Drugs List

Therapeutic Indications

Uses

Treatment of essential hypertension

Contraindications

Children under 18 years
Desensitisation therapy
Within 36 hours of discontinuing a sacubitril containing product
Addison's disease
Breastfeeding
Galactosaemia
Haemodialysis with high flux membranes
Haemodynamic instability
Hepatic encephalopathy
Hereditary angioneurotic oedema
Hypokalaemia
Idiopathic angioneurotic oedema
Porphyria
Pregnancy
Renal artery stenosis
Renal impairment - creatinine clearance below 30 ml/minute
Severe hepatic impairment
Symptomatic hyperuricaemia
Uncontrolled decompensated cardiac failure

Precautions and Warnings

Elderly
History of allergies including anaphylaxis
Immunosuppression
Restricted sodium intake
Aortic stenosis
Asthma
Atherosclerosis
Cerebral ischaemia
Collagen vascular disease
Diabetes mellitus
Electrolyte depletion
Glucose-galactose malabsorption syndrome
Gout
Hepatic cirrhosis
Hepatic impairment
History of angioedema
Hyperaldosteronism
Hyperkalaemia
Hypertrophic cardiomyopathy
Hypovolaemia
Ischaemic heart disease
Lactose intolerance
Left ventricular outflow obstruction
Malnutrition
Metabolic acidosis
Mitral stenosis
Nephrotic syndrome
Peripheral vascular disease
Renal impairment
Renovascular disorder
Systemic lupus erythematosus
Unstable cardiac disorder

Adjustment of hypoglycaemic therapy may be necessary in diabetes mellitus
Advise patient to protect skin if restarting following photosensitivity
Anaphylactoid reactions possible with haemofiltration or LDL apheresis
Anaphylaxis possible with concomitant hyposensitisation to wasp/bee venom
Advise ability to drive/operate machinery may be affected by side effects
Afro-Caribbean or black patients may show reduced response
Exclude renovascular disorder before treatment
Have available adrenaline injection 1:1000 for anaphylaxis
Contains lactose
Place patient in supine position if severe hypotension occurs
Evaluate renal function before and during treatment
Monitor serum electrolytes before and during treatment
Consider monitoring white blood cell counts in collagen vascular disease
Monitor haematological parameters periodically
Monitor serum potassium regularly
Reduce dose/discontinue if serum creatinine or blood urea increases
Advise patient to report any symptoms of infections especially sore throats
Advise patients at risk of neutropenia to report any signs of infection
Excess consumption of liquorice may increase the risk of hypokalaemia
Higher incidence of angioedema in black patients
Increased risk of hyperkalaemia with K+ suppl. and K+ sparing diuretic
May cause anaphylactic / anaphylactoid reactions
May precipitate diabetes mellitus
May precipitate gout
Withdraw and consider hyperparathyroidism if frank hypercalcaemia develops
Discontinue before parathyroid function tests
Discontinue treatment 24 hours prior to surgery
Withdraw 24 hours before desensitisation if considered necessary
Withdraw for at least 24 hours before LDL apheresis
Discontinue at first signs of jaundice,cholestasis,hepatitis
Discontinue at once if hepatic encephalopathy occurs
Discontinue if hypotension occurs, restart at lower dose and monitor
Discontinue if jaundice or other evidence of hepatic impairment occurs
Discontinue if laryngeal stridor/angioedema of face/tongue or glottis
Discontinue if photosensitivity occurs
Discontinue if symptoms of acute angle closure glaucoma occur
Advise patient not to take NSAIDs unless advised by clinician
Advise on problems of salt substitutes/high intake of potassium-rich food
Female: Ensure adequate contraception during treatment

Marked water and sodium depletion (salt free diet and/or diuretic treatment) or stenosis of the renal arteries stimulate the renin-angiotensin system. Inhibition by an ACE inhibitor, especially during the first two weeks of treatment, may lead to an abrupt fall in blood pressure and/or to functional and possibly acute renal failure, although the latter is uncommon and the time interval variable. Discontinuation of perindopril or reduction of the diuretic may be required.

Systematic testing should be carried out for clinical signs of water and electrolyte depletion, which may occur with an intercurrent episode of diarrhoea or vomiting. Marked hypotension may require the implementation of an intravenous infusion of isotonic saline.
Transient hypotension is not a contraindication to continuation of treatment. After re-establishment of a satisfactory blood volume and blood pressure, treatment can be started again either at a reduced dose or with only one of the constituents.

Elevated potassium levels may occur during ACE inhibitor therapy. Those especially at risk of hyperkalaemia include renal impairment, worsening of renal function, age (greater than 70 years), diabetes mellitus, inter-current events, in particular dehydration, acute cardiac decompensation and metabolic acidosis.
Concurrent use of potassium sparing diuretics, potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in plasma potassium. Hyperkalaemia can cause serious, sometimes fatal arrhythmias. Where combination therapy is considered essential, it should be used with caution and with frequent monitoring of plasma potassium. Advise on problems of salt substitutes/high intake of potassium-rich food.

Perindopril should be used with extreme caution in patients with collagen vascular disease, treatment with allopurinol or procainamide and therapy with immunosuppressive agents, it may lead to increased risk of neutropenia. Monitor white blood cell counts. Serious infections, unresponsive to antibiotic may develop. Periodic monitoring of white blood count is advised. Instruct patients to report signs of infection.

In certain hypertensive patients without pre-existing apparent renal lesion and for whom renal blood tests show functional renal impairment, treatment should be stopped and possibly restarted either at a low dose or with one constituent only. In these patients usual medical follow-up will include frequent monitoring of potassium and creatinine, after two weeks of treatment and then every two months during therapeutic stability period. Renal failure has been reported mainly in patients with severe heart failure or underlying renal impairment including renal artery stenosis.

If renovascular hypertension is present there may be an increased risk of severe hypotension and renal impairment.

Perindopril treatment should be stopped immediately if the patient develops angioedema of the face, extremities, lips, tongue, glottis and/or larynx. This may occur at any time during treatment. In such cases, the patient should be monitored until the oedema has disappeared. When confined to the face and lips, angioedema usually resolves without treatment. However antihistamines have been used. Angioedema involving the tongue, glottis or larynx may be fatal.
Appropriate emergency therapy should be given (e.g. adrenaline/maintenance of patent airway). The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.
Patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of angioedema while receiving an ACE inhibitor. Intestinal angioedema can occur in patients treated with ACE inhibitors, and should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

ACE inhibitors should be initiated under specialist supervision and with careful clinical monitoring in those with severe cardiac failure or in those receiving high-dose vasodilator therapy.

Symptomatic hypotension is more likely to occur in patients who have been volume-depleted and salt-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension. Patients at risk should be closely supervised during initiation of therapy and during dose adjustment. Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

A persistent, non-productive cough may occur which usually resolves itself after therapy is discontinued. An iatrogenic aetiology should be considered in the event of this symptom. If the prescription of an ACE inhibitor is still preferred, continuation of treatment may be considered.

The treatment of renovascular hypertension is revascularisation. Nonetheless, ACE inhibitors can be beneficial in patients with renovascular hypertension who are awaiting corrective surgery or when such a surgery is not possible. Treatment should be started in a hospital setting at a low dose and renal function and potassium levels should be monitored, since some patients have developed a functional renal insufficiency which was reversed when treatment was stopped.

In patients with severe cardiac insufficiency (grade IV) or in patients with insulin dependent diabetes mellitus (spontaneous tendency to increased levels of potassium), treatment should be started under medical supervision with a reduced initial dose. Treatment with beta blockers in hypertensive patients with coronary insufficiency should not be stopped, the ACE inhibitor should be added to the beta blocker.

Potassium depletion with hypokalaemia is a major risk with thiazide diuretics and thiazide-related diuretics. The risk of onset of lowered potassium levels (less than 3.4 mmol/L) should be prevented in some high risk populations such as elderly and/or malnourished subjects, whether or not they are taking multiple medications, cirrhotic patients with oedema and ascites, coronary patients and patients with cardiac failure. In such cases hypokalaemia increases the cardiac toxicity of cardiac glycosides and the risk of rhythm disorders.

Idiosyncratic reactions resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma may be caused by sulfonamide, or sulfonamide derivative drugs. Untreated acute angle-closure glaucoma can lead to permanent vision loss, prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled.

Pregnancy and Lactation

Pregnancy

Perindopril with indapamide is contraindicated during the second and third trimesters of pregnancy and should be avoided during the first trimester. If a pregnancy is planned, the switch to alternative medication with an established safety profile for use in pregnancy should be made as soon as possible. If pregnancy is confirmed, treatment with ACE inhibitors should be stopped immediately, and if appropriate, alternative therapy should be started.

Perindopril
It is not known if perindopril or its metabolite perindoprilat crosses the human placenta. The molecular weights (about 368 for the free acid and 442 for the salt form) suggest that transfer to the foetus will occur (Briggs, 2011).

ACE inhibitors are contraindicated during the second and third trimesters of pregnancy as exposure during these trimesters is known to induce human foetal toxicity (renal dysfunction, oligohydramnios, pulmonary hypoplasia, patent ductus arteriosus, delay in skull ossification, neonatal toxicity and even death). Severe and sometimes fatal anuria in the foetus and in the newborn have been observed and is thought to be caused by the compromise of the foetal renal system. Foetal renal failure resulting from in utero exposure to ACE inhibitors has been reported where dialysis has been required shortly after birth. Evidence of a risk of teratogenicity after first trimester exposure is conflicting, however, the MHRA recommends that a risk cannot be excluded. Recent data published does associate first trimester ACE inhibitor exposure with congenital CNS and cardiovascular defects. Unless treatment with an ACE inhibitor is considered absolutely essential, women who are planning to become pregnant should be switched to an alternative drug with an established safety record. If exposure has occurred in the first trimester a detailed ultrasound diagnosis is advisable. Exposure to an ACE inhibitor during pregnancy is not an indication for either invasive diagnostic procedures or termination of pregnancy. In cases involving long term prenatal therapy in the second and/ or third trimesters, the foetus should be monitored for the potential development of oligohydramnios, and foetal growth should be assessed with detailed ultrasound scans (Schaefer, 2007).

Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension.

Indapamide
Indapamide is not recommended for use during pregnancy. Animal studies in mice, rats and rabbits, reported no impaired fertility, foetal harm, or effect on postnatal development. However, foetal growth retardation was reported in studies on rats. Diuretics are contraindicated for their possible affects on the mother and therefore the foetus. The maternal hypovolaemia characteristic of the treatment of gestational hypertension with a diuretic, would adversely affect placental perfusion, which in turn could lead to intrauterine growth retardation (IUGR). 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 diuretics (Schaefer, 2007). This product should not be used in 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 ).

Lactation

The combination of perindopril with indapamide is contraindicated during lactation.

Perindopril

The effect of perindopril treatment on nursing infants has not been determined, however, due to its molecular size it is likely that perindopril and the active metabolite perindoprilat are excreted in breast milk, lactating mothers are advised not to breast feed while taking perindopril.

The MHRA has stated that although ACE inhibitors are not generally recommended for use by breastfeeding mothers they are not absolutely contraindicated and may be prescribed if treatment is considered essential. The MHRA state that ACE inhibitors should not be used by breastfeeding mothers in the first few weeks after delivery because of possible profound neonatal hypotension particularly in preterm infants. If ACE inhibitor therapy is considered essential for the mother the use of captopril, enalapril or quinapril may be considered when the infant is older. The infant should be carefully followed up for signs of hypotension should ACE inhibitor treatment be deemed necessary.

Indapamide

Indapamide is excreted in breast milk and should not be used during the breast-feeding period due to the decrease and even suppression of the milk secretion. Hypersensitivity to sulfonamide-derived drugs, hypokalaemia, and nuclear icterus might occur.

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
Abnormal vision
Acute renal failure
Agranulocytosis
Altered liver function tests
Angina pectoris
Angioedema
Anorexia
Aplastic anaemia
Arrhythmias
Asthenia
Atrial fibrillation
Blood urea increased
Blurred vision
Bradycardia
Bronchospasm
Cholestatic hepatitis
Choroidal effusion
Confusion
Constipation
Cough
Cytolytic hepatitis
Dehydration
Diarrhoea
Dizziness
Dry mouth
Dysgeusia
Dyspepsia
Dyspnoea
Electrolyte disturbances
Eosinophilic pneumonia
Epigastric pain
Erythema multiforme
Exacerbation of psoriasis
Fever
Fulminant hepatic necrosis
Gastro-intestinal disturbances
Haemolytic anaemia
Headache
Hepatic encephalopathy
Hepatic failure
Hepatic impairment
Hepatitis
Hypercalcaemia
Hyperkalaemia
Hypersensitivity reactions
Hyperuricaemia
Hypoglycaemia
Hypokalaemia
Hyponatraemia
Hypotension
Hypovolaemia
Impaired vision
Impotence
Increase in creatinine
Increase in serum glucose
Jaundice
Leucopenia
Maculopapular rash
Mood changes
Muscle weakness
Muscular cramps
Myocardial infarction
Myopia
Narrow angle glaucoma
Nausea
Neutropenia
Palpitations
Pancreatitis
Paraesthesia
Photosensitivity
Pruritus
Purpura
Rash
Renal impairment
Rhabdomyolysis
Rhinitis
Sleep disturbances
Sore throat
Stevens-Johnson syndrome
Sweating
Tachycardia
Thrombocytopenia
Tinnitus
Toxic epidermal necrolysis
Urticaria
Vasculitis
Ventricular tachycardia
Vertigo
Vomiting
Worsening of lupus erythematosus

Presentation

Oral formulations of perindopril (arginine and tosilate salts) with indapamide.

Drugs List

Therapeutic Indications

Uses

Treatment of essential hypertension

Dosage

Adults

Elderly

Patients with Renal Impairment

Contraindications

Children under 18 years
Desensitisation therapy
Within 36 hours of discontinuing a sacubitril containing product
Addison's disease
Breastfeeding
Galactosaemia
Haemodialysis with high flux membranes
Haemodynamic instability
Hepatic encephalopathy
Hereditary angioneurotic oedema
Hypokalaemia
Idiopathic angioneurotic oedema
Porphyria
Pregnancy
Renal artery stenosis
Renal impairment - creatinine clearance below 30 ml/minute
Severe hepatic impairment
Symptomatic hyperuricaemia
Uncontrolled decompensated cardiac failure

Precautions and Warnings

Elderly
History of allergies including anaphylaxis
Immunosuppression
Restricted sodium intake
Aortic stenosis
Asthma
Atherosclerosis
Cerebral ischaemia
Collagen vascular disease
Diabetes mellitus
Electrolyte depletion
Glucose-galactose malabsorption syndrome
Gout
Hepatic cirrhosis
Hepatic impairment
History of angioedema
Hyperaldosteronism
Hyperkalaemia
Hypertrophic cardiomyopathy
Hypovolaemia
Ischaemic heart disease
Lactose intolerance
Left ventricular outflow obstruction
Malnutrition
Metabolic acidosis
Mitral stenosis
Nephrotic syndrome
Peripheral vascular disease
Renal impairment
Renovascular disorder
Systemic lupus erythematosus
Unstable cardiac disorder

Adjustment of hypoglycaemic therapy may be necessary in diabetes mellitus
Advise patient to protect skin if restarting following photosensitivity
Anaphylactoid reactions possible with haemofiltration or LDL apheresis
Anaphylaxis possible with concomitant hyposensitisation to wasp/bee venom
Advise ability to drive/operate machinery may be affected by side effects
Afro-Caribbean or black patients may show reduced response
Exclude renovascular disorder before treatment
Have available adrenaline injection 1:1000 for anaphylaxis
Contains lactose
Place patient in supine position if severe hypotension occurs
Evaluate renal function before and during treatment
Monitor serum electrolytes before and during treatment
Consider monitoring white blood cell counts in collagen vascular disease
Monitor haematological parameters periodically
Monitor serum potassium regularly
Reduce dose/discontinue if serum creatinine or blood urea increases
Advise patient to report any symptoms of infections especially sore throats
Advise patients at risk of neutropenia to report any signs of infection
Excess consumption of liquorice may increase the risk of hypokalaemia
Higher incidence of angioedema in black patients
Increased risk of hyperkalaemia with K+ suppl. and K+ sparing diuretic
May cause anaphylactic / anaphylactoid reactions
May precipitate diabetes mellitus
May precipitate gout
Withdraw and consider hyperparathyroidism if frank hypercalcaemia develops
Discontinue before parathyroid function tests
Discontinue treatment 24 hours prior to surgery
Withdraw 24 hours before desensitisation if considered necessary
Withdraw for at least 24 hours before LDL apheresis
Discontinue at first signs of jaundice,cholestasis,hepatitis
Discontinue at once if hepatic encephalopathy occurs
Discontinue if hypotension occurs, restart at lower dose and monitor
Discontinue if jaundice or other evidence of hepatic impairment occurs
Discontinue if laryngeal stridor/angioedema of face/tongue or glottis
Discontinue if photosensitivity occurs
Discontinue if symptoms of acute angle closure glaucoma occur
Advise patient not to take NSAIDs unless advised by clinician
Advise on problems of salt substitutes/high intake of potassium-rich food
Female: Ensure adequate contraception during treatment

Marked water and sodium depletion (salt free diet and/or diuretic treatment) or stenosis of the renal arteries stimulate the renin-angiotensin system. Inhibition by an ACE inhibitor, especially during the first two weeks of treatment, may lead to an abrupt fall in blood pressure and/or to functional and possibly acute renal failure, although the latter is uncommon and the time interval variable. Discontinuation of perindopril or reduction of the diuretic may be required.

Systematic testing should be carried out for clinical signs of water and electrolyte depletion, which may occur with an intercurrent episode of diarrhoea or vomiting. Marked hypotension may require the implementation of an intravenous infusion of isotonic saline.
Transient hypotension is not a contraindication to continuation of treatment. After re-establishment of a satisfactory blood volume and blood pressure, treatment can be started again either at a reduced dose or with only one of the constituents.

Elevated potassium levels may occur during ACE inhibitor therapy. Those especially at risk of hyperkalaemia include renal impairment, worsening of renal function, age (greater than 70 years), diabetes mellitus, inter-current events, in particular dehydration, acute cardiac decompensation and metabolic acidosis.
Concurrent use of potassium sparing diuretics, potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in plasma potassium. Hyperkalaemia can cause serious, sometimes fatal arrhythmias. Where combination therapy is considered essential, it should be used with caution and with frequent monitoring of plasma potassium. Advise on problems of salt substitutes/high intake of potassium-rich food.

Perindopril should be used with extreme caution in patients with collagen vascular disease, treatment with allopurinol or procainamide and therapy with immunosuppressive agents, it may lead to increased risk of neutropenia. Monitor white blood cell counts. Serious infections, unresponsive to antibiotic may develop. Periodic monitoring of white blood count is advised. Instruct patients to report signs of infection.

In certain hypertensive patients without pre-existing apparent renal lesion and for whom renal blood tests show functional renal impairment, treatment should be stopped and possibly restarted either at a low dose or with one constituent only. In these patients usual medical follow-up will include frequent monitoring of potassium and creatinine, after two weeks of treatment and then every two months during therapeutic stability period. Renal failure has been reported mainly in patients with severe heart failure or underlying renal impairment including renal artery stenosis.

If renovascular hypertension is present there may be an increased risk of severe hypotension and renal impairment.

Perindopril treatment should be stopped immediately if the patient develops angioedema of the face, extremities, lips, tongue, glottis and/or larynx. This may occur at any time during treatment. In such cases, the patient should be monitored until the oedema has disappeared. When confined to the face and lips, angioedema usually resolves without treatment. However antihistamines have been used. Angioedema involving the tongue, glottis or larynx may be fatal.
Appropriate emergency therapy should be given (e.g. adrenaline/maintenance of patent airway). The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.
Patients with a history of angioedema unrelated to ACE inhibitors may be at increased risk of angioedema while receiving an ACE inhibitor. Intestinal angioedema can occur in patients treated with ACE inhibitors, and should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

ACE inhibitors should be initiated under specialist supervision and with careful clinical monitoring in those with severe cardiac failure or in those receiving high-dose vasodilator therapy.

Symptomatic hypotension is more likely to occur in patients who have been volume-depleted and salt-depleted e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension. Patients at risk should be closely supervised during initiation of therapy and during dose adjustment. Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

A persistent, non-productive cough may occur which usually resolves itself after therapy is discontinued. An iatrogenic aetiology should be considered in the event of this symptom. If the prescription of an ACE inhibitor is still preferred, continuation of treatment may be considered.

The treatment of renovascular hypertension is revascularisation. Nonetheless, ACE inhibitors can be beneficial in patients with renovascular hypertension who are awaiting corrective surgery or when such a surgery is not possible. Treatment should be started in a hospital setting at a low dose and renal function and potassium levels should be monitored, since some patients have developed a functional renal insufficiency which was reversed when treatment was stopped.

In patients with severe cardiac insufficiency (grade IV) or in patients with insulin dependent diabetes mellitus (spontaneous tendency to increased levels of potassium), treatment should be started under medical supervision with a reduced initial dose. Treatment with beta blockers in hypertensive patients with coronary insufficiency should not be stopped, the ACE inhibitor should be added to the beta blocker.

Potassium depletion with hypokalaemia is a major risk with thiazide diuretics and thiazide-related diuretics. The risk of onset of lowered potassium levels (less than 3.4 mmol/L) should be prevented in some high risk populations such as elderly and/or malnourished subjects, whether or not they are taking multiple medications, cirrhotic patients with oedema and ascites, coronary patients and patients with cardiac failure. In such cases hypokalaemia increases the cardiac toxicity of cardiac glycosides and the risk of rhythm disorders.

Idiosyncratic reactions resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma may be caused by sulfonamide, or sulfonamide derivative drugs. Untreated acute angle-closure glaucoma can lead to permanent vision loss, prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled.

Pregnancy and Lactation

Pregnancy

Perindopril with indapamide is contraindicated during the second and third trimesters of pregnancy and should be avoided during the first trimester. If a pregnancy is planned, the switch to alternative medication with an established safety profile for use in pregnancy should be made as soon as possible. If pregnancy is confirmed, treatment with ACE inhibitors should be stopped immediately, and if appropriate, alternative therapy should be started.

Perindopril
It is not known if perindopril or its metabolite perindoprilat crosses the human placenta. The molecular weights (about 368 for the free acid and 442 for the salt form) suggest that transfer to the foetus will occur (Briggs, 2011).

ACE inhibitors are contraindicated during the second and third trimesters of pregnancy as exposure during these trimesters is known to induce human foetal toxicity (renal dysfunction, oligohydramnios, pulmonary hypoplasia, patent ductus arteriosus, delay in skull ossification, neonatal toxicity and even death). Severe and sometimes fatal anuria in the foetus and in the newborn have been observed and is thought to be caused by the compromise of the foetal renal system. Foetal renal failure resulting from in utero exposure to ACE inhibitors has been reported where dialysis has been required shortly after birth. Evidence of a risk of teratogenicity after first trimester exposure is conflicting, however, the MHRA recommends that a risk cannot be excluded. Recent data published does associate first trimester ACE inhibitor exposure with congenital CNS and cardiovascular defects. Unless treatment with an ACE inhibitor is considered absolutely essential, women who are planning to become pregnant should be switched to an alternative drug with an established safety record. If exposure has occurred in the first trimester a detailed ultrasound diagnosis is advisable. Exposure to an ACE inhibitor during pregnancy is not an indication for either invasive diagnostic procedures or termination of pregnancy. In cases involving long term prenatal therapy in the second and/ or third trimesters, the foetus should be monitored for the potential development of oligohydramnios, and foetal growth should be assessed with detailed ultrasound scans (Schaefer, 2007).

Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension.

Indapamide
Indapamide is not recommended for use during pregnancy. Animal studies in mice, rats and rabbits, reported no impaired fertility, foetal harm, or effect on postnatal development. However, foetal growth retardation was reported in studies on rats. Diuretics are contraindicated for their possible affects on the mother and therefore the foetus. The maternal hypovolaemia characteristic of the treatment of gestational hypertension with a diuretic, would adversely affect placental perfusion, which in turn could lead to intrauterine growth retardation (IUGR). 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 diuretics (Schaefer, 2007). This product should not be used in 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 ).

Lactation

The combination of perindopril with indapamide is contraindicated during lactation.

Perindopril

The effect of perindopril treatment on nursing infants has not been determined, however, due to its molecular size it is likely that perindopril and the active metabolite perindoprilat are excreted in breast milk, lactating mothers are advised not to breast feed while taking perindopril.

The MHRA has stated that although ACE inhibitors are not generally recommended for use by breastfeeding mothers they are not absolutely contraindicated and may be prescribed if treatment is considered essential. The MHRA state that ACE inhibitors should not be used by breastfeeding mothers in the first few weeks after delivery because of possible profound neonatal hypotension particularly in preterm infants. If ACE inhibitor therapy is considered essential for the mother the use of captopril, enalapril or quinapril may be considered when the infant is older. The infant should be carefully followed up for signs of hypotension should ACE inhibitor treatment be deemed necessary.

Indapamide

Indapamide is excreted in breast milk and should not be used during the breast-feeding period due to the decrease and even suppression of the milk secretion. Hypersensitivity to sulfonamide-derived drugs, hypokalaemia, and nuclear icterus might occur.

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
Abnormal vision
Acute renal failure
Agranulocytosis
Altered liver function tests
Angina pectoris
Angioedema
Anorexia
Aplastic anaemia
Arrhythmias
Asthenia
Atrial fibrillation
Blood urea increased
Blurred vision
Bradycardia
Bronchospasm
Cholestatic hepatitis
Choroidal effusion
Confusion
Constipation
Cough
Cytolytic hepatitis
Dehydration
Diarrhoea
Dizziness
Dry mouth
Dysgeusia
Dyspepsia
Dyspnoea
Electrolyte disturbances
Eosinophilic pneumonia
Epigastric pain
Erythema multiforme
Exacerbation of psoriasis
Fever
Fulminant hepatic necrosis
Gastro-intestinal disturbances
Haemolytic anaemia
Headache
Hepatic encephalopathy
Hepatic failure
Hepatic impairment
Hepatitis
Hypercalcaemia
Hyperkalaemia
Hypersensitivity reactions
Hyperuricaemia
Hypoglycaemia
Hypokalaemia
Hyponatraemia
Hypotension
Hypovolaemia
Impaired vision
Impotence
Increase in creatinine
Increase in serum glucose
Jaundice
Leucopenia
Maculopapular rash
Mood changes
Muscle weakness
Muscular cramps
Myocardial infarction
Myopia
Narrow angle glaucoma
Nausea
Neutropenia
Palpitations
Pancreatitis
Paraesthesia
Photosensitivity
Pruritus
Purpura
Rash
Renal impairment
Rhabdomyolysis
Rhinitis
Sleep disturbances
Sore throat
Stevens-Johnson syndrome
Sweating
Tachycardia
Thrombocytopenia
Tinnitus
Toxic epidermal necrolysis
Urticaria
Vasculitis
Ventricular tachycardia
Vertigo
Vomiting
Worsening of lupus erythematosus

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: February 2013

Reference Sources

British National Formulary, 64th Edition (2012) 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.

Summary of Product Characteristics: Coversyl arginine plus 5 mg/1.25 mg film-coated tablets. Servier Laboratories Ltd. Revised April 2021.

MHRA Drug Safety Update: Volume 1, Issue 5, December 2007
https://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON2033216
Last accessed: February 20, 2013

MHRA Drug Safety Update: Volume 2, Issue 10, May 2009.
https://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON046451
Last accessed: February 20, 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
Perindopril Last revised: March 1, 2012
Last accessed: February 20, 2013