Pendoril Plus

Approved Indications:

• Essential Hypertension:
  Indicated in adult patients for the treatment of high blood pressure. The fixed-dose combination is appropriate when blood pressure is not adequately controlled by monotherapy.
• Stable Coronary Artery Disease:
  In patients with stable coronary disease and preserved left ventricular function, it is used to reduce the risk of cardiovascular events such as myocardial infarction and stroke.

Clinically Accepted Off-Label Uses:

• Post-Myocardial Infarction Management
• Adjunctive therapy in chronic heart failure (particularly when ACE inhibitor and diuretic therapy are needed simultaneously)
• Nephroprotection in patients with diabetic nephropathy (based on the individual effects of perindopril)

Route of Administration: Oral
Formulations Available:

• Perindopril 2 mg + Indapamide 0.625 mg
• Perindopril 4 mg + Indapamide 1.25 mg
• Perindopril 8 mg + Indapamide 2.5 mg

Adults:

• Initial dose: 2 mg/0.625 mg once daily, preferably taken in the morning before food.
• If necessary, the dose may be increased after 4 weeks to 4 mg/1.25 mg once daily, then to 8 mg/2.5 mg once daily based on clinical response.

Elderly:

• Start with the lowest available dose (2 mg/0.625 mg once daily).
• Monitor renal function and electrolytes regularly.

Renal Impairment:

• Mild to moderate impairment (eGFR ≥30 mL/min/1.73 m²):
  Use lower starting dose; close monitoring is required.
• Severe impairment (eGFR <30 mL/min/1.73 m²):
  Contraindicated.

Hepatic Impairment:

• Caution is advised. Clinical and biochemical monitoring recommended, especially in patients with a history of hepatic encephalopathy.

Pediatric Use:

• Not recommended. Safety and efficacy in children and adolescents have not been established.

Perindopril is an ACE inhibitor that prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, leading to vasodilation, decreased aldosterone production, and reduced blood pressure. Indapamide is a thiazide-like diuretic that promotes excretion of sodium and chloride in the distal convoluted tubule of the nephron, thereby reducing plasma volume and peripheral vascular resistance. Together, the combination provides a synergistic antihypertensive effect, improving blood pressure control while minimizing hypokalemia risk commonly associated with diuretics alone.

Perindopril:

• Absorption: Rapid; bioavailability ~20% as active metabolite.
• Metabolism: Hepatic hydrolysis to active metabolite perindoprilat.
• Tmax: Perindoprilat peaks at ~3–4 hours.
• Half-life: Perindoprilat ~25–30 hours (supports once-daily dosing).
• Elimination: Mainly renal (~60%).

Indapamide:

• Absorption: ~93% absorbed orally.
• Metabolism: Hepatically metabolized (CYP3A4).
• Tmax: ~1–2 hours.
• Half-life: ~14–18 hours.
• Elimination: Renal (~60%) and fecal (~20%).

• Pregnancy:
  FDA Pregnancy Category D (2nd and 3rd trimesters)
  ACE inhibitors can cause fetal injury or death when administered in the second or third trimester. Discontinue as soon as pregnancy is detected.
• Lactation:
  Indapamide is excreted in human milk in small quantities. Perindopril excretion is not well established. Use in breastfeeding women is not recommended. Alternate antihypertensives may be preferred.

• Therapeutic Class: Antihypertensive
• Subclasses:
• Perindopril: Angiotensin-Converting Enzyme (ACE) Inhibitor
• Indapamide: Thiazide-like Diuretic

• Hypersensitivity to perindopril, indapamide, sulfonamides, or any component of the formulation
• History of angioedema related to ACE inhibitor therapy
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Hepatic encephalopathy or severe hepatic impairment
• Hypokalemia or hypercalcemia
• Pregnancy and breastfeeding
• Concomitant use with aliskiren in diabetic patients or in patients with renal impairment

• Hypotension: Especially in sodium- or volume-depleted patients
• Renal Impairment: Monitor renal function regularly; dose adjustment may be necessary
• Hyperkalemia or Hypokalemia: Regular electrolyte monitoring required
• Angioedema: May occur anytime during therapy
• Cough: ACE inhibitors may induce dry, persistent cough
• Photosensitivity Reactions: Particularly with indapamide; avoid prolonged sun exposure
• Surgical Considerations: Temporary discontinuation may be necessary during surgery requiring general anesthesia

Common:

• Cardiovascular: Dizziness, hypotension, palpitations
• Neurological: Headache, fatigue, asthenia
• Gastrointestinal: Nausea, abdominal pain, dysgeusia
• Renal/Metabolic: Hypokalemia, hyperkalemia, elevated creatinine
• Respiratory: Dry cough
• Dermatological: Rash, pruritus

Serious/Rare:

• Angioedema (life-threatening)
• Stevens-Johnson syndrome (very rare)
• Hepatitis or cholestasis
• Blood disorders (agranulocytosis, thrombocytopenia)
• Electrolyte disturbances leading to arrhythmia

• Potassium supplements and potassium-sparing diuretics: ↑ risk of hyperkalemia
• NSAIDs: May reduce antihypertensive effect and impair renal function
• Lithium: ↑ risk of lithium toxicity
• Antihypertensive agents and diuretics: Additive hypotensive effect
• Alcohol: Potentiates hypotensive effects
• CYP3A4 inhibitors (e.g., ketoconazole): May ↑ indapamide plasma levels
• Aliskiren: Contraindicated in diabetics or with renal impairment

• ESC/ESH 2023 Guidelines for Hypertension:
  Recommends ACE inhibitor + thiazide(-like) diuretic combination therapy as first-line treatment for most patients with stage 1 or 2 hypertension.
• Reinforced contraindication:
  Co-administration with aliskiren in patients with diabetes or renal dysfunction is no longer recommended due to risk of hyperkalemia and renal failure.
• Stable CAD:
  Continued endorsement of perindopril-based regimens to reduce cardiovascular events in patients with preserved LV function.

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Allowable Excursions: Between 15°C and 30°C
• Humidity/Light: Store in a dry place, protected from moisture and direct sunlight
• Handling: Keep in original packaging; do not remove until time of administration
• Precautions: Keep out of reach of children; do not use if tablets are discolored or broken