Amlodipine/ Valsartan

Registered South African indications:

• Essential hypertension - mild to moderate 

Contraindications

South African recommendations

• Hypersensitivity to any of the components and any of the excipients
• History of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs)
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM) 
• Aortic valve stenosis
• Mitral valve stenosis
• Haemodynamically unstable heart failure after acute myocardial infarction
• Severe hepatic impairment (Child-Pugh C)
• Biliary cirrhosis
• Cholestasis
• Severe renal function impairment (creatinine clearance less than 30ml/min)
• Bilateral renal artery stenosis
• Renal artery stenosis in patients with a single kidney
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride
• Concomitant with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2 )
• Porphyria
• Lithium therapy: Concomitant administration may lead to toxic blood concentrations of lithium
• Pregnancy
• Lactation

Recommendations in other jurisdictions 

• Hypersensitivity to the active substances, to dihydropyridine derivatives or to any of the excipients
• Severe hepatic impairment
• Biliary cirrhosis
• Cholestasis
• Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.73 m²)
• Second and third trimesters of pregnancy
• Severe hypotension
• Shock (including cardiogenic shock)
• Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructive cardiomyopathy and high grade aortic stenosis)
• Haemodynamically unstable heart failure after acute myocardial infarction

Cautions

• First trimester of pregnancy (Recommendations in other jurisdictions)
• Women of childbearing potential
• Breastfeeding (Recommendations in other jurisdictions)
• Moderate renal impairment (South African recommendations)
• Severe renal impairment (Recommendations in other jurisdictions)
• Mild to moderate hepatic impairment
• Biliary obstructive disorders
• Volume depletion
• Kidney transplant
• Primary hyperaldosteronism
• Congestive cardiac failure
• Dual blockage of renin-angiotensin-aldosterone system
• May impair ability to drive and operate machinery

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

Dosages below include:

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

South African registered indications and dosages

Essential hypertension - mild to moderate
- In patients whose blood pressure is normalized with the individual components in the same doses as the proposed fixed dose combination of amlodipine/valsartan

Amlodipine/ Valsartan
5/80 (mg)
5/160 (mg)
10/160 (mg)
5/320 (mg)
10/320 (mg)

• Oral (fct, tab): 1 tab, dly

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Patients receiving valsartan and amlodipine from separate tablets may be switched to amlodipine/valsartan containing the same component doses

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Indications and dosages registered in other jurisdictions

Essential hypertension
- In patients whose blood pressure is not adequately controlled on amlodipine or valsartan monotherapy

Amlodipine/ Valsartan
5/80 (mg)
5/160 (mg)
10/160 (mg)

• Oral (fct): 1 tab, dly

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Amlodipine /valsartan 5mg/160mg: May be administered in patients whose blood pressure is not adequately controlled with amlodipine 5mg or valsartan 160mg alone
Amlodipine /valsartan 5mg/80mg: May be administered in patients whose blood pressure is not adequately controlled with amlodipine 5mg or valsartan 80mg alone
Amlodipine /valsartan 10mg/160mg: May be administered in patients whose blood pressure is not adequately controlled with amlodipine 10mg or valsartan 160mg alone or with amlodipine /valsartan 5mg/160mg

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Individual dose titration with the components (i.e. amlodipine and valsartan) is recommended before changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy to the fixed-dose combination may be considered

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For convenience, patients receiving valsartan and amlodipine from separate tablets may be switched to amlodipine/valsartan containing the same component doses

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

Not established for use in children below 18 years 

Pregnancy

South African recommendations

• Contraindicated
• Angiotensin-converting enzyme inhibitors (ACE-inhibitors) pass 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 newborns, have been reported after administration of ACE-inhibitors in the second and third trimester
• Amlodipine/valsartan acts directly on the renin-angiotensin system therefore a risk to the foetus cannot be excluded. When pregnancy is detected during therapy, amlodipine/valsartan must be discontinued as soon as possible. Amlodipine/valsartan must not be used during pregnancy as teratogenicity has been shown with valsartan in experimental animals
• There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction when pregnant women have inadvertently taken valsartan
• Amlodipine/valsartan must not be used in women planning to become pregnant. Healthcare professionals prescribing any products acting on the renin-angiotensin-aldosterone system (RAAS) should counsel women of childbearing potential about the potential risk of these agents during pregnancy. Suitable contraception must be used

Recommendations in other jurisdictions

• Second and third trimesters: Contraindicated
• First trimester: Caution; not recommended 
  Amlodipine
• The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses
• Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus
  Valsartan
• The use of angiotensin II receptor antagonists (AIIRAs) is not recommended during the first trimester of pregnancy 
• The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy
• Epidemiological evidence regarding the risk of teratogenicity following exposure to 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 AIIRAs, similar risks may exist for this class of drugs
• Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started
• Exposure to AIIRA therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia)
• Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended
• Infants whose mothers have taken AIIRAs should be closely observed for hypotension

Breastfeeding

South African recommendations

• Contraindicated 
• Safety in breastfeeding has not been established. It is not known whether valsartan and/or amlodipine are excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3-7%, with a maximum of 15%
• The effect of amlodipine on infants is unknown. Valsartan was excreted in the milk of lactating rats. Amlodipine/valsartan is contraindicated for women who are breastfeeding

Recommendations in other jurisdictions

• Caution; not recommended 
  Amlodipine
• Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown
  Amlodipine/valsartan
• No information is available regarding the use of amlodipine/valsartan during breastfeeding, therefore amlodipine/valsartan is not recommended and alternative treatments with better-established safety profiles during breastfeeding are preferable, especially while nursing a new-born or preterm infant 

Fertility

• There is no information on the effects of amlodipine or valsartan on human fertility. Studies in rats did not show any effects of amlodipine or valsartan on fertility

Renal Impairment

South African recommendations

• Mild: No dose adjustment recommended
• Moderate: Caution; no dose adjustment recommended
• In patients with moderate renal impairment, amlodipine /valsartan containing reduced amlodipine dosages (5mg) may need to be administered in these patients. Amlodipine is not dialysable
• Severe (CrCl<30ml/min): Contraindicated 
• GFR<60ml/min/1.73m² and coadministration of aliskiren-containing products: Contraindicated 

Recommendations in other jurisdictions

• Mild to moderate: No adjustment recommended
• Severe: Caution; no information available
• GFR<60ml/min/1.73m² and coadministration of aliskiren-containing products: Contraindicated

Hepatic Impairment

South African recommendations

• Mild to moderate: Caution; dose adjustment recommended
  Amlodipine half-life is prolonged in patients with impaired hepatic function. Amlodipine/valsartan containing lower amlodipine dosages (5mg) should therefore be administered in these patients
• Severe: Contraindicated 

Recommendations in other jurisdictions

• Mild to moderate: Caution; dose adjustment recommended
  In patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose is 80mg valsartan
  Amlodipine dosage recommendations have not been established in patients with mild to moderate hepatic impairment
  When switching eligible hypertensive patients with hepatic impairment to amlodipine or amlodipine /valsartan, the lowest available dose of amlodipine monotherapy or of the amlodipine component, respectively, should be used
• Severe: Contraindicated

Elderly

• No dose adjustment recommended

Porphyria Information

South African recommendations

• Contraindicated

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Depression
• Dizziness
• Extrapyramidal syndrome
• Headache
• Hypertonia
• Parasthesia
• Peripheral neuropathy
• Somnolence
• Syncope
• Tremor
• Hypoesthesia
• Fatigue

Cardiovascular Disorders

• Chest pain
• Postural hypotension
• Palpitations
• Tachycardia
• Arrhythmias
• Myocardial infarction
• Flushing
• Vasculitis

Respiratory Disorders

• Nasopharyngitis
• Influenza
• Cough 
• Dyspnoea
• Pharyngolaryngeal pain
• Rhinitis

Gastrointestinal Disorders

• Nausea and vomiting
• Dysgeusia
• Abdominal discomfort
• Abdominal pain
• Constipation
• Diarrhoea
• Dry mouth
• Dyspepsia
• Gastritis
• Gingival hyperplasia

Hepatobiliary Disorders

• Pancreatitis
• Abnormal liver function tests
• Hepatitis
• Jaundice
• Intrahepatic cholestasis

Genitourinary Disorders

• Increased serum creatinine
• Micturition disorder
• Nocturia
• Pollakiuria
• Polyuria
• Renal impairment
• Erectile dysfunction

Endocrine and Metabolic Disorders

• Anorexia
• Hypercalcaemia
• Hyperglycaemia
• Hyperlipidaemia
• Hyperuricaemia
• Hypokalaemia
• Hyponatraemia
• Gynaecomastia
• Increased serum potassium
• Weight changes

Musculoskeletal Disorders

• Arthralgia
• Back pain
• Joint swelling
• Muscle spasm
• Myalgia
• Ankle swelling

Skin and Subcutaneous Tissue Disorders

• Alopecia
• Angioedema
• Dermatitis bullous
• Erythema
• Erythema multiforme
• Exanthema
• Hyperhidrosis
• Photosensitivity
• Pruritis
• Rash
• Skin discolouration
• Urticaria
• Exfoliative dermatitis
• Stevens-Johnson syndrome

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
• Decreased haemoglobin
• Decreased haematocrit
• Leukopenia
• Neutropenia
• Thrombocytopenia
• Purpura

Sensory Disorders

• Visual disturbance
• Visual impairment
• Tinnitus 
• Vertigo

• Potassium sparing diuretics
• Spironolactone
• Triamterene
• Amiloride
• Antihypertensives
• CYP3A4 inhibitors
• CYP314 inducers
• Simvastatin
• Dantrolene
• Lithium
• Agents that affect serum potassium levels
• Non-steroidal anti-inflammatory drugs
• OATP1B1 transporter substrates
• Agents that act on the renin-angiotensin-aldosterone system
• Angiotensin receptor blockers
• Aliskiren

Other interactions

• Grapefruit juice

• Electrolytes
• Renal function

Amlodipine
Amlodipine is a calcium ion influx inhibitor and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. Amlodipine dilates peripheral arterioles and thus reduces afterload, it also dilates coronary arteries and arterioles which increases myocardial oxygen delivery.

Valsartan
Valsartan is an angiotensin II receptor antagonist that acts selectively at the angiotensin 1 (AT1) receptor subtype. The normal downstream actions of angiotensin II binding at this receptor include vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. Thus antagonism of AT1 produces the drug's antihypertensive effects.

COMBINATION PREPARATIONS

Amlodipine/ Valsartan

Tablet 5mg/ 80mg

• Calsar 5/80mg (Pharma Dynamics)

Tablet 5mg/160mg

• Calsar 5/160mg (Pharma Dynamics)
• Copalia (Novartis)
• Dafiro 5/160 mg (Sandoz SA)
• Exforge (Novartis) originator
• Valduo 5/160 (Forrester Pharma)
• Valvasc 5/160 (Austell Laboratories)
• Zyvasc 5/160 (Zydus Healthcare)

Tablet 5mg/320mg

• Exforge (Novartis) originator

Tablet 10mg/160mg

• Calsar 10/160mg (Pharma Dynamics)
• Copalia (Novartis)
• Dafiro 10/160 mg (Sandoz SA)
• Exforge (Novartis) originator
• Valduo 10/160 (Forrester Pharma)
• Valvasc 10/160 (Austell Laboratories)
• Zyvasc 10/160 (Zydus Healthcare)

Tablet 10mg/320mg

• Exforge (Novartis) originator
• Valduo 10/320 (Forrester Pharma)