Perindopril and Amlodipine

Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautious and should start at the lower end of the dosing range. To find the optimal starting dose and maintenance dose of patients with hepatic impairment, the patients should be individually titrated using the free combination of amlodipine and perindopril. The pharmacokinetics of amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment.

Given the effects of the individual components in this combination product on pregnancy:

Perindopril/amlodipine combination is not recommended during the first trimester of pregnancy.

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

Linked to perindopril

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated 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 antihypertensive 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.

Linked to amlodipine

The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses. Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.

Given the effects of the individual components in this combination product on lactation, perindopril/amlodipine is not recommended during lactation. A decision should therefore be made whether to discontinue nursing or to discontinue perindopril/amlodipine taking account the importance of this therapy for the mother.

Linked to 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.

Linked to 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. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of amlodipine therapy to the mother.

Fertility

Linked to perindopril

There was no effect on reproductive performance or fertility.

Linked to 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/amlodipine on the ability to drive and use machines have been performed. 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. Caution is recommended especially at the start of treatment.

a. Summary of safety profile

The most commonly reported adverse reactions with perindopril and amlodipine given separately are: oedema, somnolence, dizziness, headache (especially at the beginning of the treatment), dysgeusia, paraesthesia, visual impairment (including diplopia), tinnitus, vertigo, palpitations, flushing, hypotension (and effects related to hypotension), dyspnoea, cough, abdominal pain, nausea, vomiting, dyspepsia, change of bowel habit, diarrheoa, constipation, prurit, rash, exanthema, joint swelling (ankle swelling), muscle spasms, fatigue, asthenia.

b. Tabulated list of adverse reactions

The following undesirable effects have been observed during clinical trials and/or post-marketing use with perindopril or amlodipine 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