Usage
- This combination drug is primarily prescribed for the treatment of hypertension (high blood pressure) in patients whose blood pressure is not adequately controlled with dual therapies or as initial therapy for patients anticipated to require multiple medications to achieve blood pressure goals. It is specifically indicated for substitution therapy, meaning it should only be used in patients already stabilized on the individual components. It is not suitable for initial therapy.
- Pharmacological Classifications: This fixed-dose combination (FDC) comprises three antihypertensive agents belonging to different classes:
- Perindopril: Angiotensin-Converting Enzyme (ACE) inhibitor
- Indapamide: Thiazide-like diuretic
- Amlodipine: Calcium channel blocker (CCB), dihydropyridine type
- Mechanism of Action: The combined action of these drugs targets multiple mechanisms involved in blood pressure regulation:
- Perindopril: Inhibits the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This leads to vasodilation, reduces aldosterone secretion, and decreases sodium and water retention.
- Indapamide: Decreases sodium reabsorption in the distal convoluted tubule of the kidneys, promoting diuresis and lowering blood volume, thereby reducing blood pressure.
- Amlodipine: Inhibits calcium influx into vascular smooth muscle cells, resulting in vasodilation and decreased peripheral vascular resistance.
Alternate Names
- This triple combination is often referred to by the individual drug names (Perindopril + Indapamide + Amlodipine).
- Brand Name: Triplixam® (available in some regions).
How It Works
- Pharmacodynamics:
- The combined effects of Perindopril, Indapamide, and Amlodipine result in a synergistic reduction in blood pressure through vasodilation, reduced blood volume, and decreased peripheral vascular resistance.
- Pharmacokinetics:
- Absorption: All three components are orally absorbed, with peak plasma concentrations achieved within 1-2 hours for Perindopril and Amlodipine, and 1.5 hours for Indapamide.
- Metabolism: Perindopril is a prodrug that is hydrolyzed to its active metabolite, perindoprilat. Amlodipine undergoes extensive hepatic metabolism. Indapamide is minimally metabolized.
- Elimination: Perindopril is primarily excreted renally, while Amlodipine and Indapamide are excreted through both renal and hepatic pathways.
- Mode of Action:
- Perindopril: Inhibits ACE, blocking the renin-angiotensin-aldosterone system (RAAS).
- Indapamide: Acts on the sodium-chloride cotransporter in the distal convoluted tubule.
- Amlodipine: Blocks L-type calcium channels in vascular smooth muscle.
- Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation:
- Perindopril: ACE enzyme inhibition.
- Indapamide: Sodium-chloride cotransporter inhibition.
- Amlodipine: Calcium channel blockade.
- Elimination Pathways:
- Primarily renal excretion for Perindopril.
- Both renal and hepatic elimination for Amlodipine and Indapamide.
Dosage
Standard Dosage
Adults:
- The standard dose is one tablet daily, preferably in the morning before a meal, matching the dose levels of the individual components previously taken.
- Dose titration should be done with individual components, not the FDC, if adjustment is necessary.
Children:
- The safety and efficacy of this FDC have not been established in children. Use is not recommended.
Special Cases:
- Elderly Patients: Initiate treatment with individual components and closely monitor blood pressure and renal function due to age-related decreases in drug clearance.
- Patients with Renal Impairment: Moderate renal impairment (CrCl 30-60 mL/min): Avoid dosages of Perindopril/Indapamide 10/2.5 mg combined with Amlodipine 5 or 10 mg. Initiate treatment with the individual components and adjust accordingly. Severe renal impairment (CrCl < 30 mL/min): Contraindicated.
- Patients with Hepatic Dysfunction: Severe hepatic impairment: Contraindicated. Mild to moderate hepatic impairment: Use with caution and initiate with lower doses of the individual components.
- Patients with Comorbid Conditions: Careful monitoring is essential in patients with diabetes, heart failure, and other cardiovascular diseases.
Clinical Use Cases
- This FDC is specifically for chronic hypertension management and is not intended for use in acute clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Individual components might be utilized in these settings, but not the fixed-dose combination.
Dosage Adjustments
- Dose adjustments should be based on individual patient factors including renal/hepatic dysfunction, comorbid conditions, and therapeutic response. Titration should be done with individual drug components rather than the FDC.
Side Effects
Common Side Effects
- Peripheral edema, headache, dizziness, cough, flushing, nausea, abdominal pain.
Rare but Serious Side Effects
- Angioedema, hypotension, syncope, hyperkalemia, acute renal failure, hepatic dysfunction, pancreatitis, blood dyscrasias.
Long-Term Effects
- Electrolyte imbalances, renal impairment, worsening of heart failure.
Adverse Drug Reactions (ADR)
- Angioedema, anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Contraindications
- Hypersensitivity to any of the components (Perindopril, Indapamide, Amlodipine), sulfonamides, or other ACE inhibitors.
- History of angioedema (including hereditary or idiopathic).
- Pregnancy (second and third trimesters).
- Breastfeeding.
- Severe renal or hepatic impairment.
- Untreated decompensated heart failure.
- Concomitant use with sacubitril/valsartan or aliskiren (especially in patients with diabetes or renal impairment).
Drug Interactions
- Clinically significant interactions: Aliskiren, sacubitril/valsartan, lithium, potassium-sparing diuretics, potassium supplements, non-steroidal anti-inflammatory drugs (NSAIDs), other antihypertensives, certain immunosuppressants (e.g., cyclosporine, tacrolimus, sirolimus, everolimus), and some antidepressants.
- CYP450 Interactions: Amlodipine is a substrate of CYP3A4; concomitant use with CYP3A4 inhibitors or inducers can alter its plasma levels.
- Food and lifestyle factors: Avoid grapefruit and grapefruit juice as they can increase amlodipine levels. Alcohol can potentiate the hypotensive effects.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Contraindicated during the second and third trimesters. Not recommended during the first trimester. ACE inhibitors can cause fetal harm.
- Breastfeeding: Contraindicated. Amlodipine and Perindopril are excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: Synergistic antihypertensive effects through RAAS inhibition, diuresis, and calcium channel blockade.
- Side Effects: Edema, headache, dizziness, cough, hypotension, angioedema.
- Contraindications: Angioedema history, pregnancy, breastfeeding, severe renal/hepatic impairment.
- Drug Interactions: Aliskiren, sacubitril/valsartan, lithium, potassium-sparing diuretics, NSAIDs.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: One tablet daily, adjusted based on individual components.
- Monitoring Parameters: Blood pressure, renal function (serum creatinine, electrolytes), potassium levels, hepatic function.
Popular Combinations
- This FDC itself represents a commonly used triple combination therapy for hypertension. When blood pressure control is inadequate with this FDC, other antihypertensive agents from different classes may be added (e.g., beta-blockers, alpha-blockers, or aldosterone antagonists) as determined by a specialist.
Precautions
- General Precautions: Evaluate renal and hepatic function before starting therapy. Monitor blood pressure and electrolytes regularly. Assess for signs of angioedema.
- Specific Populations: See section on “Dosage - Special Cases”.
- Lifestyle Considerations: Advise patients to limit alcohol intake.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Amlodipine + Indapamide + Perindopril erbumine?
A: One tablet daily, administered orally, preferably in the morning before food. The specific strengths of the components should match the patient’s previous regimen of the individual drugs. This combination is not for initial therapy, but as a substitution once patients are stable on separate components.
Q2: Can this FDC be used as initial therapy for hypertension?
A: No, this FDC is not indicated for initial therapy. It is intended for substitution therapy in patients already controlled on separate medications containing the individual components.
Q3: What are the most serious side effects of this combination?
A: Angioedema, severe hypotension, hyperkalemia, acute renal failure, and hepatic dysfunction are some of the serious adverse effects.
Q4: What are the contraindications to using this triple combination?
A: Contraindications include hypersensitivity to any component, history of angioedema, pregnancy (second and third trimesters), breastfeeding, severe renal/hepatic impairment, concomitant use of sacubitril/valsartan or aliskiren.
Q5: Can this medication be prescribed to children?
A: The safety and efficacy haven’t been established in children, hence use is not recommended.
Q6: How should the dosage be adjusted in patients with renal impairment?
A: In moderate renal impairment (CrCl 30-60 mL/min), higher doses of Perindopril/Indapamide combined with Amlodipine are contraindicated. Start with the individual components and adjust as needed. The combination is contraindicated in severe renal impairment (CrCl < 30 mL/min).
Q7: Are there any drug interactions I should be aware of?
A: Yes, significant interactions can occur with aliskiren, sacubitril/valsartan, lithium, potassium-sparing diuretics, NSAIDs, other antihypertensives, and certain immunosuppressants. Concomitant use of these drugs should be carefully considered.
Q8: What should I advise my patients regarding lifestyle modifications?
A: Advise patients to limit alcohol intake as it can exacerbate the hypotensive effects. Additionally, they should avoid grapefruit and grapefruit juice, which can increase Amlodipine levels. A balanced diet low in sodium is generally recommended for hypertension management.
Q9: What monitoring parameters are essential during treatment with this FDC?
A: Regular monitoring of blood pressure, renal function (serum creatinine, electrolytes), potassium levels, and hepatic function is crucial. Patients should be instructed to report any signs or symptoms of angioedema, including swelling of the face, lips, tongue, or difficulty breathing.
