Amlodipine + Atorvastatin

Amlodipine + Atorvastatin is the combination of an antihypertensive and Antilipemic Agent belonging to the "Calcium Channel Blocker" and "HMG-CoA reductase inhibitor."

Amlodipine + Atorvastatin is a combination drug approved for treating high blood pressure (hypertension)in adults and lowering cholesterol levels in individuals at risk of Cardiovascular Disease (CVD), reducing the risk of heart-related problems.

Amlodipine is rapidly absorbed, with a half-life of 30-50 hours, reaching peak blood levels in 6-12 hours. Atorvastatin is readily absorbed, reaching peak levels in 1-2 hours and having a half-life of approximately 14 hours. Both medications are processed by the liver and eliminated through the faeces.

The common side effects of Amlodipine + Atorvastatin include headache, nausea, stomach pain, flushing (a feeling of warmth in the neck, face, ears, and trunk), ankle swelling, and elevated liver enzymes. Amlodipine + Atorvastatin is available as a tablet for convenient administration.

Amlodipine + Atorvastatin is available in the United States, Canada, the United Kingdom, India and Australia.

Amlodipine + Atorvastatin is a combination of an antihypertensive and Antilipemic Agent belonging to the "Calcium Channel Blocker" and "HMG-CoA reductase inhibitor."

Amlodipine: Amlodipine primarily affects the smooth muscle of the arteries, lowering peripheral vascular resistance by preventing calcium ion inflow. According to experimental data, Amlodipine interacts with specific membrane binding sites. It mainly exerts its therapeutic effects by dilating peripheral arterioles, which lowers cardiac workload and oxygen consumption, and by promoting coronary artery dilation, which improves oxygen supply. It is beneficial in conditions like variant angina and mitigates coronary vasoconstriction. These two distinct mechanisms prove Amlodipine's effectiveness in treating angina and hypertension.

The Onset of action of Amlodipine is not clinically established.

The Duration of Action for Amlodipine in the body is approximately 24 hours.

The Tmax was found within 6-12 hours following the administration of Amlodipine.

Vd: 21 L/kg

Half-life: 30-50 hr

Clearance: 25 L/hr

Atorvastatin: HMG-CoA reductase, an enzyme that catalyzes HMG-CoA conversion to mevalonate, is precisely and competitively inhibited by Atorvastatin. By stimulating LDL catabolism and increasing LDL receptor expression due to an inhibition in mevalonate synthesis, LDL cholesterol levels are lowered.

The Onset of Action of Atorvastatin is within (Initial effect) 3-5 days.

The Duration of Action of Atorvastatin is within 20 to 30 hours.

The Tmax of Atorvastatin is approximately 1-2 hours, and Cmax is within 1.95–252 μg/ml.

Vd: 381 L

Half-life: 14 hr for parent drug and 20-30 hr for active metabolites

Synergistic Benefits: Amlodipine + Atorvastatin combines the benefits of an Antilipemic Agent (Atorvastatin) with a calcium channel blocker (Amlodipine) to successfully treat hypertension (high blood pressure) with high cholesterol levels. Amlodipine decreases blood pressure by relaxing blood vessels, lowering the workload on the heart. Atorvastatin reduces cholesterol, lowering the risk of atherosclerosis. They work together to prevent heart attacks, strokes, and other cardiovascular events more effectively than alone. This combination can significantly minimise the risk of heart attacks, strokes, and other cardiovascular events, making it an excellent approach for managing overall cardiovascular health.

When one medication fails to regulate your blood pressure, these medications are combined.

Data Onset of action of Amlodipine + Atorvastatin is not specified.

Data duration of action of Amlodipine + Atorvastatin is not specified. Follow prescribed dosing guidelines.

The Data of Tmax of Amlodipine + Atorvastatin typically takes 6-12 hours, whereas Atorvastatin reaches Tmax in around 1-2 hours after delivery.

The Data of Cmax of Amlodipine + Atorvastatin combination is typically achieved within 6-12 hours.

Amlodipine and Atorvastatin are available in tablets.

As the physician recommends, take the medication orally once daily, generally with or without a meal.

Amlodipine is a calcium channel blocker for angina and high blood pressure. Decreasing blood vessel stress reduces cardiac strain and reduces blood flow. Antilipemic Agent (statin) Atorvastatin works in addition to a healthy diet to control cholesterol levels. It reduces "bad" LDL and triglycerides while raising "good" HDL by decreasing the amount of cholesterol the liver makes. Combining these two drugs reduces the risk of heart disease, preventing heart attacks and strokes. Besides taking medicine, maintaining a heart-healthy lifestyle that includes regular exercise, managing your weight, and giving up smoking increases the efficacy of your treatment. The combination protects against heart-related problems by preventing difficulties caused by excessive blood pressure and supporting cardiovascular health.

Amlodipine + Atorvastatin is a combination of an antihypertensive and Antilipemic Agent belonging to the "Calcium Channel Blocker" and "HMG-CoA reductase inhibitor."

Amlodipine: It prevents calcium ions from entering "slow channels" or particular voltage-sensitive regions of the myocardium and vascular smooth muscle during depolarization, resulting in relaxation of the latter and coronary vasodilation; it also increases myocardial oxygen delivery in people with vasospastic angina. Amlodipine directly affects vascular smooth muscle to cause peripheral arterial vasodilation, which lowers blood pressure and peripheral vascular resistance.

Atorvastatin: The HMG-CoA reductase enzyme is competitively inhibited by Atorvastatin. Statin drugs lower hepatic cholesterol synthesis by inhibiting HMG-CoA from being converted to mevalonate. The amount of LDL receptors on the surface of hepatic cells also rises when Atorvastatin is taken.

The Amlodipine + Atorvastatin combination has beneficial effects on hypertension by effectively lowering blood pressure and cholesterol levels through distinct mechanisms of action. It relaxes the blood arteries, allowing blood to flow freely throughout your body. It also efficiently lowers the body's elevated cholesterol levels. Lowering cholesterol also reduces the risk of heart disease, and controlling blood pressure lowers the risk of having a stroke, heart attack, or renal issues in the future. This allows individuals to stay healthier for a more extended period. Immediate benefits from taking this medication may not be noticed, but it will keep you healthy in the longer term.

Amlodipine + Atorvastatin is approved for use in the following clinical indications:

• The combination of Amlodipine and Atorvastatin is indicated for lowering cholesterol and blood pressure because it slows the progression of atherosclerosis and lowers the risk of arterial plaque formation and cardiovascular events.
• This combination medication may be indicated for those with a history of cardiovascular disease or stroke to manage the underlying risk factors such as hypertension and dyslipidemia and prevent future cardiovascular events by controlling blood pressure and enhancing cholesterol profiles.

Orally: Amlodipine + Atorvastatin is available as a tablet that can be taken orally. Amlodipine and Atorvastatin should be taken on an empty stomach or with food. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Amlodipine + Atorvastatin has various strengths, such as 2.5mg +10mg, 2.5+20mg, 2.5 mg +40mg, 5mg+10mg, 5mg +20mg, 5mg +40mg, 5mg +80mg, 10mg +10mg, 10mg +20mg, 10mg +40mg or 10mg +80mg.

Dosage Adjustment for Adult Patients

Managing Cardiovascular Disease, Hypertension/Angina, and Hyperlipidemia

Dosage must be personalized for each component for the treatment of hypertension, angina, and hyperlipidemia; the amlodipine dose may be titrated after 1 to 2 weeks and the atorvastatin dose after 2 to 4 weeks; not to exceed 10 mg amlodipine or 80 mg atorvastatin.

2.5-10 mg amlodipine; 10-80 mg atorvastatin orally qDay

Amlodipine + Atorvastatin is available in the form of Oral tablets.

Amlodipine and Atorvastatin should be used in treating hypertension, along with appropriate nutritional restrictions.

While taking this combination, it is advised to maintain a rich, heart-healthy diet low in saturated fats and cholesterol and consume plenty of vegetables, whole grains, fruits, and lean proteins. Avoid excessive consumption of grapefruit, grapefruit juice, and food rich in calcium or alcohol, as it may interact with the medication. Avoid red yeast rice products while taking amlodipine/atorvastatin, as they may contain lovastatin, increasing the risk of severe muscle and liver issues.

Regular exercise, weight reduction, and a balanced diet will help you control your blood pressure.

The dietary restriction should be individualized as per patient requirements.

Amlodipine + Atorvastatin may be contraindicated in patients with the following conditions:-

• Hypersensitivity (to the drug or any of its components)
• Pregnancy
• Severe Renal impairment
• History of Angioedema
• Concomitant use with ciclosporin, systemic fusidic acid, telaprevir, glecaprevir/pibrentasvir and tipranavir/ritonavir combinations.
• Severe Liver Impairment (Active liver disease or unexplained elevated transaminases)

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• Symptomatic hypotension may occur with Amlodipine, especially in patients with severe aortic stenosis. Due to its gradual Onset of action, acute hypotension is less likely but remains possible. Caution is advised, particularly in patients with compromised cardiac function. Monitoring blood pressure is essential.
• Congestive heart failure patients should exercise caution.
• Persistent, progressive dermatologic responses.
• Angioneurotic oedema, anaphylaxis, myositis, rhabdomyolysis, tendon rupture, hepatic failure, depressed mood, neuropathy, pancreatitis, and interstitial lung disease are only a few of the serious adverse responses associated with atorvastatin medication. Other side effects include anaphylaxis, depressed mood, neuropathy, pancreatitis, and interstitial lung disease. Precaution and vigilant monitoring are essential.
• When starting or raising the dose, Amlodipine may induce worsening angina and sudden myocardial infarction in individuals with severe obstructive coronary artery disease. Caution is advised.

It is unsafe to consume alcohol with Amlodipine + Atorvastatin

Not recommended to use during breastfeeding. However, there’s no sufficient scientific evidence traceable regarding the use and safety of Amlodipine + Atorvastatin for breastfeeding populations.

Avoid use during pregnancy.

Avoid or minimize the consumption of red yeast rice, grapefruit or grapefruit juice. Caution should be taken while consuming calcium-rich food, such as red yeast rice products.

The adverse reactions related to Amlodipine + Atorvastatin can be categorized as

• Common: Peripheral oedema, headache and fatigue
• Less Common: Dizziness or lightheadedness, nausea or stomach discomfort, flushing, myalgia
• Rare: Arthralgia, cholestatic jaundice, severe allergic reactions or visual disturbances (blurred vision)

Reports on Postmarketing

The most often reported symptoms include Myositis and Extrapyramidal disorder.

The clinically relevant drug interactions of Amlodipine and Atorvastatin are briefly summarized here.

• CYP3A4 Inhibitors: Coadministration with CYP3A4 inhibitors, such as fibrates, niacin, cyclosporine, macrolides, and azole antifungals, increases the risk of myopathy; medication should be stopped if myopathy is detected or suspected.
• CYP3A inhibitors (moderate and potent): When Amlodipine is co-administered with CYP3A inhibitors (moderate and potent), systemic exposure to the medication is increased and may necessitate dose reduction; monitor for signs of hypotension and oedema to evaluate whether dose adjustment is necessary.
• CYP3A4 inducers: Atorvastatin plasma concentrations may be decreased by concurrent treatment with CYP3A4 inducers (such as rifampicin, efavirenz, and phenytoin), Al or Mg antacids, and colestipol. Digoxin with oral contraceptives (such as norethindrone and ethinyl estradiol) may cause a rise in serum levels.
• Sildenafil: Monitor closely for hypotension when sildenafil is coadministered with Amlodipine.
• Potentially Fatal: Concomitant use with ciclosporin, telaprevir, glecaprevir/pibrentasvir and tipranavir/ritonavir combinations may potentiate the risk of myopathy or rhabdomyolysis. Co-administration with or within seven days of stopping systemic fusidic acid may increase the risk of fatal rhabdomyolysis.
• Immunosuppressants: It is advised to monitor the trough blood levels of cyclosporine and tacrolimus regularly and to alter the dose as necessary since Amlodipine may enhance the systemic exposure of cyclosporine or tacrolimus when coadministered.
• Simvastatin: Co-administration of simvastatin with Amlodipine raises the systemic exposure of simvastatin. Limit the simvastatin dose in patients on Amlodipine to 20 mg daily.

• Nausea
• Abdominal pain
• Headache
• Sleepiness
• Ankle oedema
• Flushing (a warmed sensation in the cheeks, ears, neck, and trunk)
• Palpitations
• Constipation
• Muscle ache
• Increased blood glucose levels Increased liver enzymes
• Fatigue

Amlodipine + Atorvastatin should be prudent in the following group of special populations.

• Pregnancy

Amlodipine: Pregnancy Category C

There haven't been any controlled studies conducted on pregnant women. Amlodipine should only be used during pregnancy if the benefits exceed the hazards to the developing foetus. Amlodipine maleate was given orally to pregnant rats and rabbits during key organ development periods at doses up to 10 mg amlodipine/kg/day (8 times and 23 times the maximum recommended human dose of 10 mg on a mg/m2 basis, respectively), and no teratogenicity or other embryo/fetal toxicity was found. The litter size significantly decreased by nearly 50% during mating and gestation in rats receiving the equivalent of 10 mg of amlodipine/kg/day for 14 days before mating, whereas intrauterine mortality dramatically increased (about 5-fold). Additionally, the rats' gestation and labour times were prolonged by this dosage.

Amlodipine's postmarketing data lacks info on congenital disabilities or miscarriage risks. Poorly controlled hypertension during pregnancy poses maternal and fetal risks.

Atorvastatin: Pregnancy Category X; Not for use in pregnancy.

Since safety in pregnant women has not been proved, and there is no apparent benefit of lipid-lowering medications during pregnancy, atorvastatin is prohibited for such individuals. When given to a pregnant woman, atorvastatin may damage the foetus because HMG-CoA reductase inhibitors reduce the production of cholesterol and maybe other physiologically active compounds derived from cholesterol.

Due to the high potential risk to the foetus, avoid the Amlodipine + Atorvastatin combination when pregnant. If pregnancy is detected, stop immediately and control hypertension according to pregnancy recommendations.

When using this drug while expecting or planning a pregnancy, use caution and consult a physician.

Females of reproductive potential should consider using effective contraception while on treatment to prevent potential harm.

• Lactating Mothers

There is no data on the drug in human milk or its impact on breastfeeding infants and milk production. It's recommended that nursing mothers avoid breastfeeding while on Atorvastatin/amlodipine treatment.

Although it has been demonstrated that Amlodipine + Atorvastatin pass on into human milk and Atorvastatin is found in rat milk, it is unknown if it is present in human milk.

Amlodipine: Amlodipine is present in human milk at an estimated median relative infant dose of 4.2%, according to the limited information that is currently available from a published clinical lactation study; no side effects on breastfed infants have been reported, and no data are now available on the impact of Amlodipine on milk production.

Atorvastatin: It is advised to stop breastfeeding when taking statins since the medication may enter into the milk and pose risks to nursing infants. Consider temporarily stopping statin treatment for people at reduced risk until the lactation period is through. Patients at high risk who require statins after birth should choose alternatives like baby formula rather than breastfeeding.

• Pediatric Use

Children under ten are advised not to use Amlodipine and Atorvastatin. It is considered as off-label for children older than ten. After thoroughly evaluating the potential benefits and drawbacks, the healthcare provider should decide whether to use it to treat heterozygous familial hypercholesterolemia or hypertension. If used as directed, careful medical supervision and monitoring are required.

Dosage Adjustment for Pediatric Patients

Managing Hypertension and heterozygous Familial Hypercholesterolemia (Off-Label)

For the treatment of hypertension/hyperlipidemia, each component's dosage must be individualized; the daily doses of Amlodipine and Atorvastatin may be increased after a two- to four-week titration period, respectively, with a maximum of 20 mg of Atorvastatin or 5 mg of Amlodipine per day.

Ten years: Safety and effectiveness are unknown

More than ten years: 2.5-5 mg amlodipine; 10-20 mg atorvastatin PO qDay

• Geriatric Use

Geriatric people should have their use of Amlodipine and Atorvastatin closely monitored. Elderly people may be more vulnerable to adverse drug reactions and drug interactions. It is essential to closely monitor liver and kidney function and any possible medication interactions. Depending on the individual's medical situation and drug regimen, dosage modifications may be required. It's crucial to monitor patients and consult with medical professionals regularly.

Dosage Adjustment in Kidney Impairment Patient

No dose change is necessary for mild to moderate

Dosage Adjustment in Hepatic Impairment Patient

Amlodipine + Atorvastatin is contraindicated in active liver disease.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Amlodipine + Atorvastatin. Overconsumption of Amlodipine + Atorvastatin could lead to symptoms such as severe dizziness, fainting and fast heartbeat.

There is no specific antidote or treatment for excessive intake of Amlodipine + Atorvastatin. However, immediate medical attention is essential.

Amlodipine + Atorvastatin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Management typically involves supportive measures and symptomatic treatment. Supportive therapy should be given, addressing any symptoms that persist or worsen. Activated charcoal may also be considered if the overdose is detected shortly after ingestion to reduce absorption. Monitoring the patient's vital signs, like ECG (electrocardiogram)or blood tests and correcting any electrolyte imbalances is crucial. In severe cases, gastric lavage may be performed if ingestion occurs within the previous hour. Physical treatment might be added if necessary.

Pharmacodynamic of Amlodipine + Atorvastatin

• Amlodipine: Amlodipine binds to cell membranes with a high affinity and inhibits specific membrane calcium channels to modulate calcium influx. Long-acting effects and a less frequent dose schedule are made possible by this medication's unique binding qualities.
• Atorvastatin: Humans can be pharmacologically affected by Atorvastatin and some of its metabolites. Cholesterol production and LDL clearance occur mainly in the liver, also the site of action. More closely correlated with LDL-C lowering is medication dose than systemic drug concentration. Depending on the therapeutic response, pharmacological dosages should be individualized.

Pharmacokinetics of Amlodipine + Atorvastatin

Absorption:

Amlodipine: Amlodipine is slowly and almost entirely absorbed from the digestive tract. Peak plasma concentrations are reached 6 to 12 hours after oral dosing. Amlodipine's bioavailability is estimated to be between 64 - 90%. After 7-8 days of regular medication, steady-state plasma amlodipine levels are attained. Food does not affect absorption.

Atorvastatin: Atorvastatin is well absorbed from the gastrointestinal tract, with peak blood levels occurring within 1-2 hours after oral administration. It is efficiently absorbed in the small intestine.

Distribution

Amlodipine: The plasma protein binding of Amlodipine is approximately 98%.

Atorvastatin: The average volume of distribution for atorvastatin is 381 litres. Atorvastatin is 99% bound to plasma proteins. A blood/plasma ratio of 0.25 or below suggests ineffective medication absorption by red blood cells. Atorvastatin is probably secreted in human milk, based on research in rats.

Metabolism

Amlodipine: Amlodipine is primarily (approximately 90%) converted to inactive metabolites via hepatic breakdown with 10%(parent compound) and 60% (metabolites).

Atorvastatin: Atorvastatin undergoes extensive metabolism to produce a variety of beta-oxidation compounds and ortho- and parahydroxylated derivatives. In vitro, ortho- and para-hydroxylated metabolites inhibit HMG-COA reductase to the same extent as Atorvastatin. Active metabolites are responsible for around 70% of the circulating inhibitory activity for HMG-COA reductase.

Excretion

Amlodipine: Approximately 10% of a given dose is excreted in the urine.

Atorvastatin: Atorvastatin and its metabolites are mainly eliminated through bile after hepatic and extra-hepatic metabolism. Although there's no enterohepatic recirculation, Atorvastatin has a plasma elimination half-life of about 14 hours in humans. However, the inhibitory activity on HMG-CoA reductase, which includes active metabolites, has a longer half-life of 20 to 30 hours. Urine excretion accounts for less than 2% of an orally administered dose of Atorvastatin.

Therapeutic benefits of a combination of Amlodipine and Atorvastatin

• Amlodipine, a calcium channel blocker, efficiently reduces blood pressure by relaxing blood vessels and lowering stress on the heart. This lowers the likelihood of hypertension-related problems such as heart attacks and strokes. Atorvastatin, a statin medicine, lowers LDL cholesterol levels and decreases blood vessel inflammation. The combination offers an effective approach to reducing cardiovascular risk by targeting high blood pressure and excessive cholesterol.
• Atherosclerosis is the accumulation of plaque in the wall of arteries, which can cause blockages and raise the risk of heart disease. Atorvastatin plays a vital role in slowing down the progression of atherosclerosis by lowering LDL cholesterol levels and thereby minimizing plaque accumulation. This advantage is especially significant for people who have high cholesterol levels.
• Amlodipine and Atorvastatin are used in combination to improve cardiovascular health. Lowering blood pressure and cholesterol levels relieves cardiac strain and improves healthier circulation. This can result in increased energy, decreased fatigue, and a better quality of life.

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• Lin CP, Tung YC, Hsiao FC, Yang CH, Kao YW, Lin YS, Chu YC, Chu PH. The fixed-dose combination of Amlodipine and Atorvastatin improves clinical outcomes in patients with concomitant hypertension and dyslipidemia. J Clin Hypertens (Greenwich). 2020 Oct;22(10):1846-1853. doi: 10.1111/jch.14016. Epub 2020 Aug 29. PMID: 32862551; PMCID: PMC8029959.

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