Perindopril and Indapamide

In patients with moderate renal impairment (creatinine clearance 30-60 ml/min), it is recommended to start treatment with the adequate dosage of the free combination.

In patients with creatinine clearance greater than or equal to 60 ml/min, no dose modification is required. Usual medical follow-up will include frequent monitoring of creatinine and potassium.

Given the effects of the individual components on pregnancy, perindopril/indapamide combination is not recommended during the first trimester of pregnancy.

Perindopril/indapamide combination is contraindicated during the second and third trimesters of pregnancy.

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

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.

Neither the two active substances nor the perindopril/indapamide combination affect alertness but individual reactions related to low blood pressure may occur in some patients, particularly at the start of treatment or in combination with another antihypertensive medication. As a result the ability to drive or operate machinery may be impaired.

Summary of safety profile

The administration of perindopril inhibits the renin-angiotensin-aldosterone axis and tends to reduce the potassium loss caused by indapamide.

Four percent of the patients on treatment with perindopril/indapamide combination 5 mg/1.25 mg experience hypokalaemia (potassium level <3.4 mmol/l).

The most commonly reported adverse reactions observed are:

• with perindopril: dizziness, headache, paraesthesia, dysgeusia, visual impairment, vertigo, tinnitus, hypotension, cough, dyspnoea, abdominal pain, constipation, dyspepsia, diarrhoea, nausea, vomiting, pruritus, rash, muscle spasms and asthenia.
• with indapamide: hypokalaemia, hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions and maculo-papular rashes.

Tabulated list of adverse reactions

The following undesirable effects have been observed during clinical trials and/or post-marketing use and ranked under the following frequency:

Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <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 1.5 mg and 2.5 mg, 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.