Drugs List

Therapeutic Indications

Uses

Hypertension-not adequately controlled by individual components

Contraindications

Children under 18 years
Biliary cirrhosis
Breastfeeding
Cardiac failure within 1 month of a myocardial infarction
Cardiogenic shock
Cholestasis
Left ventricular outflow obstruction
Pregnancy
Renal dialysis
Renal impairment - glomerular filtration rate below 30ml/minute/1.73m sq
Severe aortic stenosis
Severe bilateral renal artery stenosis
Severe hepatic impairment
Severe hypotension
Severe unilateral stenosis of solitary functioning kidney
Unstable angina

Precautions and Warnings

Elderly
Females of childbearing potential
Acute porphyria
Aortic stenosis
Bilateral renal artery stenosis
Electrolyte depletion
Hepatic impairment
Hypertrophic obstructive cardiomyopathy
Hypovolaemia
Mitral stenosis
Peripheral vascular disease
Renal impairment - creatinine clearance 30-60ml/minute
Renovascular disorder
Severe congestive cardiac failure
Severe generalised atherosclerosis
Unilateral stenosis of solitary functioning kidney

Patients with primary aldosteronism may not benefit from this treatment
Reduce dose in patients with hepatic impairment
Advise ability to drive/operate machinery may be affected by side effects
Afro-Caribbean or black patients may show reduced response
Correct volume and/or salt depletion before initiating therapy
Place patient in supine position if severe hypotension occurs
Evaluate renal function before and during treatment
Monitor serum electrolytes before and during treatment
Monitor serum potassium regularly
Increased risk of hyperkalaemia with K+ suppl. and K+ sparing diuretic
Advise patient to seek advice at first indications of pregnancy
Discontinue if angioedema occurs
Advise patient not to take NSAIDs unless advised by clinician
Advise on problems of salt substitutes/high intake of potassium-rich food
Grapefruit prod increase dihydropyridine Ca channel blocker bioavailability
Female: Ensure adequate contraception during treatment

Renal function and electrolytes should be checked before starting treatment and monitored during therapy, especially in patients post myocardial infarction, those with heart failure and when treating hypertension in children or adolescents. Side effects (such as hyperkalaemia) are more common in patients with renal impairment- the dose may need to be reduced. A specialist should be involved if renal function is significantly reduced.

Monitor plasma potassium, particularly in the elderly, patients with renal impairment, in the presence of other conditions (fever, dehydration) which affect renal function and patients in whom potassium supplements / retaining medication is essential.

In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g. patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/ or progressive azotaemia and in rare cases with acute renal failure and/ or death. As valsartan is an angiotensin II antagonist, it cannot be excluded that the use of this medication may be associated with impairment of the renal function.

Avoid use in patients with known or suspected renovascular disease, unless the blood pressure cannot be controlled with other drugs. Use with particular precaution in patients who have undiagnosed and clinically silent renovascular disease.

Co-administration of NSAIDS may reduce the antihypertensive effect of angiotensin II receptor antagonists, increase serum potassium and exacerbate renal impairment.

Pregnancy and Lactation

Pregnancy

Valsartan
Contraindicated in pregnancy. Adequate contraception is recommended for women of childbearing potential. When pregnancy is diagnosed, treatment should be immediately discontinued and if possible an alternative treatment started.

Angiotensin II receptor antagonists may be associated with similar risks as ACE inhibitors. Angiotensin II receptor antagonist exposure 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).

The MHRA states that the use of angiotensin II receptor antagonists in late pregnancy has been associated with adverse effects on the foetal kidney and other congenital anomalies, therefore angiotensin II receptor antagonists should not be used at any stage during of pregnancy unless absolutely necessary and only then after the potential risks and benefits have been discussed with the patient.

Exposure to angiotensin II receptor antagonists during the first trimester has been inconclusive, however, a small increase in risk cannot be excluded and a detailed ultrasound is recommended.

If pregnancy is detected during therapy, Valsartan should be discontinued as soon as possible and alternative treatment should be offered. Guidelines advise that women who are taking angiotensin II receptor blockers are told that there is an increased risk of congenital abnormalities if these drugs are taken during pregnancy and other antihypertensive treatments should be discussed and offered.

Amlodipine
Some dihydropyridine compounds have been found to be teratogenic in animals. However, amlodipine was found not to be teratogenic or embryotoxic in rats and rabbits up to 8 and 23 times, respectively, the maximum human dose based on BSA (MRHD) during their respective periods of major organogenesis. Effects on reproduction in animals were found at high dosages (including delayed parturition, difficult labour and impaired foetal and pup survival) (Briggs, 2011). There is no adequate data for the use of amlodipine in pregnant women. The molecular weight of amlodipine is low enough that passage to the foetus should be expected. Calcium channel blockers may inhibit labour (Schaefer,2007). In the first trimester, calcium antagonists are considered to be second-line therapy. Manufacturers advise amlodipine should not be administered during pregnancy or to women of childbearing potential unless effective contraception is used unless clearly needed. Schaefer (2007) suggests that if exposure to amlodipine has occurred during the first trimester, a detailed ultrasound diagnosis is advisable. Overall exposure to a calcium antagonist during pregnancy is not an indication for either invasive diagnostic procedures or termination of pregnancy.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Licensed in pregnancy? - Contraindicated

Recommended for use in pregnancy? - No

Known human teratogen? - Yes, angiotensin II receptor antagonists

Other information - Methyldopa, labetalol, hydralazine, modified-release preparations of nifedipine are the drugs with most safety data during pregnancy.

Lactation

Valsartan
Contraindicated during breastfeeding.

Schaefer (2007) suggests that accidental administration of a single dose does not require weaning, however, therapy should be changed to an antihypertensive which has been better studied in breastfeeding. The MHRA concludes that the use of angiotensin II receptor antagonists in breastfeeding mothers is not recommended. Alternative agents with more established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm baby.

Amlodipine
There is no adequate data for the use of amlodipine in breastfeeding. Hale (2010) comments that because most calcium channel blockers readily transfer into milk, that the same should be assumed for this drug. The molecular weight of amlodipine is low enough that excretion into breast milk should be expected. No paediatric concerns have been reported but the infant should be observed for bradycardia or hypotension upon prolonged use. Guidelines from NICE recommend that women who still need antihypertensive treatment in the postnatal period are told that there is insufficient evidence on the safety in babies receiving breast milk of amlodipine. Some manufacturers advise patients to stop breast feeding during treatment with amlodipine as it is not known whether amlodipine is excreted in breast milk. Schaefer (2007) comments that individual doses of amlodipine do not require limitation of breastfeeding, but therapy should be changed. An alternative drug may be preferred.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Considered suitable or recommended by manufacturer? - No

Drug substances licensed in infants? - No

Side Effects

Abdominal pain
Alopecia
Altered bowel habit
Angioedema
Anorexia
Anxiety
Arrhythmias
Arthralgia
Asthenia
Atrial fibrillation
Back pain
Chest pain
Cholestatic jaundice
Confusion
Constipation
Cough
Decrease in haemoglobin and haematocrit
Depression
Diarrhoea
Dizziness
Dry mouth
Dyspepsia
Dyspnoea
Electrolyte disturbances
Erectile dysfunction
Erythema
Erythema multiforme
Exanthema
Exfoliative dermatitis
Extrapyramidal effects
Facial oedema
Fatigue
Flushing
Gastritis
Gingival hyperplasia
Gynaecomastia
Headache
Hepatitis
Hyperglycaemia
Hyperhidrosis
Hypersensitivity reactions
Hypertonia
Hypoesthesia
Hypotension
Impaired co-ordination
Impotence
Increases in hepatic enzymes
Influenza
Joint swelling
Leucopenia
Malaise
Mood changes
Muscle spasm
Myalgia
Myocardial infarction
Nasopharyngitis
Nausea
Neutropenia
Oedema
Orthostatic hypotension
Pain
Palpitations
Pancreatitis
Paraesthesia
Peripheral neuropathy
Peripheral oedema
Pharyngolaryngeal pain
Photosensitivity
Pitting Oedema
Pollakiuria
Polyuria
Pruritus
Purpura
Rash
Renal failure
Renal impairment
Rhinitis
Sensation of heaviness
Serum bilirubin increased
Serum creatinine increased
Skin discolouration
Sleep disturbances
Somnolence
Stevens-Johnson syndrome
Syncope
Tachycardia
Taste disturbances
Thrombocytopenia
Tinnitus
Tremor
Urinary abnormalities
Urticaria
Vasculitis
Ventricular tachycardia
Vertigo
Visual disturbances
Vomiting
Weight changes

Presentation

All formulations of amlodipine with valsartan.

Drugs List

Therapeutic Indications

Uses

Hypertension-not adequately controlled by individual components

Dosage

Individual dose titration with the components is recommended prior to administering the fixed combination dose formulation

Adults

Elderly

Patients with Hepatic Impairment

Contraindications

Children under 18 years
Biliary cirrhosis
Breastfeeding
Cardiac failure within 1 month of a myocardial infarction
Cardiogenic shock
Cholestasis
Left ventricular outflow obstruction
Pregnancy
Renal dialysis
Renal impairment - glomerular filtration rate below 30ml/minute/1.73m sq
Severe aortic stenosis
Severe bilateral renal artery stenosis
Severe hepatic impairment
Severe hypotension
Severe unilateral stenosis of solitary functioning kidney
Unstable angina

Precautions and Warnings

Elderly
Females of childbearing potential
Acute porphyria
Aortic stenosis
Bilateral renal artery stenosis
Electrolyte depletion
Hepatic impairment
Hypertrophic obstructive cardiomyopathy
Hypovolaemia
Mitral stenosis
Peripheral vascular disease
Renal impairment - creatinine clearance 30-60ml/minute
Renovascular disorder
Severe congestive cardiac failure
Severe generalised atherosclerosis
Unilateral stenosis of solitary functioning kidney

Patients with primary aldosteronism may not benefit from this treatment
Reduce dose in patients with hepatic impairment
Advise ability to drive/operate machinery may be affected by side effects
Afro-Caribbean or black patients may show reduced response
Correct volume and/or salt depletion before initiating therapy
Place patient in supine position if severe hypotension occurs
Evaluate renal function before and during treatment
Monitor serum electrolytes before and during treatment
Monitor serum potassium regularly
Increased risk of hyperkalaemia with K+ suppl. and K+ sparing diuretic
Advise patient to seek advice at first indications of pregnancy
Discontinue if angioedema occurs
Advise patient not to take NSAIDs unless advised by clinician
Advise on problems of salt substitutes/high intake of potassium-rich food
Grapefruit prod increase dihydropyridine Ca channel blocker bioavailability
Female: Ensure adequate contraception during treatment

Renal function and electrolytes should be checked before starting treatment and monitored during therapy, especially in patients post myocardial infarction, those with heart failure and when treating hypertension in children or adolescents. Side effects (such as hyperkalaemia) are more common in patients with renal impairment- the dose may need to be reduced. A specialist should be involved if renal function is significantly reduced.

Monitor plasma potassium, particularly in the elderly, patients with renal impairment, in the presence of other conditions (fever, dehydration) which affect renal function and patients in whom potassium supplements / retaining medication is essential.

In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g. patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/ or progressive azotaemia and in rare cases with acute renal failure and/ or death. As valsartan is an angiotensin II antagonist, it cannot be excluded that the use of this medication may be associated with impairment of the renal function.

Avoid use in patients with known or suspected renovascular disease, unless the blood pressure cannot be controlled with other drugs. Use with particular precaution in patients who have undiagnosed and clinically silent renovascular disease.

Co-administration of NSAIDS may reduce the antihypertensive effect of angiotensin II receptor antagonists, increase serum potassium and exacerbate renal impairment.

Pregnancy and Lactation

Pregnancy

Valsartan
Contraindicated in pregnancy. Adequate contraception is recommended for women of childbearing potential. When pregnancy is diagnosed, treatment should be immediately discontinued and if possible an alternative treatment started.

Angiotensin II receptor antagonists may be associated with similar risks as ACE inhibitors. Angiotensin II receptor antagonist exposure 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).

The MHRA states that the use of angiotensin II receptor antagonists in late pregnancy has been associated with adverse effects on the foetal kidney and other congenital anomalies, therefore angiotensin II receptor antagonists should not be used at any stage during of pregnancy unless absolutely necessary and only then after the potential risks and benefits have been discussed with the patient.

Exposure to angiotensin II receptor antagonists during the first trimester has been inconclusive, however, a small increase in risk cannot be excluded and a detailed ultrasound is recommended.

If pregnancy is detected during therapy, Valsartan should be discontinued as soon as possible and alternative treatment should be offered. Guidelines advise that women who are taking angiotensin II receptor blockers are told that there is an increased risk of congenital abnormalities if these drugs are taken during pregnancy and other antihypertensive treatments should be discussed and offered.

Amlodipine
Some dihydropyridine compounds have been found to be teratogenic in animals. However, amlodipine was found not to be teratogenic or embryotoxic in rats and rabbits up to 8 and 23 times, respectively, the maximum human dose based on BSA (MRHD) during their respective periods of major organogenesis. Effects on reproduction in animals were found at high dosages (including delayed parturition, difficult labour and impaired foetal and pup survival) (Briggs, 2011). There is no adequate data for the use of amlodipine in pregnant women. The molecular weight of amlodipine is low enough that passage to the foetus should be expected. Calcium channel blockers may inhibit labour (Schaefer,2007). In the first trimester, calcium antagonists are considered to be second-line therapy. Manufacturers advise amlodipine should not be administered during pregnancy or to women of childbearing potential unless effective contraception is used unless clearly needed. Schaefer (2007) suggests that if exposure to amlodipine has occurred during the first trimester, a detailed ultrasound diagnosis is advisable. Overall exposure to a calcium antagonist during pregnancy is not an indication for either invasive diagnostic procedures or termination of pregnancy.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Licensed in pregnancy? - Contraindicated

Recommended for use in pregnancy? - No

Known human teratogen? - Yes, angiotensin II receptor antagonists

Other information - Methyldopa, labetalol, hydralazine, modified-release preparations of nifedipine are the drugs with most safety data during pregnancy.

Lactation

Valsartan
Contraindicated during breastfeeding.

Schaefer (2007) suggests that accidental administration of a single dose does not require weaning, however, therapy should be changed to an antihypertensive which has been better studied in breastfeeding. The MHRA concludes that the use of angiotensin II receptor antagonists in breastfeeding mothers is not recommended. Alternative agents with more established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm baby.

Amlodipine
There is no adequate data for the use of amlodipine in breastfeeding. Hale (2010) comments that because most calcium channel blockers readily transfer into milk, that the same should be assumed for this drug. The molecular weight of amlodipine is low enough that excretion into breast milk should be expected. No paediatric concerns have been reported but the infant should be observed for bradycardia or hypotension upon prolonged use. Guidelines from NICE recommend that women who still need antihypertensive treatment in the postnatal period are told that there is insufficient evidence on the safety in babies receiving breast milk of amlodipine. Some manufacturers advise patients to stop breast feeding during treatment with amlodipine as it is not known whether amlodipine is excreted in breast milk. Schaefer (2007) comments that individual doses of amlodipine do not require limitation of breastfeeding, but therapy should be changed. An alternative drug may be preferred.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Considered suitable or recommended by manufacturer? - No

Drug substances licensed in infants? - No

Side Effects

Abdominal pain
Alopecia
Altered bowel habit
Angioedema
Anorexia
Anxiety
Arrhythmias
Arthralgia
Asthenia
Atrial fibrillation
Back pain
Chest pain
Cholestatic jaundice
Confusion
Constipation
Cough
Decrease in haemoglobin and haematocrit
Depression
Diarrhoea
Dizziness
Dry mouth
Dyspepsia
Dyspnoea
Electrolyte disturbances
Erectile dysfunction
Erythema
Erythema multiforme
Exanthema
Exfoliative dermatitis
Extrapyramidal effects
Facial oedema
Fatigue
Flushing
Gastritis
Gingival hyperplasia
Gynaecomastia
Headache
Hepatitis
Hyperglycaemia
Hyperhidrosis
Hypersensitivity reactions
Hypertonia
Hypoesthesia
Hypotension
Impaired co-ordination
Impotence
Increases in hepatic enzymes
Influenza
Joint swelling
Leucopenia
Malaise
Mood changes
Muscle spasm
Myalgia
Myocardial infarction
Nasopharyngitis
Nausea
Neutropenia
Oedema
Orthostatic hypotension
Pain
Palpitations
Pancreatitis
Paraesthesia
Peripheral neuropathy
Peripheral oedema
Pharyngolaryngeal pain
Photosensitivity
Pitting Oedema
Pollakiuria
Polyuria
Pruritus
Purpura
Rash
Renal failure
Renal impairment
Rhinitis
Sensation of heaviness
Serum bilirubin increased
Serum creatinine increased
Skin discolouration
Sleep disturbances
Somnolence
Stevens-Johnson syndrome
Syncope
Tachycardia
Taste disturbances
Thrombocytopenia
Tinnitus
Tremor
Urinary abnormalities
Urticaria
Vasculitis
Ventricular tachycardia
Vertigo
Visual disturbances
Vomiting
Weight changes

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: April 2013

Reference Sources

British National Formulary, 65th Edition (March - September 2013) Pharmaceutical Press, London.

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.

Summary of Product Characteristics: Exforge 5mg/80mg, 5mg/160mg, 10mg/160mg film coated tablets. Novartis Pharmaceutical UK Ltd. Revised October 2012.

MHRA Drug Safety Update: Volume 1, Issue 5 December 2007.
Available at: https://www.mhra.gov.uk/home/groups/pl-p/documents/publication/con2033217.pdf
Last accessed: April 12, 2013.

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Amlodipine Last revised: October 2, 2012
Last accessed: April 12, 2013

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Valsartan Last revised: September 29, 2009
Last accessed: April 12, 2013