Olmesartan + Amlodipine + Hydrochlorothiazide

Oral
Hypertension

CrCl (mL/min)	Dosage
<30	Contraindicated.

Moderate: Max: 20 mg olmesartan/5 mg amlodipine/12.5 mg hydrochlorothiazide once daily. Severe: Contraindicated.

Hypersensitivity to olmesartan, amlodipine, hydrochlorothiazide or other sulfonamide-derived drugs. Anuria, shock (including cardiogenic shock), severe hypotension, obstruction of the outflow tract of the left ventricle (e.g. high-grade aortic stenosis), haemodynamically unstable heart failure after acute MI; refractory hypokalaemia, hypercalcaemia, hyponatraemia and symptomatic hyperuricaemia; cholestasis, biliary obstructive disorders. Severe renal and hepatic impairment. Pregnancy and lactation. Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²).

Patient with hypovolaemia and/or Na depletion, severe CHF, unstented unilateral or bilateral renal artery stenosis; prediabetes or diabetes mellitus, parathyroid disease, primary aldosteronism; aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy; SLE, history of allergy or bronchial asthma; ascites due to cirrhosis. Not indicated for initial therapy. Mild to moderate renal and hepatic impairment. Elderly.

Significant: Increased angina and/or MI, symptomatic hypotension (particularly in volume- and/or Na-depleted patients); fluid or electrolyte imbalance (e.g. hypokalaemia, hyponatraemia, hypochloraemic alkalosis, hypomagnesaemia, hypercalcaemia, hyperkalaemia); hyperuricaemia or frank gout, increased cholesterol and triglyceride levels; impaired glucose tolerance; sprue-like enteropathy (e.g. severe, chronic diarrhoea with significant weight loss); renal function deterioration and/or increased serum creatinine; increased risk of non-melanoma skin cancer (e.g. basal cell carcinoma and squamous cell carcinoma); exacerbation or activation of SLE; hypersensitivity reactions, peripheral oedema, angioedema; photosensitivity, choroidal effusion (with visual field defect), acute transient myopia, acute angle-closure glaucoma. Very rarely, severe cases of acute respiratory toxicity including acute respiratory distress syndrome.
Cardiac disorders: Palpitations.
Gastrointestinal disorders: Nausea, constipation, diarrhoea.
General disorders and administration site conditions: Fatigue, asthenia.
Musculoskeletal and connective tissue disorders: Muscle spasm, joint swelling.
Nervous system disorders: Headache, dizziness.
Renal and urinary disorders: UTI, pollakiuria.
Respiratory, thoracic and mediastinal disorders: Nasopharyngitis, URTI.

PO: D

This drug may cause dizziness, headache, nausea or fatigue, if affected, do not drive or operate machinery. Avoid prolonged exposure to sunlight and UV rays, wear sunscreen or protective clothing when going outdoors.

Monitor blood pressure, heart rate, serum electrolytes and renal function. Assess for signs and symptoms of hypotension, peripheral oedema and angioedema.

Symptoms: Olmesartan: Hypotension, tachycardia; bradycardia (if parasympathetic [vagal] stimulation occurred). Amlodipine: Excessive peripheral vasodilation with marked hypotension including shock and reflex tachycardia. Rarely, non-cardiogenic pulmonary oedema. Hydrochlorothiazide: Nausea, somnolence, electrolyte depletion (e.g. hypochloraemia, hypokalaemia), dehydration. Management: Symptomatic and supportive treatment. Perform gastric lavage for recent intake. Administer activated charcoal immediately or up to 2 hours after ingestion in healthy patients. Provide active support of CV system, including close monitoring of heart and lung function, elevation of extremities and attention to circulating fluid volume and urine output for clinically significant hypotension. Administer a vasoconstrictor for restoring vascular tone and blood pressure. May also consider giving IV Ca gluconate.

Increases serum concentrations of lithium. May potentiate antihypertensive effect with baclofen, amifostine and other antihypertensive drugs. May enhance the orthostatic hypotensive effect with antidepressants, barbiturates and narcotics. May reduce antihypertensive effects with NSAIDs (e.g. aspirin [>3 g/day], COX-2 inhibitors).
Olmesartan: May increase serum K level with K-sparing diuretics, K supplements, salt substitutes containing K or other drugs that may increase serum K levels (e.g. heparin). Reduced systemic exposure and peak plasma concentration with colesevelam.
Amlodipine: May increase exposure of simvastatin, ciclosporin, mTOR inhibitors (e.g. everolimus, sirolimus, tacrolimus, temsirolimus). May reduce serum concentration with moderate or strong CYP3A4 inducers (e.g. rifampicin). May enhance the hyperkalaemic and negative inotropic effects with dantrolene. Increased serum concentration with moderate or strong CYP3A4 inhibitors (e.g. protease inhibitors, azole antifungals, verapamil, diltiazem, macrolides).
Hydrochlorothiazide: Potentiated K-depleting effect with drugs associated with K loss and hypokalaemia (e.g. ACTH, amphotericin B, benzylpenicillin, carbenoxolone, corticosteroids, laxatives, salicylic acid derivatives, other kaliuretic diuretics). May increase serum Ca concentration with Ca salts. Impaired absorption with colestyramine and colestipol resins. May decrease the therapeutic effect of antidiabetic agents (e.g. insulin). May potentiate the effects of non-depolarising skeletal muscle relaxants (e.g. tubocurarine). May potentiate myelosuppressive effects of cytotoxic agents (e.g. cyclophosphamide, methotrexate). May increase the risk of adverse reactions caused by amantadine. May increase the risk of hyperuricaemia and gout-type complications with ciclosporin. May increase the risk of cardiotoxic effects with digitalis glycosides, antiarrhythmics and certain antipsychotics (e.g. thioridazine, chlorpromazine, haloperidol). Increased bioavailability with anticholinergic agents (e.g. atropine, biperiden). May enhance the hyperglycaemic effect of β-blockers and diazoxide.
Potentially Fatal: Olmesartan: Increased risk of hypotension, hyperkalaemia and reduced renal function (including acute renal failure) with aliskiren or ACE inhibitors.

May potentiate the orthostatic hypotensive effect with alcohol.
Amlodipine: Increased blood pressure lowering effects with grapefruit or grapefruit juice. May decrease plasma concentration with St. John's wort.

Description:
Mechanism of Action: Olmesartan is a selective and competitive nonpeptide angiotensin II receptor antagonist. It blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by inhibiting its binding to angiotensin II type 1 (AT₁) receptors found in many tissues including vascular smooth muscle and adrenal gland.
Amlodipine, a dihydropyridine Ca-channel blocker, is a peripheral arterial vasodilator. It acts directly on vascular smooth muscle which causes a reduction in peripheral vascular resistance and blood pressure.
Hydrochlorothiazide is a thiazide diuretic. It inhibits the reabsorption of Na in the distal tubules, leading to increased excretion of Na, water, K and hydrogen ions.
Onset: Amlodipine: Antihypertensive effect: 24-48 hours.
Hydrochlorothiazide: Diuresis: Approx 2 hours.
Duration: Amlodipine: Antihypertensive effect: Approx 24 hours.
Hydrochlorothiazide: 6-12 hours.
Pharmacokinetics:
Absorption: Olmesartan: Bioavailability: 26%. Time to peak plasma concentration: 1-2 hours.
Amlodipine: Well absorbed. Bioavailability: Approx 64-90%. Time to peak plasma concentration: 6-12 hours.
Hydrochlorothiazide: Rapidly and well absorbed from the gastrointestinal tract. Bioavailability: 65-75%. Time to peak plasma concentration: Approx 1-5 hours.
Distribution: Olmesartan: Volume of distribution: 17 L. Plasma protein binding: Approx 99%.
Amlodipine: Crosses the placenta and enters breast milk. Volume of distribution: 21 L/kg. Plasma protein binding: Approx 93%.
Hydrochlorothiazide: Crosses the placenta and enters breast milk. Volume of distribution: 3.6-7.8 L/kg. Plasma protein binding: Approx 40-68%.
Metabolism: Olmesartan: Olmesartan medoxomil undergoes rapid and complete ester hydrolysis in the gastrointestinal tract into active olmesartan.
Amlodipine: Extensively metabolised in the liver into inactive metabolites.
Excretion: Olmesartan: Via faeces (50-65%); urine (35-50%). Terminal elimination half-life: 10-15 hours.
Amlodipine: Via urine (10% as unchanged drug, 60% as metabolites). Terminal elimination half-life: Approx 30-50 hours.
Hydrochlorothiazide: Via urine (≥61% as unchanged drug). Elimination half-life: Approx 6-15 hours.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 158781, Olmesartan. https://pubchem.ncbi.nlm.nih.gov/compound/Olmesartan. Accessed Oct. 24, 2023.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 2162, Amlodipine. https://pubchem.ncbi.nlm.nih.gov/compound/Amlodipine. Accessed Oct. 26, 2023.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 3639, Hydrochlorothiazide. https://pubchem.ncbi.nlm.nih.gov/compound/Hydrochlorothiazide. Accessed Oct. 24, 2023.

Store between 15-30°C.

Angiotensin II Antagonists / Calcium Antagonists / Diuretics

C09DX03 - olmesartan medoxomil, amlodipine and hydrochlorothiazide ; Belongs to the class of angiotensin II receptor blockers (ARBs), other combinations. Used in the treatment of cardiovascular disease.

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