Amlodipine/ Valsartan/ Hydrochlorothiazide

Registered South African indications:

• Essential hypertension
  - In patients stabilised on the individual components given at the same doses

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. Should a woman become pregnant while receiving amlodipine/ valsartan/ hydrochlorothiazide, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine.

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Hypersensitivity to other sulphonamides and dihydropyridine derivatives
• History of angioedema related to previous therapy with angiotensin receptor blockers (ARBs): These patients must never again be given these medicines
• Concomitant use of fluoroquinolones with ACE inhibitors/angiotensin receptor blockers is contraindicated in patients with moderate (creatinine clearance <60 ml/min) to severe renal function impairment (creatinine clearance less than 30 ml/min) and in the elderly
• Concomitant use of with aliskiren-containing medicines in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²)
• Lithium therapy: concomitant administration with may lead to toxic blood concentrations of lithium
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride
• Hereditary or idiopathic angioedema
• Severe hepatic impairment (Child-Pugh C)
• Should not be given to patients with Addison's disease
• Anuria, severe renal impairment (creatinine clearance less than 30 ml/min) and patients undergoing dialysis
• Refractory hypokalaemia, hyponatraemia, hypercalcaemia and symptomatic hyperuricaemia
• Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructive cardiomyopathy (HOCM) and high-grade aortic stenosis and mitral valve stenosis)
• Bilateral renal artery stenosis, renal artery stenosis in patients with a single kidney
• Pregnancy: Should be discontinued as soon as possible when pregnancy is suspected
• Breastfeeding
• Porphyria
• Children under 18 years of age, as safety and efficacy have not been established
• Patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip

South African recommendations

Caution in the following patient groups

• Mild to moderate hepatic impairment
• Biliary obstructive disorders
• Elderly

Use in hypertensive crisis

• The safety and efficacy of amlodipine in hypertensive crisis have not been established

Renal impairment

• Amlodipine/valsartan/hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min), anuria, or those undergoing dialysis
• Thiazide diuretics may precipitate uraemia in chronic kidney disease. Periodic monitoring of serum electrolytes (especially potassium), creatinine, and uric acid is recommended
• Use is not recommended in patients with bilateral renal artery stenosis or renal artery stenosis in a single kidney, as blood urea and creatinine may increase
• No data exists for use in patients with recent kidney transplants

Sodium and/or volume depletion

• Excessive hypotension may occur in volume- and/or salt-depleted patients, especially when starting treatment or increasing doses
• Hypotension should be corrected before starting therapy, or the treatment initiated under close supervision
• If hypotension occurs, place the patient supine and administer IV 0.9% sodium chloride if necessary

Serum electrolyte changes

• Amlodipine/valsartan/hydrochlorothiazide combination: Valsartan and hydrochlorothiazide may counterbalance effects on serum potassium, but monitoring is required
• Valsartan: Avoid concomitant use with potassium supplements, potassium-sparing diuretics, or salt substitutes containing potassium. Monitor potassium levels
• Hydrochlorothiazide: Monitor for hypokalaemia, hyperkalaemia, hyponatraemia, hypochloraemic alkalosis, and hypomagnesaemia. Treat any imbalances before initiating or continuing treatment. Periodic monitoring of serum electrolytes is essential

Cardiac conditions

• Special caution in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy
• Calcium channel blockers (like amlodipine) may worsen outcomes in patients with heart failure
• In patients with coronary artery disease and/or heart failure, especially on the maximum dose (10/320/25 mg), caution is warranted due to limited data

Systemic lupus erythematosus

• Hydrochlorothiazide may exacerbate or activate systemic lupus erythematosus

Metabolic effects

• Hydrochlorothiazide may alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid. In diabetic patients, dosage adjustments of insulin or oral hypoglycaemic medicines may be required
• Due to the hydrochlorothiazide component, this combination medicine is contraindicated in symptomatic hyperuricemia
• Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia as well as precipitate gout in susceptible patients
• Thiazides reduce urinary calcium excretion and may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Contraindicated in patients with hypercalcaemia and should only be used after correction of any pre-existing hypercalcaemia (see Contraindications). Discontinue if hypercalcaemia develops during treatment
• Thiazides reduce calcium excretion and may unmask hyperparathyroidism. Discontinue prior to parathyroid testing

Angioedema

• Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue, has been reported in patients treated with valsartan. Some of these patients previously experienced angioedema with other medicines including ACE inhibitors
• Discontinue immediately in patients who develop angioedema and should not be re-administered

Drug interactions: Fluoroquinolones

• Concomitant use with fluoroquinolones may increase the risk of acute kidney injury, particularly in elderly or renally impaired patients. Monitor renal function

Primary hyperaldosteronism

• Amlodipine/valsartan/hydrochlorothiazide is not recommended in patients with primary hyperaldosteronism due to lack of response to angiotensin II antagonists

Photosensitivity

• Photosensitivity reactions have been reported. Discontinue treatment if they occur. Sun protection is advised if re-treatment is necessary

Acute angle-closure glaucoma

• Hydrochlorothiazide, a sulphonamide, has been associated with an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to a week of treatment initiation
• Untreated acute-angle closure glaucoma can lead to permanent vision loss
• The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle closure glaucoma may include a history of sulphonamide or
  penicillin allergy

Hypersensitivity reactions

• Use with caution in patients with known hypersensitivity to angiotensin receptor blockers or sulphonamides. Reactions are more likely in patients with allergy or asthma

Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS)

• Concomitant use of ACE inhibitors, ARBs, or aliskiren increases the risk of hypotension, hyperkalaemia, and renal impairment. Dual blockade is contraindicated. Use only if absolutely necessary, under specialist supervision

Non-melanoma skin cancer (NMSC)

• Increased risk of BCC and SCC with cumulative hydrochlorothiazide exposure. Patients should be advised to monitor for skin lesions and limit sun/UV exposure
• Contraindicated in patients with a history of NMSC

Effects on ability to drive and use machines

• Amlodipine/ valsartan/ hydrochlorothiazide can lead to dizziness or weariness. Patients should be advised not to drive, operate machinery or perform hazardous tasks until they know how the treatment affects them

Forms avail. in SA and covered in this monograph: fct, tab

South African registered indications and dosages

Essential hypertension
- In patients stabilised on the individual components given at the same doses

Amlodipine/ Valsartan/ Hydrochlorothiazide
5/160/12.5 (mg)
10/160/12.5 (mg)
5/160/25 (mg)
10/160/25 (mg)
10/320/25 (mg)

• Oral (tab): 1 tab, dly; Max dose (10/320/25mg): 1 tab/24hrs

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Amlodipine/ valsartan/ hydrochlorothiazide is not indicated for the initial therapy of hypertension

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If a tablet shows signs of cracking, the tablet should not be taken

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Patients stabilised with valsartan, amlodipine and hydrochlorothiazide (HCTZ) from separate tablets may be switched to this combination, containing the same component doses

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The maximum antihypertensive effect is reached within two weeks after a change in dose

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Amlodipine/ valsartan/ hydrochlorothiazide can be taken with or without food. It is recommended to take with some water.

Not established for use in children below 18 years

Pregnancy 

South African recommendations

• Contraindicated
• Amlodipine/valsartan/hydrochlorothiazide is contraindicated in pregnancy as teratogenicity has been shown in experimental animals (see Contraindications and Boxed warning)
• Medicines affecting the renin-angiotensin system, such as amlodipine/valsartan/hydrochlorothiazide, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women
• When pregnancy is detected, amlodipine/valsartan/hydrochlorothiazide should be discontinued as soon as possible. Pregnant women should be informed of the potential hazards to the foetus and must not take amlodipine/valsartan/hydrochlorothiazide during pregnancy
• Patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy
• When pregnancy is diagnosed, treatment with amlodipine/valsartan/hydrochlorothiazide should be stopped immediately and if appropriate, alternative therapy should be started
• Foetal exposure to ACE inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spina bifida) and of kidney malformations
• Amlodipine/valsartan/hydrochlorothiazide passes through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in new-borns, have been reported after administration of amlodipine/valsartan/hydrochlorothiazide during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur
• Women of childbearing potential / contraception in males and females: Women of childbearing age should use effective contraception

Breastfeeding

South African recommendations

• Contraindicated
• It is not known whether valsartan and/or amlodipine are excreted in human milk. Valsartan was excreted in the milk of lactating rats. Hydrochlorothiazide is excreted into breast milk
• Amlodipine/valsartan/hydrochlorothiazide is contraindicated in women who are breastfeeding

Fertility

South African recommendations

• There is no data on fertility with amlodipine/valsartan/hydrochlorothiazide

South African recommendations

• Mild to moderate: No dose adjustment recommended
• Severe (CrCl<30 ml/min): Contraindicated
• Concomitant use of fluoroquinolones with ACE inhibitors/angiotensin receptor blockers: Moderate to severe (CrCl <60 ml/min): Contraindicated
• Coadministration with aliskiren-containing medicines in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²): Contraindicated

South African recommendations

• Mild to moderate or biliary obstructive disorders: Caution; no dose adjustment recommended
  The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function but dose recommendations have not been established. Particular caution should be exercised when administering to patients with hepatic impairment or biliary obstructive disorders
• Severe hepatic impairment (Child-Pugh C): Contraindicated

South African recommendations

• Caution; no dose adjustment recommended
  Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of 10mg/320mg/25mg, since available data in this patient population are limited
• Concomitant use of fluoroquinolones with ACE inhibitors/angiotensin receptor blockers in elderly: Contraindicated

Amlodipine/ Valsartan/ Hydrochlorothiazide

Blood and Lymphatic System Disorders

Frequency unknown

• Thrombocytopenia

Immune System Disorders

Frequency unknown

• Angioedema

Metabolism and Nutrition Disorders

Frequent

• Hypokalaemia

Less frequent

• Anorexia
• Hypercalcaemia
• Hyperlipidaemia
• Hyperuricaemia
• Hyponatraemia

Frequency unknown

• Blood potassium increased

Psychiatric Disorders

Less frequent

• Insomnia/sleep disorders

Nervous System Disorders

Frequent

• Dizziness
• Headache

Less frequent

• Abnormal coordination
• Dysgeusia
• Lethargy
• Paraesthesia
• Peripheral neuropathy
• Somnolence
• Syncope
• Postural dizziness 
• Exertional dizziness 

Eye Disorders

Less frequent

• Visual impairment

Ear and Labyrinth Disorders

Less frequent

• Vertigo

Cardiac Disorders

Less frequent

• Tachycardia

Vascular Disorders

Frequent

• Hypotension

Less frequent

• Orthostatic hypotension
• Phlebitis
• Thrombophlebitis

Frequency unknown

• Vasculitis

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Cough
• Dyspnoea
• Throat irritation

Gastrointestinal Disorders

Frequent

• Dyspepsia

Less frequent

• Abdominal discomfort and pain
• Breath odour
• Diarrhoea
• Dry mouth
• Nausea
• Vomiting

Hepato-biliary Disorders

Frequency unknown

• Elevation of liver function values including serum bilirubin

Skin and Subcutaneous Tissue Disorders

Less frequent

• Hyperhidrosis
• Pruritus

Musculoskeletal, Connective Tissue and Bone Disorders

Less frequent

• Back pain
• Joint swelling
• Muscle spasm
• Muscular weakness
• Myalgia
• Pain in extremity

Renal and Urinary Disorders

Frequent

• Pollakiuria

Less frequent

• Blood creatinine increased
• Renal impairment
• Acute renal failure

Reproductive System and Breast Disorders

Less frequent

• Impotence

General Disorders and Administration Site Conditions

Frequent

• Fatigue
• Oedema

Less frequent

• Asthenia
• Discomfort
• Malaise
• Non-cardiac chest pain
• Abasia
• Gait disturbance

Investigations

Less frequent

• Blood urea nitrogen increased
• Blood uric acid increased
• Blood potassium decreased
• Weight increase

Amlodipine

Blood and Lymphatic System Disorders

Less frequent

• Thrombocytopenia sometimes with purpura
• Leucocytopenia

Immune System Disorders

Less frequent

• Hypersensitivity
• Allergic reactions
• Angioedema

Metabolism and Nutrition Disorders

Less frequent

• Hyperglycaemia

Psychiatric Disorders

Less frequent

• Insomnia
• Mood changes
• Anxiety
• Depression
• Confusion

Nervous System Disorders

Frequent

• Headache
• Somnolence
• Dizziness

Less frequent

• Tremor
• Hypoesthesia
• Dysgeusia
• Paraesthesia
• Syncope
• Hypertonia
• Peripheral neuropathy
• Neuropathy

Frequency unknown

• Extrapyramidal syndrome

Eye Disorders

Less frequent

• Visual impairment
• Diplopia
• Visual disturbance

Ear and Labyrinth Disorders

Less frequent

• Tinnitus

Cardiac Disorders

Frequent

• Palpitations

Less frequent

• Dysrhythmia
• Bradycardia
• Atrial fibrillation
• Ventricular tachycardia
• Myocardial infarction

Vascular Disorders

Frequent

• Flushing

Less frequent

• Hypotension
• Vasculitis

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Dyspnoea
• Rhinitis
• Cough

Gastrointestinal Disorders

Frequent

• Vomiting
• Abdominal pain
• Nausea

Less frequent

• Dyspepsia
• Dry mouth
• Constipation
• Diarrhoea
• Vomiting
• Pancreatitis
• Gastritis
• Gingival hyperplasia
• Change of bowel habit

Hepato-biliary Disorders

Less frequent

• Liver function test abnormal including blood bilirubin increase
• Hepatitis
• Jaundice
• Intrahepatic cholestasis

Skin and Subcutaneous Tissue Disorders

Less frequent

• Alopecia
• Hyperhidrosis
• Pruritus
• Rash
• Purpura
• Skin discolouration
• Photosensitivity
• Exfoliative dermatitis
• Urticaria
• Erythema multiforme
• Stevens-Johnson syndrome
• Exanthema
• Quincke oedema

Frequency unknown

• Vasculitis necrotising
• Toxic epidermal necrolysis

Musculoskeletal, Connective Tissue and Bone Disorders

Frequent

• Ankle swelling

Less frequent

• Back pain
• Muscle spasms
• Myalgia
• Arthralgia

Renal and Urinary Disorders

Less frequent

• Micturition disorder
• Nocturia
• Pollakiuria

Reproductive System and Breast Disorders

Less frequent

• Gynecomastia
• Erectile dysfunction
• Impotence

General Disorders and Administration Site Conditions

Frequent

• Oedema
• Fatigue

Less frequent

• Asthenia
• Pain
• Malaise
• Non-cardiac chest pain

Investigations

Less frequent

• Weight decreased
• Weight increased
• Hepatic enzyme increased (mostly consistent with cholestasis)

Valsartan

Infections and Infestations

Frequency unknown

• Viral infections
• Upper respiratory tract infection
• Sinusitis
• Pharyngitis
• Rhinitis

Blood and Lymphatic System Disorders

Frequency unknown

• Decrease in haemoglobin
• Decrease in haematocrit
• Neutropenia
• Thrombocytopenia sometimes with purpura

Immune System Disorders

Frequency unknown

• Hypersensitivity including serum sickness
• Angioedema

Psychiatric Disorders

Frequency unknown

• Insomnia
• Decreased libido

Ear and Labyrinth Disorders

Less frequent

• Vertigo

Vascular Disorders

Frequency unknown

• Vasculitis

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Cough

Gastrointestinal Disorders

Less frequent

• Abdominal pain
• Discomfort

Hepato-biliary Disorders

Frequency unknown

• Abnormal liver function test, including blood bilirubin increase

Skin and Subcutaneous Tissue Disorders

Frequency unknown

• Rash
• Pruritus
• Angioedema
• Dermatitis bullous

Musculoskeletal, Connective Tissue and Bone Disorders

Frequency unknown

• Myalgia

Renal and Urinary Disorders

Frequency unknown

• Elevation of serum creatinine
• Increased blood urea
• Renal failure and impairment

General Disorders and Administrative Site Conditions

Less frequent

• Fatigue

Investigations

Frequency unknown

• Blood potassium increased

Hydrochlorothiazide

Neoplasms Benign, Malignant and Unspecified

Frequency unknown

• Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma)

Blood and Lymphatic System Disorders

Less frequent

• Thrombocytopenia
• Purpura
• Leucopenia
• Agranulocytosis
• Bone marrow failure
• Haemolytic anaemia
• Aplastic anaemia

Immune System Disorders

Less frequent

• Hypersensitivity reactions - respiratory distress including pneumonitis and pulmonary oedema

Metabolism and Nutrition Disorders

Frequent

• Hypokalaemia
• Increased blood lipids
• Hyponatremia
• Hypomagnesaemia
• Hyperuricaemia

Less frequent

• Hypercalcaemia
• Hyperglycaemia
• Glycosuria and worsening of diabetic metabolic state
• Hypochloraemic alkalosis

Psychiatric Disorders

Less frequent

• Insomnia
• Sleep disorders
• Depression

Nervous System Disorders

Less frequent

• Headache
• Dizziness
• Sleep disorders
• Paraesthesia

Eye Disorders

Less frequent

• Visual impairment
• Acute angle closure glaucoma

Cardiac Disorders

Less frequent

• Dysrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation)

Vascular Disorders

Frequent

• Orthostatic hypotension

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Respiratory distress
• Pulmonary oedema
• Pneumonitis

Gastrointestinal Disorders

Frequent

• Decreased appetite
• Mild nausea
• Vomiting

Less frequent

• Abdominal discomfort
• Constipation
• Diarrhoea
• Pancreatitis

Hepato-biliary disorders

Less frequent

• Intrahepatic cholestasis
• Jaundice

Skin and Subcutaneous Tissue Disorders

Frequent

• Urticaria, and other forms of rash

Less frequent

• Photosensitivity reaction
• Necrotizing vasculitis
• Toxic epidermal necrolysis
• Cutaneous lupus erythematosus-like reactions
• Reactivation of cutaneous lupus erythematosus
• Erythema multiforme
• Purpura

Musculoskeletal, Connective Tissue and Bone Disorders 

Less frequent

• Muscle spasms

Renal and Urinary Disorders 

Less frequent

• Acute renal failure
• Renal dysfunction

Reproductive System and Breast Disorders

Frequent

• Impotence

General Disorders and Administrative Site Conditions

Less frequent

• Pyrexia
• Asthenia

Investigations

Frequent

• Increased lipids

Less frequent

• Glycosuria

Amlodipine/ Valsartan/ Hydrochlorothiazide

• Angiotensin-converting-enzyme (ACE) inhibitors
• Angiotensin II receptor blockers (ARBs)
• Fluoroquinolones
• Aliskiren
• Lithium
• NSAIDs

Amlodipine

• Ketoconazole
• Itraconazole
• Ritonavir
• CYP3A4 inhibitors
• Protease inhibitors
• Azole antifungals
• Macrolides
• Erythromycin
• Clarithromycin
• Verapamil
• Diltiazem
• Carbamazepine
• Phenobarbitone
• Phenytoin
• Fosphenytoin
• Primidone
• Rifampicin
• Simvastatin
• Dantrolene

Valsartan

• Heparin
• Potassium-sparing diuretics
• Potassium supplements
• Salt substitutes containing potassium
• Rifampicin
• Ciclosporin
• Ritonavir

Hydrochlorothiazide

• Barbiturates
• Narcotics
• Amantadine
• Atropine
• Biperiden
• Cisapride
• Insulin
• Oral antidiabetic medicines
• Metformin
• Beta blockers
• Diazoxide
• Carbamazepine
• Ciclosporin
• Cytotoxic medicines
• Cyclophosphamide
• Methotrexate
• Digoxin
• Iodine contrast media
• Ion-exchange resins
• Cholestyramine
• Colestipol
• Kaliuretic diuretics
• Corticosteroids
• Laxatives
• ACTH
• Amphotericin
• Carbenoxolone
• Penicillin G
• Salicylic acid derivatives
• Anti-dysrhythmics
• Antidepressants
• Antipsychotics
• Antiepileptics
• Class Ia anti-dysrhythmics
• Class III anti-dysrhythmics
• Probenecid
• Sulphinpyrazone
• Allopurinol
• Methyldopa
• Non-depolarising muscle relaxants
• Guanethidine
• Noradrenaline
• Vasodilators
• Calcium channel blockers
• ACE inhibitors
• ARBs
• Direct renin inhibitors (DRIS)
• Adrenaline
• Vitamin D
• Calcium salts

Other interactions

• Grapefruit juice
• Hypericum perforatum
• Alcohol

Specific cases may require

• Serum electrolytes (including potassium), creatinine and uric acid serum levels
• Blood pressure
• Renal function

Amlodipine/valsartan/hydrochlorothiazide combines three antihypertensive active ingredients with complementary mechanisms to control blood pressure in patients with essential hypertension: amlodipine belongs to the calcium antagonist class, valsartan to the angiotensin II (Ang II) antagonist class and hydrochlorothiazide belongs to the thiazide diuretics class of medicines. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

Amlodipine
The amlodipine component of the tablet inhibits the transmembrane entry of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle, causing a reduction in peripheral vascular resistance and reduction in blood pressure. Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilatation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Plasma concentrations correlate with effect in both young and elderly patients. In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria. Haemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when co-administered with beta blockers to humans.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with beta blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. Amlodipine has been studied in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.

Valsartan
Valsartan is an orally active, and specific angiotensin II receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 20 000-fold) greater affinity for the AT1 receptor than for the AT2 receptor. Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate. In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved within 4 - 6 hours. The antihypertensive effect persists over 24 hours after administration. During repeated administration, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term therapy. Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.

Hydrochlorothiazide
The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the thiazide diuretic action and inhibition of sodium chloride transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na, Cl. symporter perhaps by competing for the Cl - site, thereby affecting electrolyte reabsorption mechanisms: - directly increasing sodium and chloride excretion to an approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium.

COMBINATION PREPARATIONS

Valsartan/ Hydrochlorothiazide/ Amlodipine

Tablet 160mg/12.5mg/5mg 

• Co-Copalia (Novartis)
• Co Exforge (Novartis) originator

Tablet 160mg/25mg/5mg 

• Co-Copalia (Novartis)
• Co Exforge (Novartis) originator

Tablet 160mg/12.5mg/10mg 

• Co-Copalia (Novartis)
• Co Exforge (Novartis) originator

Tablet 160mg/25mg/10mg 

• Co-Copalia (Novartis)
• Co Exforge (Novartis) originator

Tablet 320mg/25mg/10mg 

• Co Exforge (Novartis) originator