Perindopril, Amlodipine and Indapamide

In patients with mild to moderate hepatic impairment, perindopril/indapamide/amlodipine should be administrated with caution, as dosage recommendations for amlodipine in these patients have not been established.

Given the effects of the individual components on pregnancy, perindopril/indapamide/amlodipine combination is not recommended during the first trimester of pregnancy. Perindopril/indapamide/amlodipine is contraindicated during the second and third trimesters of pregnancy.

Perindopril

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contra-indicated during the second and third trimesters of pregnancy.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension.

Indapamide

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of indapamide in pregnant women. Prolonged exposure to thiazide during the third trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause a feto-placental ischemia and growth retardation. Moreover, rare cases of hypoglycemia and thrombocytopenia in neonates have been reported following exposure near term.

Amlodipine

The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses.

Perindopril/indapamide/amlodipine combination is not recommended during lactation. A decision should therefore be made whether to discontinue nursing or to discontinue perindopril/indapamide/amlodipine taking account the importance of this therapy for the mother.

Perindopril

Because no information is available regarding the use of perindopril during breastfeeding, perindopril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Indapamide

There is insufficient information on the excretion of indapamide/metabolites in human milk. Hypersensitivity to sulfonamide-derived medicines and hypokalaemia might occur. A risk to newborns/infants cannot be excluded. Indapamide is closely related to thiazide diuretics which have been associated, during breast-feeding, with a decrease or even suppression of milk lactation.

Amlodipine

Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

Fertility

Common to perindopril and indapamide

Reproductive toxicity studies showed no effect on fertility in female and male rats. No effects on human fertility are anticipated.

Amlodipine

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility.

No studies on the effects of perindopril/indapamide/amlodipine combination on the ability to drive and use machines have been performed.

Perindopril and indapamide have no influence on the ability to drive and use machines but individual reactions related to low blood pressure may occur in some patients.

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients suffer from dizziness, headache, fatigue, weariness or nausea, the ability to react may be impaired.

As a result the ability to drive or operate machinery may be impaired. Caution is recommended especially at the start of treatment.

Summary of the safety profile

The most commonly reported adverse reactions with perindopril, indapamide and amlodipine given separately are: hypokalaemia, dizziness, headache, paraesthesia, somnolence, dysgeusia, visual impairment, diplopia, tinnitus, vertigo, palpitations, flushing, hypotension (and effects related to hypotension), cough, dyspnoea, gastro-intestinal disorders (abdominal pain, constipation, diarrhoea, dyspepsia, nausea, vomiting, change in bowel habit), pruritus, rash, rash maculo-papular, muscle spasms, ankle swelling, asthenia, oedema and fatigue.

Tabulated list of adverse reactions

The following undesirable effects have been observed with perindopril, indapamide or amlodipine during treatment and ranked under the following frequency: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000), very rare (<1/10000); not known (cannot be estimated from the available data).

^* Frequency calculated from clinical trials for adverse events detected from spontaneous report

Description of selected adverse reactions

During phase II and III studies comparing indapamide 1.5mg and 2.5mg, plasma potassium analysis showed a dose-dependent effect of indapamide:

• Indapamide 1.5 mg: Plasma potassium <3.4 mmol/l was seen in 10% of patients and <3.2 mmol/l in 4% of patients after 4 to 6 weeks treatment. After 12 weeks treatment, the mean fall in plasma potassium was 0.23 mmol/l.
• Indapamide 2.5 mg: Plasma potassium <3.4 mmol/l was seen in 25% of patients and <3.2 mmol/l in 10% of patients after 4 to 6 weeks treatment. After 12 weeks treatment, the mean fall in plasma potassium was 0.41 mmol/l.