Drugs List

Therapeutic Indications

Uses

Hypertension-not adequately controlled by individual components

Contraindications

Children under 18 years
Biliary obstruction
Breastfeeding
Cardiac failure within 1 month of a myocardial infarction
Cardiogenic shock
Left ventricular outflow obstruction
Pregnancy
Renal impairment - creatinine clearance below 20ml/minute
Severe aortic stenosis
Severe bilateral renal artery stenosis
Severe hepatic impairment
Severe hypotension
Severe unilateral stenosis of solitary functioning kidney

Precautions and Warnings

Elderly
Acute porphyria
Aortic stenosis
Bilateral renal artery stenosis
Cerebrovascular disorder
Hypertrophic obstructive cardiomyopathy
Hyponatraemia
Hypovolaemia
Ischaemic heart disease
Mild hepatic impairment
Mitral stenosis
New York Heart Association class III failure
New York Heart Association class IV failure
Peripheral vascular disease
Renal impairment - creatinine clearance 20-60ml/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
Advise patient that first dose hypotension may occur
Afro-Caribbean or black patients may show reduced response
Correct volume and/or salt depletion before initiating therapy
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
Abrupt withdrawal may be associated with exacerbation of angina
Discontinue & do not restart if sprue-like enteropathy confirmed by biopsy
Pregnancy confirmed: Discontinue this medication
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

Olmesartan with amlodipine should be used with caution in patients with acute porphyria due to the amlodipine component. Amlodipine is classed as probably not porphyrogenic ( NAPOS, 2010).

Sprue-like enteropathy
In very rare cases severe chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of olmesartan in cases where no other etiology is identified. In cases where symptoms disappear and sprue-like enteropathy is confirmed by biopsy, treatment with olmesartan should not be restarted.

Pregnancy and Lactation

Pregnancy

Olmesartan with amlodipine is contraindicated during pregnancy.

Animal studies on rats and rabbits reported not teratogenicity at the equivalent to the maximum human dose of olmesartan, however at higher doses rat studies reported decreased pup weight & weight gain, delays in development milestones, and dose related increases in the incidence of renal pelvis dilation (Briggs, 2011). It is not known whether olmesartan crosses the human placenta, however, the molecular weight is low enough that passage to the infant should be expected. Angiotensin II receptor antagonists like olmesartan are associated with similar effects to ACE inhibitors. Foetal toxic effects include; anuria, oligohydramnios, foetal hypocalvaria, intrauterine growth retardation (IUGR), prematurity and patent ductus arteriosus (Briggs, 2011). Oligohydramnios associated with anuria may produce foetal limb contractures, craniofacial deformations and pulmonary hypoplasia. Severe anuria and hypotension that are resistant to treatment may occur in the newborn. Newborn renal function and blood pressure should be closely monitored (Briggs, 2011).

If pregnancy occurs during treatment, olmesartan must be discontinued immediately and an alternative antihypertensive with greater experience in pregnancy should be considered. If first trimester exposure occurs, a detailed ultrasound examination is recommended to check the kidneys and the skull. Overall exposure during the second or third trimester is not an indication for invasive diagnostic procedure or termination of pregnancy. Long-term exposure during the second or third trimester should led to foetal monitoring for oligohydramnios and foetal growth (Schaefer, 2007). The renal function and blood pressure of the newborn should be monitored. There is insufficient experience of olmesartan during pregnancy, however, drugs that act directly on the renin angiotensin system administered during the second and third trimester have been shown to cause foetal and neonatal injury (hypotension, renal dysfunction, oliguria and/or anuria, oligohydramnios, skull hypoplasia, intrauterine growth retardation, lung hypoplasia, facial abnormalities, limb contracture) and even death (Briggs, 2011).

Data and experience relating to amlodipine is limited. It is not known whether amlodipine transfers to the foetus, however, the molecular weight is low enough that transfer should be expected. Olmesartan has a greater risk profile than amlodipine so the recommendations regarding olmesartan should be followed for the combination product.

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 ).

Lactation

Olmesartan with amlodipine is contraindicated in breastfeeding women. Olmesartan is excreted in the milk of rats, it is unknown if it is excreted in human milk. However, the molecular weights of olmesartan and amlodipine are low enough that excretion in breast milk should be expected (Briggs, 2011). The effects on the newborn are unknown. 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 lactation. The MHRA concludes that the use of angiotensin II receptor antagonists in breastfeeding mothers is not recommended. Alternative antihypertensive treatments with more established safety profiles during breastfeeding are preferable, especially whilst nursing a newborn or preterm baby.

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

Side Effects

Abdominal pain
Acute renal failure
Allergic dermatitis
Alopecia
Altered bowel habit
Anaphylactic reaction
Angina pectoris
Angioneurotic oedema
Anxiety
Arrhythmias
Arthralgia
Arthritis
Asthenia
Blood urea increased
Bronchitis
Chest pain
Cholestasis
Confusion
Cough
Creatine phosphokinase increased
Depression
Disturbances of gastrointestinal function
Dizziness
Dry mouth
Dyspepsia
Dyspnoea
Erectile dysfunction
Erythema multiforme
Exanthema
Exfoliative dermatitis
Facial flushing
Fatigue
Gamma glutamyl transferase (GGT) increased
Gastritis
Gastro-enteritis
Gingival hyperplasia
Gynaecomastia
Haematuria
Headache
Hepatitis
Hyperglycaemia
Hyperkalaemia
Hypersensitivity reactions
Hypertonia
Hypertriglyceridaemia
Hypoaesthesia
Hypotension
Impotence
Increased sweating
Increased uric acid level
Increases in hepatic enzymes
Influenza-like symptoms
Irritability
Jaundice
Lethargy
Leucopenia
Malaise
Mood changes
Muscle spasm
Musculoskeletal pain
Myocardial infarction
Oedema
Orthostatic hypotension
Pain
Painful extremities
Palpitations
Pancreatitis
Paraesthesia
Peripheral neuropathy
Peripheral oedema
Photosensitivity
Postural dizziness
Pruritus
Purpura
Quincke's oedema
Rash
Reduced libido
Reduced plasma potassium levels
Renal impairment
Rhabdomyolysis
Rhinitis
Serum creatinine increased
Skin discolouration
Sleep disturbances
Sprue-like enteropathy
Stevens-Johnson syndrome
Syncope
Tachycardia
Taste disturbances
Thrombocytopenia
Tinnitus
Tremor
Urinary frequency
Urinary tract infections
Urticaria
Vasculitis
Vertigo
Visual disturbances
Weight changes

Presentation

Oral formulations of olmesartan with amlodipine.

Drugs List

Therapeutic Indications

Uses

Hypertension-not adequately controlled by individual components

Dosage

Adults

Elderly

Patients with Renal Impairment

Patients with Hepatic Impairment

Additional Dosage Information

Contraindications

Children under 18 years
Biliary obstruction
Breastfeeding
Cardiac failure within 1 month of a myocardial infarction
Cardiogenic shock
Left ventricular outflow obstruction
Pregnancy
Renal impairment - creatinine clearance below 20ml/minute
Severe aortic stenosis
Severe bilateral renal artery stenosis
Severe hepatic impairment
Severe hypotension
Severe unilateral stenosis of solitary functioning kidney

Precautions and Warnings

Elderly
Acute porphyria
Aortic stenosis
Bilateral renal artery stenosis
Cerebrovascular disorder
Hypertrophic obstructive cardiomyopathy
Hyponatraemia
Hypovolaemia
Ischaemic heart disease
Mild hepatic impairment
Mitral stenosis
New York Heart Association class III failure
New York Heart Association class IV failure
Peripheral vascular disease
Renal impairment - creatinine clearance 20-60ml/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
Advise patient that first dose hypotension may occur
Afro-Caribbean or black patients may show reduced response
Correct volume and/or salt depletion before initiating therapy
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
Abrupt withdrawal may be associated with exacerbation of angina
Discontinue & do not restart if sprue-like enteropathy confirmed by biopsy
Pregnancy confirmed: Discontinue this medication
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

Olmesartan with amlodipine should be used with caution in patients with acute porphyria due to the amlodipine component. Amlodipine is classed as probably not porphyrogenic ( NAPOS, 2010).

Sprue-like enteropathy
In very rare cases severe chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of olmesartan in cases where no other etiology is identified. In cases where symptoms disappear and sprue-like enteropathy is confirmed by biopsy, treatment with olmesartan should not be restarted.

Pregnancy and Lactation

Pregnancy

Olmesartan with amlodipine is contraindicated during pregnancy.

Animal studies on rats and rabbits reported not teratogenicity at the equivalent to the maximum human dose of olmesartan, however at higher doses rat studies reported decreased pup weight & weight gain, delays in development milestones, and dose related increases in the incidence of renal pelvis dilation (Briggs, 2011). It is not known whether olmesartan crosses the human placenta, however, the molecular weight is low enough that passage to the infant should be expected. Angiotensin II receptor antagonists like olmesartan are associated with similar effects to ACE inhibitors. Foetal toxic effects include; anuria, oligohydramnios, foetal hypocalvaria, intrauterine growth retardation (IUGR), prematurity and patent ductus arteriosus (Briggs, 2011). Oligohydramnios associated with anuria may produce foetal limb contractures, craniofacial deformations and pulmonary hypoplasia. Severe anuria and hypotension that are resistant to treatment may occur in the newborn. Newborn renal function and blood pressure should be closely monitored (Briggs, 2011).

If pregnancy occurs during treatment, olmesartan must be discontinued immediately and an alternative antihypertensive with greater experience in pregnancy should be considered. If first trimester exposure occurs, a detailed ultrasound examination is recommended to check the kidneys and the skull. Overall exposure during the second or third trimester is not an indication for invasive diagnostic procedure or termination of pregnancy. Long-term exposure during the second or third trimester should led to foetal monitoring for oligohydramnios and foetal growth (Schaefer, 2007). The renal function and blood pressure of the newborn should be monitored. There is insufficient experience of olmesartan during pregnancy, however, drugs that act directly on the renin angiotensin system administered during the second and third trimester have been shown to cause foetal and neonatal injury (hypotension, renal dysfunction, oliguria and/or anuria, oligohydramnios, skull hypoplasia, intrauterine growth retardation, lung hypoplasia, facial abnormalities, limb contracture) and even death (Briggs, 2011).

Data and experience relating to amlodipine is limited. It is not known whether amlodipine transfers to the foetus, however, the molecular weight is low enough that transfer should be expected. Olmesartan has a greater risk profile than amlodipine so the recommendations regarding olmesartan should be followed for the combination product.

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 ).

Lactation

Olmesartan with amlodipine is contraindicated in breastfeeding women. Olmesartan is excreted in the milk of rats, it is unknown if it is excreted in human milk. However, the molecular weights of olmesartan and amlodipine are low enough that excretion in breast milk should be expected (Briggs, 2011). The effects on the newborn are unknown. 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 lactation. The MHRA concludes that the use of angiotensin II receptor antagonists in breastfeeding mothers is not recommended. Alternative antihypertensive treatments with more established safety profiles during breastfeeding are preferable, especially whilst nursing a newborn or preterm baby.

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

Side Effects

Abdominal pain
Acute renal failure
Allergic dermatitis
Alopecia
Altered bowel habit
Anaphylactic reaction
Angina pectoris
Angioneurotic oedema
Anxiety
Arrhythmias
Arthralgia
Arthritis
Asthenia
Blood urea increased
Bronchitis
Chest pain
Cholestasis
Confusion
Cough
Creatine phosphokinase increased
Depression
Disturbances of gastrointestinal function
Dizziness
Dry mouth
Dyspepsia
Dyspnoea
Erectile dysfunction
Erythema multiforme
Exanthema
Exfoliative dermatitis
Facial flushing
Fatigue
Gamma glutamyl transferase (GGT) increased
Gastritis
Gastro-enteritis
Gingival hyperplasia
Gynaecomastia
Haematuria
Headache
Hepatitis
Hyperglycaemia
Hyperkalaemia
Hypersensitivity reactions
Hypertonia
Hypertriglyceridaemia
Hypoaesthesia
Hypotension
Impotence
Increased sweating
Increased uric acid level
Increases in hepatic enzymes
Influenza-like symptoms
Irritability
Jaundice
Lethargy
Leucopenia
Malaise
Mood changes
Muscle spasm
Musculoskeletal pain
Myocardial infarction
Oedema
Orthostatic hypotension
Pain
Painful extremities
Palpitations
Pancreatitis
Paraesthesia
Peripheral neuropathy
Peripheral oedema
Photosensitivity
Postural dizziness
Pruritus
Purpura
Quincke's oedema
Rash
Reduced libido
Reduced plasma potassium levels
Renal impairment
Rhabdomyolysis
Rhinitis
Serum creatinine increased
Skin discolouration
Sleep disturbances
Sprue-like enteropathy
Stevens-Johnson syndrome
Syncope
Tachycardia
Taste disturbances
Thrombocytopenia
Tinnitus
Tremor
Urinary frequency
Urinary tract infections
Urticaria
Vasculitis
Vertigo
Visual disturbances
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: June 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.

Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.

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

Summary of Product Characteristics: Sevikar 20 mg/5 mg, 40 mg/ 5 mg, 40 mg/ 10 mg Film-Coated Tablets. Daiichi Sankyo UK Limited. Revised November 2014.

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 02, 2012
Last accessed: June 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
Olmesartan. Last revised: September 29, 2009
Last accessed: June 12, 2013