Valsartan/ Hydrochlorothiazide

Registered South African indications:

• Hypertension - mild to moderate 

Contraindications

South African recommendations

• Known hypersensitivity to valsartan, hydrochlorothiazide or to any of the excipients in this combination product
• A history of angioedema related to previous therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Severe renal function impairment (creatinine clearance less than 30ml/min)
• Bilateral renal artery stenosis
• Renal artery stenosis in patients with a single kidney
• Aortic stenosis
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride
• Concomitant use of fluoroquinolones with ACE inhibitors/angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (creatinine clearance ≤30ml/min) and in elderly patients
• Porphyria
• Lithium therapy: Concomitant administration with valsartan/ hydrochlorothiazide may lead to toxic blood concentrations of lithium
• Pregnancy
• Lactation
• Concomitant use of valsartan/ hydrochlorothiazide with aliskiren-containing medicines is contraindicated
• Refractory hypokalaemia, hyponatraemia, hypercalcaemia and symptomatic hyperuricaemia
• Patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip

Recommendations in other jurisdictions

• Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide-derived medicinal products or to any of the excipients
• Second and third trimester of pregnancy
• Severe hepatic impairment, biliary cirrhosis and cholestasis
• Severe renal impairment (creatinine clearance <30ml/min)
• Anuria
• Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia
• Concomitant use of valsartan/ hydrochlorothiazide with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.73 m²)

Cautions

South African recommendations

• Women of childbearing age
• Moderate renal impairment
• Hepatic impairment
• Sodium and/or volume-depleted patients
  - Those receiving doses of diuretics
• Systemic lupus erythematosus
• Coadministration with other antihypertensive agents
• Coadministration with ACE inhibitors or beta blockers
• Coadministration with agents that may alter potassium levels
• Coadministration with insulin or oral antidiabetic agents
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• First trimester of pregnancy
  - Patients planning pregnancy
• Breastfeeding
• Mild to moderate hepatic impairment without cholestasis
• Progressive liver disease
• Sodium and/or volume-depleted patients
  - Those receiving high doses of diuretics
• Severe chronic heart failure
• Those whose renal function may depend on the activity of the renin-angiotensin system e.g., patients with severe congestive heart failure
• Primary hyperaldosteronism
• Recent kidney transplantation
• History of angioedema
• Systemic lupus erythematosus
• Diabetes mellitus
• History of photosensitivity
• History of hypersensitivity to other angiotensin II receptor antagonists
• Post-myocardial infarction
• Dual blockade of renin-angiotensin-aldosterone system
• History of non-melanoma skin cancer
• History of acute respiratory distress syndrome
• Unilateral or bilateral renal artery stenosis
• Stenosis of the artery to a solitary kidney
• Aortic or mitral stenosis
• Hypertrophic obstructive cardiomyopathy 
• Asthma
• Patients with allergy
• Untreated acute angle closure glaucoma
• Sunlight and UV exposure
• Risk factors for acute angle closure glaucoma
  - History of sulfonamide or penicillin allergy
• Coadministration with agents that may increase potassium levels
• May impair ability to drive and operate machinery

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

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Hypertension - mild to moderate
- In those whose blood pressure has been stabilised at the same dosages of the individual components given together

Valsartan/ Hydrochlorothiazide
80/12.5 (mg)
160/12.5 (mg)
160/25 (mg)
320/12.5 (mg)
320/25 (mg)

• Oral (tab): 1 tab, dly with or without food

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When clinically appropriate either valsartan/ hydrochlorothiazide 80mg/12.5mg, 160mg/12.5mg or 320mg/12.5mg may be used. When necessary valsartan/ hydrochlorothiazide 160mg/25mg or 320mg/25mg may be used

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The maximum antihypertensive effect is seen within 2-4 weeks

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Indications and dosages registered in other jurisdictions

Essential hypertension 
- In those whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy

Valsartan/ Hydrochlorothiazide
80/12.5 (mg)
160/12.5 (mg)
160/25 (mg)

• Oral (fct): 1 tab, dly with or without food; Max: 320/25 (mg)/24hrs

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Dose titration with the individual components is recommended. In each case, up-titration of individual components to the next dose should be followed in order to reduce the risk of hypotension and other adverse events

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When clinically appropriate direct change from monotherapy to the fixed combination may be considered in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy, provided the recommended dose titration sequence for the individual components is followed

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 The clinical response to valsartan/ hydrochlorothiazide should be evaluated after initiating therapy and if blood pressure remains uncontrolled, the dose may be increased by increasing either one of the components to a maximum dose of valsartan/ hydrochlorothiazide 320mg/25mg

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The antihypertensive effect is substantially present within 2 weeks

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In most patients, maximal effects are observed within 4 weeks. However, in some patients, 4-8 weeks treatment may be required. This should be taken into account during dose titration

Not established for use in children

Pregnancy

South African recommendations

• Contraindicated
• Valsartan/hydrochlorothiazide should not be used in pregnancy as teratogenicity has been shown in experimental animals
• Valsartan/hydrochlorothiazide should be discontinued as soon as possible when pregnancy is suspected
• Women of childbearing age should ensure adequate contraception

Recommendations in other jurisdictions

• First trimester: Caution; not recommended 
• Second and third trimester: Contraindicated
• The use of angiotensin II receptor antagonists is not recommended during first trimester of pregnancy. The use of angiotensin II receptor antagonists is contraindicated during the second and third trimester of pregnancy
• Epidemiological evidence regarding the risk of teratogenicity following exposure to angiotensin-converting enzyme inhibitors (ACE-inhibitors) during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of agents. Unless continued angiotensin II receptor antagonists therapy is considered essential, 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 angiotensin II receptor antagonists should be stopped immediately and, if appropriate, alternative therapy should be started
• Angiotensin II receptor antagonists therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia)
• Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended
• Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension
• There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta
• Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia

Breastfeeding

South African recommendations

• Contraindicated 
• The safety in breastfeeding has not been established
• Valsartan/hydrochlorothiazide should be used with care, if at all, during breastfeeding
• Hydrochlorothiazide crosses the placenta and is excreted in breast milk. Thus, it is not advisable to use valsartan/hydrochlorothiazide in breastfeeding mothers

Recommendations in other jurisdictions

• Caution; not recommended
• No information is available regarding the use of valsartan during breastfeeding
• Hydrochlorothiazide is excreted in human milk. Therefore the use of valsartan/hydrochlorothiazide during breastfeeding is not recommended
• Alternative treatments with better established safety profiles during breastfeeding are preferable, especially while breastfeeding a newborn or preterm infant

Fertility

• No information available

Renal Impairment

South African recommendations

• Mild (CrCl>70ml/min): No dose adjustment recommended 
• Moderate (CrCl≥30-<70ml/min): Caution; no dose adjustment recommended 
• Severe (CrCl<30ml/min): Contraindicated 
  In patients with moderate to severe renal impairment (CrCl<70ml/min) and patients undergoing dialysis no data are available for valsartan/hydrochlorothiazide. Valsartan is highly bound to plasma protein and is not removed by dialysis whereas clearance of hydrochlorothiazide will be achieved by dialysis

Recommendations in other jurisdictions

• Mild to moderate (CrCl≥30ml/min): No dose adjustment recommended
• Severe (CrCl<30ml/min): Contraindicated 
• GFR<60ml/min/1.73m² and coadministration of aliskiren-containing products: Contraindicated 

Hepatic Impairment

South African recommendations

• Mild to moderate (of non-biliary origin and without cholestasis): Caution; no dose adjustment recommended 
• Severe: Caution; no information available 

Recommendations in other jurisdictions

• Mild to moderate (without cholestasis): Caution; dose adjustment recommended
  The dose of valsartan should not exceed 80mg
• Severe: Contraindicated

Elderly

• No dose adjustment recommended
  A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in young subjects; however, this has not been shown to have any clinical significance 

Porphyria Information

South African recommendations

• Contraindicated
  Safety in porphyria has not been established

Recommendations in other jurisdictions

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Prohibited - At all times

Valsartan/ Hydrochlorothiazide

Central Nervous System Disorders

• Dizziness
• Paraesthesia
• Syncope
• Fatigue

Cardiovascular Disorders

• Hypotension

Respiratory Disorders

• Cough
• Non cardiogenic pulmonary oedema

Gastrointestinal Disorders

• Diarrhoea

Hepatobiliary Disorders

• Increased serum bilirubin

Genitourinary Disorders

• Renal impairment
• Increased serum uric acid
• Increased serum creatinine
• Increased blood urea nitrogen

Endocrine and Metabolic Disorders

• Dehydration
• Hypokalaemia
• Hyponatraemia

Musculoskeletal Disorders

• Myalgia
• Arthralgia

Immune, Blood and Lymphatic System Disorders

• Neutropenia

Sensory Disorders

• Tinnitus
• Blurred vision

Valsartan

Cardiovascular Disorders

• Vasculitis

Gastrointestinal Disorders

• Abdominal pain

Hepatobiliary Disorders

• Elevated hepatic function values

Genitourinary Disorders

• Renal failure

Endocrine and Metabolic Disorders

• Increased serum potassium
• Hyponatraemia

Skin and Subcutaneous Tissue Disorders

• Angioedema
• Bullous dermatitis
• Rash
• Pruritus

Immune, Blood and Lymphatic System Disorders

• Decreased haemoglobin
• Decreased haematocrit
• Thrombocytopenia
• Other hypersensitivity reactions
  - Serum sickness

Sensory Disorders

• Vertigo

Hydrochlorothiazide

Central Nervous System Disorders

• Depression
• Sleep disturbances
• Headache
• Dizziness
• Paraesthesia
• Asthenia

Cardiovascular Disorders

• Postural hypotension
• Cardiac arrhythmias

Respiratory Disorders

• Acute respiratory distress syndrome
• Respiratory distress
  - Pulmonary oedema
  - Pneumonitis

Gastrointestinal Disorders

• Loss of appetite
• Nausea and vomiting
• Constipation
• Gastrointestinal discomfort
• Diarrhoea

Hepatobiliary Disorders

• Pancreatitis
• Intrahepatic cholestasis
• Jaundice

Genitourinary Disorders

• Renal dysfunction
• Acute renal failure
• Impotence

Endocrine and Metabolic Disorders

• Hypokalaemia
• Increased serum lipids
  - Increased cholesterol
  - Increased triglycerides
• Hyponatraemia
• Hypomagnesaemia
• Hyperuricaemia
• Hypercalcaemia
• Hyperglycaemia
• Glycosuria
• Altered glucose tolerance
• Hypochloraemic alkalosis
• Worsening of diabetic metabolic state

Musculoskeletal Disorders

• Muscle spasm

Skin and Subcutaneous Tissue Disorders

• Urticaria and other forms of rash
• Photosensitivity
• Necrotising vasculitis
• Toxic epidermal necrolysis
• Cutaneous lupus erythematosus-like reactions
• Reactivation of cutaneous lupus erythematosus
• Erythema multiforme
• Non-melanoma skin cancer
  - Basal cell carcinoma
  - Squamous cell carcinoma

Immune, Blood and Lymphatic System Disorders

• Pyrexia
• Hypersensitivity reactions
• Thrombocytopenia sometimes with purpura
• Agranulocytosis
• Leucopenia
• Haemolytic anaemia
• Bone marrow failure
• Aplastic anaemia
• Exacerbation or activation of systemic lupus erythematosus

Sensory Disorders

• Visual impairment
• Acute angle closure glaucoma
• Acute transient myopia
• Choroidal effusion

• Aliskiren-containing products
• Fluoroquinolones
• Spironolactone
• Triamterene
• Amiloride
• Lithium
• Other antihypertensive agents
• Guanethidine
• Vasodilators
• Angiotensin-converting-enzyme inhibitors
• Angiotensin II receptor blockers
• Beta blockers
• Calcium channel blockers
• Pressor amines
• Noradrenaline
• Adrenaline
• Nonsteroidal anti-inflammatory drugs
• COX-2 inhibitors
• Acetylsalicylic acid (>3g/day)
• Agents that act on the renin-angiotensin-aldosterone system
• Agents that increase serum potassium levels
• Potassium-sparing diuretics
• Potassium supplements
• Heparin
• OATP1B1/OATP1B3 inhibitors
• Hepatic efflux transporter MRP2
• Rifampicin
• Ritonavir
• Ciclosporin
• Digoxin
• Indomethacin
• Kaliuretic diuretics
• Corticosteroids
• Laxatives
• Adrenocorticotropic hormone
• Amphotericin
• Carbenoxolone
• Penicillin G
• Salicylic acid and derivatives
• Agents that could induce torsades de pointes
• Class Ia and Class III antiarrhythmics
• Antipsychotics
• Antidepressants
• Antiepileptics
• Digitalis glycosides
• Calcium salts
• Vitamin D
• Antidiabetic agents
• Insulin
• Metformin
• Diazoxide
• Beta blockers
• Agents used in the treatment of gout
• Probenecid
• Sulfinpyrazone
• Allopurinol
• Anticholinergic agents
• Agents affecting gastric motility
• Atropine
• Biperiden
• Amantadine
• Ion exchange resins
• Cholestyramine
• Colestipol
• Cytotoxic agents
• Cyclophosphamide
• Methotrexate
• Non-depolarising skeletal muscle relaxants
• Tubocurarine
• Curare derivatives
• Methyldopa
• Cisapride
• Barbiturates
• Narcotics

Other interactions

• Salt substitutes containing potassium
• Alcohol
• Iodine contrast media

• Electrolytes
• Renal function
• Blood pressure
• Heart rate

Valsartan
Valsartan is an orally active and specific angiotensin II (Ang 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 Ang 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. Valsartan is not known to bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

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 NaCl 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. The renin-aldosterone link is mediated by angiotensin II, so with coadministration of valsartan the reduction in serum potassium is less pronounced as observed under monotherapy with hydrochlorothiazide.

COMBINATION PREPARATIONS

Valsartan/ Hydrochlorothiazide

Tablet 80mg/12.5mg 

• Co-Diovan (Novartis) originator
• Co-Migroben (Novartis)
• Co-Tareg (Novartis)
• Co-Zomevek 80/12,5 Tablet (Sandoz)
• Diolo Co (Ranbaxy)
• Dynaval Co (Pharma Dynamics) Discontinued: 25/06/2020
• Regoval Co (Pharma Dynamics)

Tablet 160mg/12.5mg 

• Co-Diovan (Novartis) originator
• Co-Migroben (Novartis)
• Co-Tareg (Novartis)
• Co-Zomevek 160/12,5 Tablet (Sandoz)
• Diolo Co (Ranbaxy)
• Dynaval Co (Pharma Dynamics) Discontinued: 25/06/2020
• Regoval Co (Pharma Dynamics)

Tablet 160mg/25mg 

• Co-Diovan Plus (Novartis) originator
• Co-Migroben (Novartis)
• Co-Tareg Plus (Novartis)
• Co-Zomevek 160/25 Tablet (Sandoz)
• Dynaval Co (Pharma Dynamics) Discontinued: 25/06/2020
• Regoval Co (Pharma Dynamics)

Tablet 320mg/12.5mg 

• Co-Diovan (Novartis) originator

Tablet 320mg/25mg 

• Co-Diovan (Novartis) originator