Perindopril and Amlodipine

Interactions

Perindopril and Amlodipine interacts in the following cases:

Hepatic impairment

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.

Pregnancy

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.

Nursing mothers

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.

Carcinogenesis, mutagenesis and fertility

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.

Effects on ability to drive and use machines

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.

Adverse reactions


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).

MedDRA
System Organ Class
Undesirable Effects Frequency
Amlodipine Perindopril
Infections and
infestations
Rhinitis Uncommon Very rare
Blood and the
lymphatic System
Disorders
Eosinophilia- Uncommon*
Leukopenia/neutropenia Very rare Very rare
Agranulocytosis or pancytopenia - Very rare
Thrombocytopenia Very rare Very rare
Haemolytic anaemia enzyme specific in patients with a
congenital deficiency of G-6PDH
- Very rare
Immune System
Disorders
Hypersensitivity Very rare Uncommon
Endocrine disorders Syndrome of inappropriate antidiuretic hormone secretion
(SIADH)
- Rare
Metabolism and
Nutrition
Disorders
Hypoglycaemia - Uncommon*
Hyperkalaemia, reversible on discontinuation - Uncommon*
Hyponatraemia- Uncommon*
Hyperglycaemia Very rare-
Psychiatric
disorders
Insomnia Uncommon-
Mood altered (including anxiety) Uncommon Uncommon
Depression Uncommon-
Sleep disorder- Uncommon
Nervous System
disorders
Somnolence (especially at the beginning of the treatment) Common Uncommon*
Dizziness (especially at the beginning of the treatment) Common Common
Headache (especially at the beginning of the treatment) Common Common
Dysgeusia UncommonCommon
Tremor Uncommon-
HypoaesthesiaUncommon -
ParaesthesiaUncommonCommon
Syncope Uncommon Uncommon*
Confusional state Rare Very rare
HypertoniaVery rare-
Neuropathy peripheral Very rare-
Cerebrovascular accident possibly secondary to excessive
hypotension in high-risk patients
- Very rare
Extrapyramidal disorder (extrapyramidal syndrome) Not known-
Eye Disorders Visual impairment Common Common
Diplopia Common-
Ear and
labyrinth
disorders
Tinnitus UncommonCommon
Vertigo- Common
Cardiac
Disorders
Palpitations Common Uncommon*
Tachycardia- Uncommon*
Angina pectoris - Very rare
Myocardial infarction, possibly secondary to excessive
hypotension in high risk patients
Very rare Very rare
Arrythmia (including bradycardia, ventricular tachycardia and
atrial fibrillation)
UncommonVery rare
Vascular
Disorders
Flushing CommonRare*
Hypotension (and effects related to hypotension) Uncommon Common
Vasculitis Very Rare Uncommon*
Raynaud’s phenomenon- Not known
Respiratory,
Thoracic and
Mediastinal
Disorders
DyspnoeaCommonCommon
Cough Uncommon Common
Bronchospasm- Uncommon
Eosinophilic pneumonia- Very rare
Gastro-intestinal
Disorders
Gingival hyperplasia Very rare-
Abdominal pain Common Common
NauseaCommon Common
Vomiting UncommonCommon
DyspepsiaCommonCommon
Change of bowel habit Common-
Dry mouth Uncommon Uncommon
Diarrheoa CommonCommon
Constipation Common Common
Pancreatitis Very rare Very rare
GastritisVery rare-
Hepato-biliary
Disorders
Hepatitis, jaundice Very rare-
Hepatitis either cytolitic or cholestatic- Very rare
Hepatic enzymes increased (mostly consistent with cholestasis) Very rare-
Skin and
Subcutaneous
Tissue Disorders
Quincke’s oedemaVery rare-
Angioedema of face, extremities, lips, mucous membranes, tongue,
glottis and/or larynx
Very rareUncommon
Erythema multiform Very rare Very rare
Alopecia Uncommon-
Purpura Uncommon-
Skin discolouration Uncommon-
Hyperhidrosis Uncommon Uncommon
Prurit Uncommon Common
Rash, exanthema Uncommon Common
Urticaria Uncommon Uncommon
Photosentivity reactionsVery rareUncommon*
Pemphigoid- Uncommon*
Psoriasis aggravation- Rare
Stevens-Johnson SyndromeVery rare-
Exfoliative dermatitis Very rare-
Toxic epidermal necrolysis Not known-
Musculoskeletal
and Connective
Tissue Disorders
Joint swelling (ankle swelling) Common-
Arthralgia Uncommon Uncommon*
Myalgia UncommonUncommon*
Muscle spasmsCommon Common
Back painUncommon-
Renal and Urinary
Disorders
Micturition disorder, nocturia, pollakiuria Uncommon-
Renal failure- Uncommon
Acute renal failure- Rare
Anuria/Oliguria- Rare*
Reproductive
System and Breast
Disorders
Erectile dysfunctionUncommon Uncommon
GynaecomastiaUncommon -
General Disorders
and Administration
Site Conditions
OedemaVery common -
Oedema peripheral- Uncommon*
FatigueCommon-
Chest pain Uncommon Uncommon*
Asthenia Common Common
Pain Uncommon-
MalaiseUncommon Uncommon*
Pyrexia- Uncommon*
Investigations Weight increased, weight decreased Uncommon-
Blood urea increased - Uncommon*
Blood creatinine increased - Uncommon*
Blood bilirubin increase - Rare
Hepatic enzyme increase - Rare
Haemoglobin decreased and haematocrit decreased - Very rare
Injury, poisoning
and procedural
complications
Fall- Uncommon*

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

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