Perindopril and Bisoprolol

In patients with renal impairment, the recommended dose of bisoprolol/perindopril should be based on creatinine clearance as outlined in the table below:

Dosage adjustment in renal impairment:

Based on existing data on monocomponents, bisoprolol/perindopril combination is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy.

Bisoprolol

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn (reduce placental perfusion associated with growth retardation, intrauterine death, abortion or early labour and adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the foetus and newborn infant). If treatment with beta-adrenoceptor blockers is necessary, beta-1-selective adrenoceptor blockers are preferable.

Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, the uteroplacental blood flow and the foetal growth should be monitored. In case of harmful effects on pregnancy or the foetus alternative treatment should be considered. The newborn infant must be closely monitored.

Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.

Perindopril

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 inhibitor 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.

Bisoprolol/perindopril combination is not recommended during lactation.

It is not known whether bisoprolol is excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol.

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.

Fertility

There are no clinical data on fertility with the use of bisoprolol/perindopril.

Bisoprolol/perindopril combination has no direct influence on the ability to drive and use machines but individual reactions related to low blood pressure may occur in some patients, particularly at the start of treatment or upon change of medication as well as in conjunction with alcohol.

As a result the ability to drive or operate machinery may be impaired.

Summary of the safety profile

The most common adverse reactions to bisoprolol include headache, dizziness, worsening of heart failure, hypotension, cold extremities, nausea, vomiting, abdominal pain, diarrhoea, constipation, asthenia and fatigue. The most common adverse reactions reported in clinical trials and observed with perindopril include headache, dizziness, vertigo, paraesthesia, visual disturbance, tinnitus, hypotension, cough, dyspnoea, nausea, vomiting, abdominal pain, diarrhoea, constipation, dysgeusia, dyspepsia, rash, pruritus, muscle cramps and asthenia.

Tabulated list of adverse reactions

The following undesirable effects have been observed during clinical trials and/or post-marketing use with bisoprolol or perindopril given separately and ranked under the MedDRA classification by body system and 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.
^** These symptoms especially occur at the beginning of the therapy. They are generally mild and often disappear within 1-2 weeks.