~25%
• Peak Plasma Time: 2–4 hours
• Protein Binding: 94–97%
• Metabolism: Minimal; not significantly metabolized by CYP enzymes
• Half-Life: 6 hours
• Elimination: Primarily fecal (83%); ~13% renal

Hydrochlorothiazide:

• Absorption: 60–70% orally bioavailable
• Peak Plasma Time: 1.5–2 hours
• Protein Binding: 40–70%
• Metabolism: Not metabolized
• Half-Life: 6–15 hours
• Elimination: Primarily renal (unchanged in urine)

• Pregnancy:
  FDA Pregnancy Category D (2nd and 3rd trimesters).
  Valsartan can cause fetal injury or death when administered during the second and third trimesters. Discontinue as soon as pregnancy is detected.
• Lactation:
  Hydrochlorothiazide is excreted in breast milk and may reduce milk production. Valsartan’s excretion is unknown. Not recommended during breastfeeding; alternative therapies are preferred.

• Primary Class:
  Angiotensin II Receptor Blocker (ARB) + Thiazide Diuretic
• Subclasses:
  Valsartan – ARB (Non-peptide)
  Hydrochlorothiazide – Thiazide-type diuretic

• Known hypersensitivity to valsartan, hydrochlorothiazide, sulfonamide-derived drugs, or any formulation excipients
• Anuria
• Severe renal impairment (CrCl <30 mL/min)
• Severe hepatic impairment, including biliary cirrhosis
• Pregnancy (especially second and third trimesters)
• Concomitant use with aliskiren in patients with diabetes mellitus

• Volume-Depletion:
  Risk of hypotension, especially after the first dose; correct hypovolemia before initiation.
• Electrolyte Imbalance:
  Risk of hypokalemia, hyponatremia, and hypomagnesemia due to hydrochlorothiazide.
• Renal Function Monitoring:
  Use caution in patients with renal artery stenosis or those at risk of acute renal failure.
• Liver Disease:
  Worsening hepatic function may occur; monitor closely.
• Metabolic Effects:
  May cause hyperuricemia, hyperglycemia, and increase in cholesterol/triglycerides.
• Photosensitivity:
  Hydrochlorothiazide may increase photosensitivity—advise sun protection.

Common Adverse Effects:

• Cardiovascular: Hypotension, orthostatic hypotension, dizziness
• Renal: Elevated creatinine, increased BUN
• Electrolytes: Hypokalemia, hyponatremia
• GI: Nausea, abdominal pain
• Neurologic: Fatigue, headache
• Dermatologic: Rash, photosensitivity

Serious Adverse Effects:

• Angioedema
• Acute renal failure
• Severe hypotension
• Stevens-Johnson Syndrome (rare)
• Electrolyte imbalances (life-threatening in rare cases)

• ACE Inhibitors/Aliskiren: Increased risk of renal impairment, hyperkalemia, and hypotension
• NSAIDs: May reduce antihypertensive efficacy and worsen renal function
• Lithium: Increased lithium serum levels and toxicity risk
• Diuretics or Other Antihypertensives: Additive hypotensive effect
• Digitalis Glycosides: Electrolyte disturbances may enhance digoxin toxicity
• CYP450 Interactions: Minimal, as valsartan is not significantly metabolized by CYP enzymes

• 2023 ACC/AHA Hypertension Guidelines:
  Confirms use of ARB + thiazide combinations as effective second-line or combination first-line agents in patients with stage 2 hypertension.
• FDA Safety Update:
  Reinforces contraindication of ARBs during pregnancy due to fetal harm.
• EMA Notice:
  Recommends periodic renal function and potassium monitoring, particularly in elderly patients and those with comorbidities.

• Temperature: Store below 30°C (86°F)
• Humidity: Store in a dry place, protected from moisture
• Light Protection: Keep in original packaging to protect from light
• Handling Precautions: Do not break or crush tablets
• Reconstitution: Not applicable (oral tablet)