Atorvastatin, Amlodipine and Perindopril

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.

Atorvastatin

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.

Perindopril

The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contra-indicated during the 2^nd and 3^rd 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.

Amlodipine

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

Atorvastatin/perindopril/amlodipine combination is contraindicated during lactation.

Atorvastatin

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.

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.

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.

Women of childbearing potential

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

Fertility

Atorvastatin

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

Perindopril

There was no effect on reproductive performance or fertility.

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 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.

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)).

^* 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).