Atorvastatin, Amlodipine and Perindopril


Atorvastatin, Amlodipine and Perindopril interacts in the following cases:

Moderate renal impairment, severe renal impairment

Atorvastatin/perindopril/amlodipine combination is not suitable for patients with creatinine clearance <60mL/min. In these patients, an individual dose titration with the monocomponents is recommended. Routine monitoring of potassium and creatinine are part of normal medical practice for patients with renal impairment.


Atorvastatin/perindopril/amlodipine combination is contraindicated during pregnancy.


Safety in pregnant women has not been established. No controlled clinical trials with atorvastatin have been conducted in pregnant women. Rare reports of congenital anomalies following intrauterine exposure to HMGCoA reductase inhibitors have been received. Animal studies have shown toxicity to reproduction.

Maternal treatment with atorvastatin may reduce the fetal levels of mevalonate which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and ordinarily discontinuation of lipid-lowering medicinal products during pregnancy should have little impact on the long-term risk associated with primary hypercholesterolaemia.

For these reasons, atorvastatin should not be used in women who are pregnant, trying to become pregnant or suspected to be pregnant. Treatment with atorvastatin should be suspended for the duration of pregnancy or until confirmation of the absence of pregnancy.


The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contra-indicated during the 2nd and 3rd 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. 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 trimestersis known to induce human foetoxicity (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.


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

Nursing mothers

Atorvastatin/perindopril/amlodipine combination is contraindicated during lactation.


It is not known whether atorvastatin or its metabolites are excreted in human milk. In rats, plasma concentrations of atorvastatin and its active metabolites are similar to those in milk. Because of the potential for serious adverse reactions, women taking atorvastatin should not breast-feed their infants. Atorvastatin is contraindicated during breastfeeding.


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.


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.

Carcinogenesis, mutagenesis and fertility

Women of childbearing potential

Women of child-bearing potential should use appropriate contraceptive measures during treatment with atorvastatin/perindopril/amlodipine.



In animal studies atorvastatin had no effect on male or female fertility.


There was no effect on reproductive performance or fertility.


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 have been performed on the effect of atorvastatin/perindopril/amlodipine on the ability to drive and use machines.

  • Atorvastatin has negligible influence on the ability to drive and use machines. Perindopril 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 in combination with another antihypertensive medication.
  • Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired.

As a result the ability to drive or operate machinery may be impaired in patients taking atorvastatin/perindopril/amlodipine. Caution is recommended especially at the start of treatment.

Adverse reactions

Summary of the profile

The most commonly reported adverse reactions with atorvastatin, perindopril and amlodipine given separately include: nasopharyngitis, allergic reactions, hyperglycaemia, headache, pharyngolaryngeal pain, epistaxis, constipation, flatulence, dyspepsia, nausea, diarrhoea, change of bowel habit, myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling, ankle swelling, back pain, liver function test abnormal, blood creatine kinase increased, somnolence, dizziness, palpitations, flushing, abdominal pain, oedema, fatigue, paresthaesia, visual disturbance, diplopia, tinnitus, vertigo, hypotension, cough, dyspnoea, vomiting, dysgeusia, rash, pruritus, asthenia.

Tabulated list of adverse reactions

The following undesirable effects have been observed during treatment with atorvastatin, perindopril, amlodipine, or given separately and ranked under the MedDRA classification by body system and under heading of frequency using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data)).

System Organ
Undesirable effects Frequency
Atorvastatin Perindopril Amlodipine
Infections and
Nasopharyngitis Common- -
Rhinitis- Very rare Uncommon
Blood and
lymphatic system
Thrombocytopenia Rare Very rare Very rare
Leucopenia/neutropenia- Very rare Very rare
Eosinophilia- Uncommon* -
Agranulocytosis or pancytopenia- Very rare-
Haemolytic anaemia in patients
with a congenital deficiency of
- Very rare-
Immune system
Allergic reactions Common- Very rare
Anaphylaxis Very rare- -
Syndrome of inappropriate
antidiuretic hormone
- Rare-
Metabolism and
Hyperglycaemia Common- Very rare
Hypoglycaemia Uncommon Uncommon* -
Hyponatraemia- Uncommon*-
Hyperkalaemia reversible on
- Uncommon* -
Anorexia Uncommon- -
Insomnia Uncommon- Uncommon
Mood swings- Uncommon Uncommon
Sleep disorder Uncommon-
Depression - Uncommon* Uncommon
Nightmares Uncommon- -
Confusion- Very rare Rare
Nervous system
Somnolence- Uncommon* Common
DizzinessUncommon Common Common
Headache Common Common Common
Tremor- - Uncommon
Dysgeusia Uncommon Common Uncommon
Syncope- Uncommon* Uncommon
Hypoesthesia Uncommon- Uncommon
ParesthaesiaUncommonCommon Uncommon
Hypertonia- - Very rare
Peripheral neuropathy Rare- Very rare
Stroke possible secondary to
excessive hypotension in highrisk patients
- Very rare-
Amnesia Uncommon--
Extrapyramidal disorder
(extrapyramidal syndrome)
- - Not known
Myasthenia gravis Not known- -
Eye disorders Visual disturbancesRare Common Common
Diplopia-- Common
Vision blurred Uncommon--
Ocular myasthenia Not known- -
Ear and
TinnitusUncommonCommon Uncommon
Vertigo- Common-
Hearing loss Very Rare- -
Myocardial infarction secondary
to excessive hypotension in
high-risk patients
- Very rare Very rare
Angina pectoris - Very rare -
Arrhythmia (including
bradycardia, ventricular
tachycardia and atrial
- Very rare Uncommon
Palpitations- Uncommon* Common
Hypotension (and effects related
to hypotension)
- Common Uncommon
Vasculitis- Uncommon* Very rare
Stroke possible secondary to
excessive hypotension in high-
risk patients
- Very rare-
Flushing- Rare* Common
Raynaud’s phenomenon- Not known-
thoracic and
Pharyngolaryngeal pain Common- -
Epistaxis Common- -
Cough- Common Uncommon
Dyspnoea- Common Common
Bronchospasm-Uncommon -
Eosinophilic pneumonia - Very rare-
Nausea CommonCommon Common
VomitingUncommon Common Uncommon
Abdominal pain upper and lower UncommonCommon Common
Dyspepsia Common Common Common
Diarrhoea CommonCommon-
Dry mouth- Uncommon Uncommon
PancreatitisUncommon Very rare Very rare
Gastritis- - Very rare
Gingival hyperplasia- - Very rare
Change of bowel habit--Common
Eructation Uncommon- -
Flatulence Common--
Hepatitis either cytolytic or
UncommonVery rare Very rare
Jaundice- - Very rare
Cholestasis Rare- -
Hepatic failure Very rare--
Skin and
tissue disorders
Rash Uncommon CommonUncommon
Pruritus Uncommon Common Uncommon
Urticaria Uncommon Uncommon Very rare
Purpura- - Uncommon
Skin discolouration-- Uncommon
Hyperhidrosis- Uncommon Uncommon
Exanthema- - Uncommon
AlopeciaUncommon- Uncommon
Angioedema Rare Uncommon Very rare
Exfoliative dermatitis-- Very rare
Pemphigoid - Uncommon*-
Psoriasis aggravation - Rare*-
Stevens-Johnson syndrome Rare- Very rare
Photosensitivity reactions- Uncommon* Very rare
Toxic epidermal necrolysis Rare- Not known
Erythema multiforme Rare Very rare Very rare
and connective
tissue disorders
Joint swellingCommon- -
Ankle swelling-- Common
Pain in extremity Common- -
Arthralgia Common Uncommon* Uncommon
Muscle spasms Common Common Common
MyalgiaCommon Uncommon* Uncommon
Back pain Common - Uncommon
Neck pain Uncommon- -
Muscle fatigue Uncommon- -
Myopathy Rare- -
Myositis Rare- -
Rhabdomyolysis Rare- -
Muscle rupture Rare- -
Tendinopathy sometimes
complicated by rupture
Rare- -
Lupus-like syndrome Very rare--
Immune-mediated necrotizing
Not known - -
Renal and
urinary disorders
Micturition disorder- - Uncommon
Nocturia- - Uncommon
Increased urinary frequency- - Uncommon
Renal insufficiency- Uncommon-
Acute renal failure- Rare-
Anuria/Oliguria- Rare*-
system and
breast disorders
Impotence/erectile dysfunction- UncommonUncommon
Gynaecomastia Very rare- Uncommon
disorders and
site conditions
AstheniaUncommon Common Uncommon
FatigueUncommon- Common
Chest pain Uncommon Uncommon* Uncommon
Pain- - Uncommon
Malaise Uncommon Uncommon* Uncommon
Oedema peripheral Uncommon Uncommon* Common
Pyrexia Uncommon Uncommon* -
Investigations Blood urea increased-Uncommon* -
Blood creatinine increased- Uncommon*-
Hepatic enzymes increased- Rare Very rare**
Blood bilirubin increased- Rare-
Weight increase Uncommon- Uncommon
White blood cells urine positive Uncommon- -
Weight decrease- - Uncommon
Liver function test abnormal Common- -
Blood creatine kinase increased Common- -
Haemoglobin decreased and
haematocrit decreased
- Very rare-
Injury, poisoning
and procedural
Fall - Uncommon*-

* Frequency calculated from clinical trials for adverse events detected from spontaneous report
** Mostly consistent with cholestasis

Exceptional cases of extrapyramidal syndrome have been reported with amlodipine.

As with other HMG-CoA reductase inhibitors elevated serum transaminases have been reported in patients receiving atorvastatin. These changes were usually mild, transient, and did not require interruption of treatment. Clinically important (>3 times upper normal limit) elevations in serum transaminases occurred in 0.8% patients on atorvastatin. These elevations were dose related and were reversible in all patients.

Elevated serum creatine kinase (CK) levels greater than 3 times upper limit of normal occurred in 2.5% of patients on atorvastatin, similar to other HMG-CoA reductase inhibitors in clinical trials. Levels above 10 times the normal upper range occurred in 0.4% atorvastatin -treated patients.

The following adverse events have been reported with some statins:

  • Sexual dysfunction.
  • Depression.
  • Exceptional cases of interstitial lung disease, especially with long term therapy.
  • Diabetes Mellitus: Frequency will depend on the presence or absence of risk factors (fasting blood glucose ≥5.6 mmol/L, BMI>30kg/m², raised triglycerides, history of hypertension).

Cognitive impairment

There have been rare post-marketing reports of cognitive impariment (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally non-serious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).

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