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Drugs List
Therapeutic Indications
Dosage
Administration
Contraindications
Precautions and Warnings
Pregnancy and Lactation
Side Effects
Monograph

Precautions and Warnings

Symptomatic hypotension may occur in patients who are volume and/or sodium depleted due to vigorous diuretic therapy, dietary salt restriction, diarrhoea, or vomiting. Such conditions should be corrected prior to treatment with irbesartan.

Renal function and electrolytes should be checked before starting treatment and monitored during therapy, especially in patients post myocardial infarction, those with heart failure . 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.

Periodic monitoring of potassium, creatinine and uric acid serum levels is recommended in patients with renal impairment. Thiazide-diuretic associated azotaemia may occur in patients with impaired renal function. In patients with creatinine clearance greater than 30ml/minute but less than 60ml/minute, the fixed dose combination should be used with caution. If creatinine clearance is less than 30ml/minute, the fixed dose combination should not be used.

Patients with bilateral or unilateral (in the case of a single functioning kidney) renal artery stenosis are at increased risk of severe hypotension and renal impairment. There has been no experience regarding the use of irbesartan with hydrochlorothiazide after a recent kidney transplant. Caution is therefore advised in these patients.

In patients whose vascular tone and renal function depend on the renin-angiotensin-aldosterone system (e.g. severe cardiac failure, underlying renal disease including renal artery stenosis) treatment with angiotensin II receptor antagonists such as irbesartan, may be associated with acute hypotension, azotaemia, oliguria or rarely acute renal failure. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in myocardial infarction or stroke.

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 (including peripheral vascular disease or severe generalised atherosclerosis).

In hepatic impairment and progressive liver disease, thiazide induced alterations in fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience of irbesartan with hydrochlorothiazide in hepatic impairment. Use with caution in this population.

Use with caution in patients with aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy, and ischaemic cardiovascular disease/cardiopathy. Excessive blood pressure decrease may result in myocardial infarction or stroke.

Patients with a history of allergy or bronchial asthma have an increased likelihood of hypersensitivity reactions to hydrochlorothiazide.

Exacerbation or activation of systemic lupus erythematosus has been reported with thiazides.

Diabetes mellitus - thiazide therapy may decrease glucose tolerance and aggravate or precipitate diabetes. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus may become manifest during therapy. Irbesartan may induce hypoglycaemia. Monitor blood glucose in patients with diabetes mellitus, diabetic control may be needed.

Cholesterol and triglyceride increases have been seen with thiazide diuretic therapy. However, minimal or no effects have been seen when using low doses such as 12.5mg hydrochlorothiazide.

Thiazides may cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia and hypochloraemic alkalosis) and the irbesartan component may cause hyperkalaemia. Therefore, periodic determination of serum electrolytes should be performed at appropriate intervals. Risk of hyperkalaemia is greatest in diabetes mellitus, renal impairment and/or cardiac failure and in the elderly. The use of potassium containing salt substitutes or a high intake of potassium rich foods may lead to significant increases in serum potassium. Potassium-sparing diuretics, potassium supplements, potassium containing salt substitutes or drugs that may increase serum potassium levels should be co-administered cautiously with monitoring of potassium levels.
There is an increased risk of hypokalaemia in patients with cirrhosis of the liver, brisk diuresis, inadequate oral electrolytes, concurrent adrenocorticotrophic hormone (ACTH) or corticosteroids..

Urinary excretion of calcium is decreased during thiazide therapy. There may be a slight intermittent elevation of serum calcium in the absence of known calcium metabolism disorders. Note: Marked hypercalcaemia may be evidence of hyperparathyroidism. Discontinue thiazides before carrying out tests for parathyroid function.

Thiazides increase urinary excretion of magnesium and therefore hypomagnesaemia may occur. There is an increased risk in patients with alcoholic cirrhosis.

Hyperuricaemia may occur, and gout may be precipitated by thiazide therapy.

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system.

Angiotensin II antagonists may be less effective in blood pressure reduction in black and Afro-Caribbean patients than in the non-black population, especially those with left ventricular hypertrophy.

Discontinue treatment if photosensitivity reactions occur. If re-administration of the diuretic is necessary, protect exposed areas of skin from the sun or artificial UVA light.

Hydrochlorothiazide may rarely cause acute transient myopia and acute angle-closure glaucoma within hours to weeks of drug initiation. Symptoms include acute onset or decreased visual acuity or ocular pain. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Use with caution in nephrotic syndrome and in patients who are malnourished.

Alcohol consumption may induce orthostatic hypotension.

Warn patient that occasional dizziness or weariness may occur during treatment and this should be taken into account when driving or operating machinery.

Advise patients not to take NSAIDs concurrently with this medication as the antihypertensive effect may be attenuated.

Hydrochlorothiazide contained in this medication could produce a positive analytic result in an anti-doping test.

Contains lactose and therefore patients with glucose-galactose malabsorption syndrome or those who are lactose intolerant should not take this medicine.

Women of child bearing age should use adequate contraception. A switch to an alternative antihypertensive should be carried out in advance of a planned pregnancy. Discontinue immediately should pregnancy occur.

Dose dependent increased risk of non-melanoma skin cancer with exposure to increasing cumulative doses of hydrochlorothiazide.

Use with caution in patients who have had previous skin cancer.

Advise patient to monitor for and report any skin changes.

Advise patient to minimise exposure to sunlight and avoid sunlamps during therapy.

Rare cases of acute respiratory toxicity including acute respiratory distress syndrome (ARDS) have been reported following treatment with hydrochlorothiazide. Symptoms can develop within minutes to hours of taking hydrochlorothiazide. If a diagnosis of ARDS is suspected, treatment should be withdrawn. This product should not be administered to a patient who has previously developed ARDS associated with hydrochlorothiazide.

Pregnancy and Lactation

Pregnancy

All angiotensin II receptor antagonists are contraindicated during pregnancy. Unless continued therapy with irbesartan is considered essential, patients planning pregnancy should be changed to an alternative anti-hypertensive treatment which has established data on safety of use during pregnancy. Adequate contraceptive measures should be used whilst on this medication. If pregnancy occurs this drug should be discontinued immediately. Angiotensin II is essential for normal kidney development. Use of this drug in the 2nd and 3rd trimesters has been associated with teratogenicity and severe fetal and neonatal toxicity identical to that seen with ACE inhibitors. Toxic foetal effects may include anuria, oligohydramnios, fetal hypocalvaria, hyperkalaemia, decreased renal function, intrauterine growth retardation, prematurity, patent ductus arteriosus, decreased calcification of the skull and death. Anuria-associated with anhydramnios/oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension may also occur in the newborn following in utero exposure to irbesartan. Available data also suggest an increased risk of congenital anomaly when exposure of angiotensin II receptor antagonists was limited to the first trimester of pregnancy.

It is not known whether irbesartan crosses the placenta in humans, but due to the low molecular weight (about 429) it is expected. Placental transfer has been seen in rats and rabbits.

A detailed ultrasound diagnosis is advisable if first trimester exposure has occurred. Exposure to an angiotensin-II receptor antagonist during pregnancy is not an indication for either termination of pregnancy or invasive diagnostic procedures (Schaefer 2007). Foetuses should be monitored and assessed with ultrasound scans following long term prenatal therapy in the second or third trimesters (Schaefer 2007). Briggs (2011) also suggests that newborn renal function and blood pressure should be closely monitored.

Hydrochlorothiazide may reduce plasma volume and reduce uteroplacental blood flow. It may also cause foetal electrolyte disturbances and is not recommended in pregnancy.

Animal studies of hydrochlorothiazide in mice, rats and rabbits reported no external malformations, however no internal examination was undertaken. Hydrochlorothiazide is known to cross the placenta. Other risks to the foetus or newborn include bone marrow depression, hypoglycaemia, thrombocytopenia, hyponatraemia, hypokalaemia, jaundice and death from maternal complications. Prolonged labour has also been described as the result of inhibition of smooth muscle action caused by hydrochlorothiazide.

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? - No, contraindicated

Known human teratogen? - Irbesartan - unknown, known class effect. Hydrochlorothiazide - Yes

Animal data - Renal pelvic cavitation, hydroureter, absence of renal papilla, subcutaneous oedema.

Crosses placenta? - Irbesartan - unknown, considered likely. Hydrochlorothiazide - yes

Effects on foetus - Irbesartan may cause patent ductus arteriosus, prematurity, intrauterine growth retardation, hypocalvaria, oligohydramnios, anuria, renal failure, decreased calcification of the skull, lung hypoplasia and death. Hydrochlorothiazide will exacerbate the hypovolaemia characteristic to hypertension in pregnancy and could therefore reduce placental perfusion, adversely affecting the foetus.

Lactation

This product is contraindicated while breastfeeding.

The safety of irbesartan has not been established during breastfeeding. The low molecular weight (about 429) indicates that excretion into breast milk should be expected. Irbesartan is excreted in the milk of lactating rats.

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 while nursing a newborn or preterm baby.

Accidental administration of single dosages does not require weaning of therapy. However, patients should be switched to an antihypertensive that has been better studied during breastfeeding (Schaefer 2007).

Hydrochlorothiazide is excreted in small quantities into breast milk. There have been reports of thrombocytopenia in the nursing infants of mothers receiving a thiazide diuretic, however, the risk is considered low by, Hale (2010) and Briggs (2011). Thiazide diuretics have been used in large quantities to suppress lactation. Overall, hydrochlorothiazide is considered safe while breastfeeding (Briggs, 2011, Schaefer, 2007, and Hale, 2010).

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

Drug excreted in breast milk? Irbesartan - unknown, considered likely. Hydrochlorothiazide - yes

Considered suitable or recommended by manufacturer? - No, contraindicated

UK Drugs in Lactation Advisory Service Classification - Irbesartan , unclassified. Hydrochlorothiazide, classified safe except in large quantities.

Drug substance licensed in infants? - No

Drug known to affect lactation? - Hydrochlorothiazide will suppress lactation, if administered in large quantities.

Presentation

Tablets containing irbesartan 150mg with hydrochlorothiazide 12.5mg
Tablets containing irbesartan 300mg with hydrochlorothiazide 12.5mg
Tablets containing irbesartan 300mg with hydrochlorothiazide 25mg

Drugs List

COAPROVEL 150mg+12.5mg tablets

COAPROVEL 300mg+12.5mg tablets

COAPROVEL 300mg+25mg tablets

irbesartan 150mg and hydrochlorothiazide 12.5mg tablets

irbesartan 300mg and hydrochlorothiazide 12.5mg tablets

irbesartan 300mg and hydrochlorothiazide 25mg tablets

Therapeutic Indications

Uses

Treatment of essential hypertension in patients whose blood pressure is not controlled by irbesartan or hydrochlorothiazide alone.

Dosage

Dose titration with the individual components is recommended. When clinically appropriate, direct change from monotherapy to the fixed combinations may be considered.

Intravascular volume and/or sodium depletion should be corrected prior to administration of irbesartan with hydrochlorothiazide.

Adults

Tablet to be taken once daily.

150mg irbesartan with 12.5mg hydrochlorothiazide
OR if inadequately controlled, 300mg irbesartan with 12.5mg hydrochlorothiazide
OR if inadequately controlled, 300mg irbesartan with 25mg hydrochlorothiazide.

Irbesartan with hydrochlorothiazide may be administered with other antihypertensive agents when necessary.

Doses above 300mg irbesartan with 25mg hydrochlorothiazide once daily are not recommended.

Elderly

Lower initial doses of diuretics may be appropriate in some elderly patients. Dose titration with individual products is recommended.

Children

Safety and effectiveness not established in children under 18 years.

Patients with Renal Impairment

Creatinine clearance equal to or greater than 30ml/minute
No dosage adjustment is necessary. The fixed dose combination should be administered with caution.

Creatinine clearance below 30ml/minute
Due to the hydrochlorothiazide component this product is not recommended for these patients. Loop diuretics are preferred to thiazides in this population.

There is no experience regarding administration in patients with a recent kidney transplantation.

Patients with Hepatic Impairment

No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Thiazides should be used with caution in patients with impaired hepatic function.

Not recommended in patients with severe hepatic impairment.

Administration

For oral administration. To be taken with or without food.

Contraindications

Hypersensitivity to sulfonamide derivatives

Severe renal impairment (creatinine clearance below 30ml/minute)

Refractory hypokalaemia

Hypercalcaemia

Hyponatraemia

Symptomatic hyperuricaemia

Addison's disease

Severe hepatic impairment

Biliary cirrhosis

Cholestasis

Breastfeeding (see Lactation section)

Pregnancy (see Pregnancy section)

Galactosaemia

Children under 18 years

Severe bilateral renal artery stenosis

Severe unilateral renal artery stenosis