Atorvastatin+ Aspirin

Atorvastatin+ Aspirin belonging to the Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and (HMG-CoA) Reductase Inhibitor, respectively, used for treating dyslipidemia associated with the atherosclerotic arterial disease with the risk of myocardial infarction, stroke and/or peripheral vascular disease.

Aspirin is rapidly and well absorbed from the gastrointestinal tract orally. As food reduces the rate but not the extent of absorption, the oral bioavailability is 50-75%.Aspirin is widely and readily distributed into most body tissues and fluids, and Aspirin is said to cross the placenta and enter breast milk. The volume of distribution of Aspirin was found to be 10 L.Aspirin is partially hydrolyzed by esterases in the gastrointestinal mucosa to active salicylate, which is then conjugated in the liver into salicylic acyl glucuronide,salicyluric acid, salicyl phenolic glucuronide, gentisic acid, and gentisuric acid. Aspirin is mainly excreted Via urine. The percentage of Excretion via metabolites includes the following: 75% as salicyuric acid, 10% as salicylic acid, 10% as phenolic glucuronide, and 5% as acyl glucuronide.

Atorvastatin is rapidly absorbed from the gastrointestinal tract. The Bioavailability of Atorvastatin is approximately 14% and approximately 30% for atorvastatin and equipotent metabolites. The time to peak plasma concentration achieved for atorvastatin is about 1-2 hours. The volume of distribution achieved by Atorvastatin is approximately 381 L. Atorvastatin is metabolized in the liver by CYP3A4 isoenzyme into active ortho- and para hydroxylated derivatives and various β-oxidation products. Atorvastatin is said to undergo extensive first-pass metabolism in the gastrointestinal mucosa and liver. Atorvastatin is mainly excreted via the bile; urine is <2% as an unchanged drug. The Elimination half-life of Atorvastatin is approximately 14 hours (atorvastatin); approx 20-30 hours (equipotent metabolites).

Atorvastatin+ Aspirin shows common side effects like headache, rash, gastrointestinal ulcerations, abdominal pain, upset stomach, heartburn, drowsiness, cramping, nausea, gastritis, bleeding, muscle weakness, ankle swelling (edema), dark urine and slow heart rate.

Atorvastatin+ Aspirin is available in the form of Oral Capsules.

Atorvastatin+ Aspirin is available in India, the US, and Japan.

Atorvastatin+ Aspirin belonging to the Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and (HMG-CoA) Reductase Inhibitor, respectively, used for treating dyslipidemia associated with the atherosclerotic arterial disease with risk of myocardial infarction, stroke and/or peripheral vascular disease.

Aspirin: Aspirin is a salicylate that exhibits analgesic, anti-inflammatory, and antipyretic activities. It is an irreversible inhibitor of cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, directly inhibiting prostaglandins' biosynthesis. It inhibits platelet aggregation via acetylation of platelet cyclooxygenase, thus irreversibly preventing the formation of platelet aggregating factor thromboxane A2.

Atorvastatin: Atorvastatin is said to be statin medication and also a competitive inhibitor of the enzyme HMG-CoA reductase .This catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Atorvastatin is found to be acting primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low-density lipoprotein (LDL) receptors, increasing LDL's hepatic uptake. Atorvastatin also reduces Very-Low-Density Lipoprotein-Cholesterol (VLDL-C), serum triglycerides (TG), and also Intermediate Density Lipoproteins (IDL), and a number of apolipoprotein B (apo B) which contain particles. Still, it increases High-Density Lipoprotein Cholesterol (HDL-C).

The peak effect of Atorvastatin+ Aspirin can be observed within 3 to 5 hours.

The Data on the onset of action of Atorvastatin+ Aspirin is not available.

The Cmax and Tmax of Atorvastatin+ Aspirin have not been reported.

The Data on the duration of Action of Atorvastatin+ Aspirin is not available.

Atorvastatin+ Aspirin is available in the form of Oral Capsules.

Atorvastatin+ Aspirin is used to treat dyslipidemia associated with atherosclerotic arterial disease with a risk of myocardial infarction, stroke, or peripheral vascular disease.

Cardiovascular risk reduction: Both aspirin and atorvastatin are commonly used to reduce the risk of cardiovascular events such as heart attack and stroke. Aspirin works by inhibiting platelet aggregation and reducing blood clot formation, while atorvastatin helps lower cholesterol levels and reduce inflammation in the blood vessels.

Synergistic effect: Studies have suggested that the combination of aspirin and atorvastatin may have a synergistic effect in reducing cardiovascular risk. This means that the combination may be more effective than either drug alone.

Simplified treatment: Taking a combination of aspirin and atorvastatin may simplify treatment for patients who require both drugs. Instead of having to take two separate medications, they can take one pill that contains both drugs.

Cost-effective: In some cases, taking a combination pill may be more cost-effective than taking two separate medications.

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

• Prevention of heart attacks: Atorvastatin+ Aspirin is used to prevent heart attacks in patients who have already had a heart attack or are at high risk of having one.
• Prevention of strokes: This combination drug is also used to prevent strokes in patients who have already had a stroke or are at high risk of having one.
• Lowering cholesterol levels: Atorvastatin is a type of medication known as a statin, which is used to lower cholesterol levels in the blood.
• Prevention of blood clots: Aspirin is a type of medication known as an antiplatelet agent, which helps to prevent blood clots from forming.
• Management of angina: Atorvastatin+ Aspirin may also be used to manage the symptoms of angina, which is chest pain or discomfort that occurs when the heart does not get enough oxygen-rich blood.

Myocardial Infarction:

For the treatment of myocardial infarction is Atorvastatin+ Aspirin 20mg also taken orally divided into 4 doses as per the directions of the medical practitioner.

Stroke:

For the prevention of stroke, the recommended dose of Atorvastatin+ Aspirin 20mg also taken orally divided into 4 doses as per the directions of the medical practitioner taken orally.

Peripheral Vascular Disease:

For the treatment of peripheral vascular disease (narrowing or blockage of arteries that supply blood to the legs and arms), the recommended dose of Atorvastatin+ Aspirin 20mg also taken orally divided into 4 doses as per the directions of the medical practitioner also taken orally.

The combination of Atorvastatin+ Aspirin is available as following strengths:

• 10 mg (Atorvastatin 10 mg and Aspirin 75 mg)
• 20 mg (Atorvastatin 20 mg and Aspirin 75 mg)

Atorvastatin+ Aspirin is available in the form of Oral Capsules.

• Dosage Adjustment in Kidney Patient

For patients with a creatinine clearance (CrCl) above 10 mL/minute, no dosage adjustment is usually necessary for Atorvastatin+ Aspirin. However, it is important to use the lowest effective dose and limit the duration of therapy, especially for patients at high risk of developing adverse effects such as acute kidney injury. Such high-risk patients may include those with chronic kidney disease, volume depletion, and older age.

In patients with a CrCl below 10 mL/minute, it is recommended to avoid using Atorvastatin+ Aspirin due to the potential risk of adverse effects. A healthcare provider may recommend alternative medications or adjust the dosage of any other medications being used to manage the patient's condition.

• Dosage Adjustment in Hepatic Impairment Patient

It is advised to avoid use of Atorvastatin+ Aspirin in severe liver injury.

Avoid green, leafy vegetables, which are high in vitamin K and can decrease the ability of Aspirin to thin the blood.

Alcohol intake should be avoided as it might lead to increased damage to gastrointestinal mucosa and prolonged bleeding time due to the additive effects of acetylsalicylic acid and alcohol. Patients having three or more alcoholic drinks per day should consult their physician before use.

Grapefruit juice should be avoided as it has a direct interaction with statins. It is advised to moderate the intake of taking saturated fats with statins to help lower their LDL cholesterol and overall risk of cardiovascular disease.

Atorvastatin+ Aspirin is contraindicated in patients with

• Patients who are hypersensitive to Atorvastatin+ Aspirin, salicylates, nonsteroidal analgesics, antipyretics, anti-inflammatory drugs (NSAIDs), or other ingredients in the product or component of the container.
• Active or Severe hepatic failure, renal failure, or congestive heart failure
• Acute gastrointestinal ulcer
• History of gastrointestinal ulcers
• Hemorrhagic diathesis
• Patients with a history of asthma, which is induced by the administration of salicylates or substances with similar action, notably NSAIDs
• Combination with methotrexate at doses of 15mg/week or more
• Active liver disease, which might include unexplained persistent elevations in hepatic transaminase levels
• Pregnancy

The physician should closely monitor the patients as well as keep pharmacovigilance as follows:

• General

Aspirin is one of the most frequent causes of accidental poisoning in toddlers and infants. The Tablets should be kept well out of the reach of children.

Atorvastatin+ Aspirin should be administered cautiously patients with the following:

• Uncontrolled hypertension
• Renal function, Impaired hepatic or cardiovascular circulation
• A history of bleeding tendencies, with significant anemia and/or hypothrombinemia
• Concomitant treatment with anticoagulants
• Concomitant therapy with NSAIDs, such as ibuprofen or naproxen, in patients on an Aspirin regimen

• Hypersensitivity

Atorvastatin+ Aspirin might precipitate bronchospasm and also induce asthma attacks or other hypersensitivity reactions, due to the presence of Aspirin as one of the combination. The present risk factors include bronchial asthma, hay fever, nasal polyps, or chronic respiratory disease. This also applies to patients who show allergic reactions, such as cutaneous reactions, itching, and urticaria, to other substances.

• Hematologic

Due to the effect on platelet aggregation, Aspirin may be associated with an increased risk of bleeding. It is advised that caution is necessary when Atorvastatin+ Aspirin and anticoagulants are prescribed concurrently, as the salicylates (Aspirin) can depress the prothrombin concentration in the plasma.

• Perioperative Considerations

Due to its inhibitory effect on platelet aggregation, which persists several days after administration, Aspirin in Atorvastatin+ Aspirin combination might lead to increased bleeding during and after surgical operations (including minor surgeries, e.g., dental extractions).

• Skeletal Muscle

Rare cases of the rhabdomyolysis with an acute renal failure secondary to myoglobinuria had been reported with that of atorvastatin. A history of renal impairment might be a risk factor for the development of rhabdomyolysis. Such patients merit closer to monitoring for the skeletal muscle effects.

Atorvastatin, occasionally might cause myopathy, defined as the muscle aches or muscle weakness in conjunction with increase in creatine phosphokinase (CPK) values less than 10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs example cyclosporine and potent CYP3A4 inhibitors such as clarithromycin, itraconazole, and HIV protease inhibitors , might increase the risk of myopathy/rhabdomyolysis.

Patients should be advised to promptly report an unexplained muscle pain, weakness,

or tenderness particularly if it is accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Atorvastatin+Aspirin. It is advised that Atorvastatin+Aspirin therapy should be discontinued if markedly elevated CPK levels occur, or myopathy is diagnosed or if suspected.The recommended human dose of Atorvastatin is 80 mg/day.

• Use in Patients with Recent Stroke or Transient Ischemic Attack (TIA)

In a post hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) studies where drug atorvastatin 80 mg versus placebo when administered in 4,731 subjects without Congestive Heart Disease who had a stroke or Transient Ischemic Attack within the preceding six months, a higher incidence of the hemorrhagic stroke was seen in the drug atorvastatin 80 mg group compared to that of placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p = 0.0168). The incidence of a fatal hemorrhagic stroke was found to be similar across treatment groups (17 versus 18 for the atorvastatin as well as placebo groups, respectively). The incidence of a nonfatal hemorrhagic stroke was found to be significantly higher in the drug atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic as well as lacunar stroke on study entry, were found to be associated with an increased incidence of hemorrhagic stroke in the atorvastatin group.

Alcohol can increase the risk of liver damage when taken with atorvastatin+ aspirin.. Alcohol consumption can increase the liver's workload, which can lead to liver damage and potentially increase the risk of side effects associated with atorvastatin.

It can also increase the risk of stomach bleeding and ulcers. Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) that can irritate the stomach lining, and alcohol consumption can increase the stomach's sensitivity to aspirin, leading to potential complications.

Aspirin and its metabolites pass into breast milk in small quantities. Since no adverse effects on the infants have been observed after occasional use, interruption of breastfeeding is usually unnecessary. However, on regular use or intake of high doses, breastfeeding should be discontinued early.

It is unknown whether the drug atorvastatin is excreted in the human milk. It had been observed that nursing rat pups had plasma and liver drug levels of the 50% and 40%, respectively, of that in their mother's milk. Animal breast milk drug levels might not accurately reflect human breast milk levels.

Pregnancy Category B

Acetylsalicylic acid inhibits prostaglandin synthesis. Inhibition of prostaglandin synthesis might adversely affect the pregnancy or embryo/fetal development. Data from epidemiological studies raise concerns about an increased risk of miscarriage and malformations after using a prostaglandin synthesis inhibitor in early pregnancy. The trouble is believed to grow with the dose and duration of therapy. Available data do not support any association between the intake of acetylsalicylic acid and an increased risk of miscarriage. For acetylsalicylic acid, the available epidemiological data regarding malformation are not consistent, but an increased risk of gastroschisis could not be excluded. A prospective study with exposure in early pregnancy (1st-4th month) of about 14,800 mother-child pairs has not yielded any association with an elevated rate of malformations.

Pregnancy Category X

Atorvastatin is found to be contraindicated in women who are or might become pregnant. Serum cholesterol as well as triglycerides levels increase during the normal pregnancy. Statins do not offer any benefit during pregnancy as cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is said to be a chronic process, and discontinuing lipid-lowering medications during pregnancy should have little impact on the long-term outcomes of a primary hypercholesterolemia therapy.

There are found to be no adequate and well-controlled studies of atorvastatin use during pregnancy. However there have been rare reports of congenital anomalies following an intrauterine exposure to statins. The Drug Atorvastatin should only be used only if the potential benefits outweigh the potential risks associated with the drug.

Grapefruit and grapefruit juice can increase the blood levels of atorvastatin, which may increase the risk of side effects such as muscle pain, liver damage, and kidney failure. Therefore, it's important to avoid consuming grapefruit or grapefruit juice while taking atorvastatin.

Similarly, taking aspirin with certain foods may increase the risk of stomach bleeding and ulcers. Foods that are high in acidity, such as tomatoes, citrus fruits, and spicy foods, can irritate the stomach lining and increase the stomach's sensitivity to aspirin.

The adverse reactions related to Atorvastatin+ Aspirin can be categorized as follows:

Common:

• Upset stomach, nausea, or vomiting
• Diarrhea or constipation
• Headache
• Dizziness
• Muscle aches or weakness
• Myopathy
• Myalgia
• Rhabdomyolysis
• Changes in liver function tests
• Musculoskeletal pain,
• Muscle fatigue,
• Neck pain,
• Joint swelling
• Urticaria

Less common :

• Allergic reactions such as rash, hives, or swelling
• Tinnitus (ringing in the ears)
• Increased risk of bleeding or bruising
• Changes in blood sugar levels
• Sleep disturbances or insomnia
• Confusion or memory problems
• Changes in vision

Rare:

• Severe muscle damage or rhabdomyolysis (breakdown of muscle tissue)
• Liver failure or hepatitis
• Kidney failure or nephritis
• Pancreatitis (inflammation of the pancreas)
• Anemia or low platelet counts
• Neurological Disorder
• Stevens-Johnson syndrome (a rare, serious skin disorder)

The clinically relevant drug interactions of Atorvastatin+ Aspirin are briefly summarized here:

Methotrexate, used at 15mg/week or less: Salicylates may retard the elimination of methotrexate by decreasing the renal clearance of methotrexate, displacing methotrexate from protein binding sites, and thereby increasing its hematological toxicity.

Aspirin

Anticoagulants, thrombolytics / other inhibitors of platelet aggregation/hemostasis, e.g., warfarin, heparin: Caution is necessary when salicylates and anticoagulants, thrombolytics / other inhibitors of platelet aggregation/hemostasis prescribed concurrently, as salicylates can depress the concentration of prothrombin in the plasma, leading to an increased risk of bleeding. Oral hypoglycemics, e.g., insulin, sulfonylureas: Large doses of salicylates have a hypoglycemic action and may enhance the effect of oral hypoglycemic agents. People with diabetes receiving concurrent salicylate and hypoglycemic therapy should be monitored closely: reduction of the sulfonylurea

hypoglycemic drug dosage may be necessary.

Diuretics: Diuretics, in combination with acetylsalicylic acid at higher doses, lead to decreased glomerular filtration via decreased prostaglandin synthesis. As a result, sodium excretion might be reduced by salicylate administration.

Uricosuric Agents: Salicylates in large doses are uricosuric agents; smaller amounts may

depress uric acid clearance and thus decrease the uricosuric effects of other drugs.

Valproic Acid: Salicylates may alter valproic acid (VPA) metabolism and may displace VPA from protein binding sites, possibly intensifying the effects of VPA. Caution is recommended when VPA is administered concomitantly with salicylates. Glucocorticoids (systemic), except hydrocortisone used as replacement therapy in

Addison’s disease: Decreased blood salicylate levels during corticosteroid treatment and risk of salicylate overdose after this treatment is stopped via increased elimination of salicylates by corticosteroids. Concurrent use may increase the incidence of gastrointestinal bleeding and ulceration.

Angiotensin Converting Enzyme (ACE) Inhibitors: ACE inhibitors' hyponatremic and hypotensive effects might be diminished by the concomitant administration of Aspirin due to its indirect impact on the renin-angiotensin conversion pathway (i.e., inhibition of vasodilatory prostaglandins leading to decreased glomerular filtration). The potential interaction may be related to the dose of Aspirin (3g/day or more).

Selective Serotonin Reuptake Inhibitors (SSRIs): Increased risk of upper gastrointestinal bleeding due to synergistic effects.

Digoxin: Plasma concentrations of digoxin are increased due to decreased renal Excretion.

NSAIDS: Aspirin and other NSAIDs: Using other NSAIDs with salicylates may increase the risk of ulcers and gastrointestinal bleeding due to a synergistic effect.

Ibuprofen: Ibuprofen can interfere with the anti-platelet effect of low-dose Aspirin acid (81-325 mg per day). Long-term daily use of ibuprofen may render Aspirin less effective when used for cardioprotection and stroke prevention. To minimize this interaction, regular users of ibuprofen and low-dose, immediate-release Aspirin should take the ibuprofen at least one hour after and 11 hours before the daily Aspirin dose. Delayed-release (e.g., enteric-coated) Aspirin is not recommended when using ibuprofen regularly.

Naproxen: Naproxen may attenuate the irreversible platelet inhibition induced by acetylsalicylic acid. Clinical pharmacodynamics data suggest that concurrent (same-day) naproxen sodium dosage for more than one day consecutively inhibits the effect of low-dose acetylsalicylic acid on platelet activity. This inhibition might persist for several days after stopping naproxen sodium therapy. The clinical relevance of this interaction has yet to be discovered. Treatment with naproxen in patients with increased cardiovascular risk may limit the cardiovascular protection of acetylsalicylic acid. Healthcare professionals should advise consumers and patients regarding the appropriate concomitant use of NSAIDs (i.e., ibuprofen or naproxen) and Aspirin.

Atorvastatin

Potent Inhibitors of CYP 3A4: Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of Atorvastatin with potent inhibitors of CYP 3A4 could lead to increase in plasma concentrations of atorvastatin. The extent of interaction a

s well as potentiation of effects depends on the variability of effect on CYP 3A4

Clarithromycin: Atorvastatin AUC had significantly increased with a concomitant administration of Atorvastatin 80 mg with clarithromycin (500 mg two times a day) compared to that of Atorvastatin alone. Therefore, in patients taking clarithromycin, should cautiously be use when the Atorvastatin dose exceeds 20 mg.

Combination of Protease Inhibitors: Atorvastatin AUC was found to be significantly increased with a concomitant administration of Atorvastatin 40 mg along with ritonavir plus saquinavir (400 mg twice daily) or Atorvastatin 20 mg along with lopinavir plus ritonavir (400 mg + 100 mg two times a day) compared to that of drug Atorvastatin alone. Therefore, in patients who are taking HIV protease inhibitors, should cautiously use when the Atorvastatin dose exceeds 20 mg.

Itraconazole: Atorvastatin AUC was found to be significantly increase with a concomitant administration of the drug Atorvastatin 40 mg as well as itraconazole 200 mg. Therefore, it is advised that , in patients taking itraconazole, should cautiously use Atorvastatin when the dose exceeds 20 mg.

Grapefruit Juice: Grapefruit might contains one or more component that inhibit enzyme CYP 3A4 and could increase plasma concentrations of drug atorvastatin, especially with aN excessive grapefruit juice consumption (>1.2 liters per day).

Cyclosporine: Atorvastatin as well as atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 such as cyclosporine) could increase the bioavailability of drug atorvastatin. Atorvastatin AUC was significantly increased with a concomitant administration of drug Atorvastatin 10 mg along with cyclosporine 5.2 mg/kg/day compared to Atorvastatin alone. In cases where the co-administration of Atorvastatin with cyclosporine is necessary, Atorvastatin should be at most 10 mg.

Rifampin or other Inducers of the Cytochrome P450 3A4: Concomitant administration of the drug Atorvastatin with inducers such as cytochrome P450 3A4 (e.g., efavirenz, rifampin) could lead to variable reductions in the plasma concentrations of drug atorvastatin. Due to the dual interaction mechanism of drug rifampin, simultaneous co-administration of Atorvastatin along with rifampin is recommended, as a delayed administration of Atorvastatin after administration of rifampin had lead to a significant reduction in atorvastatin plasma concentrations.

Digoxin: When multiple doses of Atorvastatin+ digoxin were co-administered, steady-state plasma digoxin concentrations was found to be increased by approximately 20%. Patients taking digoxin should be monitored regularly.

Oral Contraceptives: Co-administration of the Atorvastatin and an oral contraceptive increased the AUC values for the norethindrone as well as ethinyl estradiol. These reports should be considered when selecting an oral contraceptive for a woman taking Atorvastatin.

Warfarin: Atorvastatin is found to have no clinically significant effect on the prothrombin time when administered to patients who were receiving chronic warfarin treatment.

The common side effects of Atorvastatin+ Aspirin include the following:

• Headache
• Rash
• Gastrointestinal ulcerations
• Abdominal pain
• Upset stomach
• Heartburn
• Drowsiness
• Cramping
• Nausea
• Gastritis
• Bleeding
• Muscle weakness
• Ankle swelling (edema)
• Dark urine
• Slow heart rate

• Pregnancy

Pregnancy Category B

Acetylsalicylic acid inhibits prostaglandin synthesis. Inhibition of prostaglandin synthesis might adversely affect the pregnancy or embryo/fetal development. Data from epidemiological studies raise concerns about an increased risk of miscarriage and malformations after using a prostaglandin synthesis inhibitor in early pregnancy. The trouble is believed to grow with the dose and duration of therapy. Available data do not support any association between the intake of acetylsalicylic acid and an increased risk of miscarriage. For acetylsalicylic acid, the available epidemiological data regarding malformation are not consistent, but an increased risk of gastroschisis could not be excluded. A prospective study with exposure in early pregnancy (1st-4th month) of about 14,800 mother-child pairs has not yielded any association with an elevated rate of malformations.

Pregnancy Category X

Atorvastatin is found to be contraindicated in women who are or might become pregnant. Serum cholesterol as well as triglycerides levels increase during the normal pregnancy. Statins do not offer any benefit during pregnancy as cholesterol and cholesterol derivatives are needed for the normal fetal development. Atherosclerosis is said to be a chronic process, and discontinuing lipid-lowering medications during pregnancy should have little impact on the long-term outcomes of a primary hypercholesterolemia therapy.

There are found to be no adequate and well-controlled studies of atorvastatin use during pregnancy. However there has been rare reports of congenital anomalies following an intrauterine exposure to statins. The Drug Atorvastatin should only be used only if the potential benefits outweighs the potential risks associated with the drug.

• Nursing Mothers

Aspirin and its metabolites pass into breast milk in small quantities. Since no adverse effects on the infants have been observed after occasional use, interruption of breastfeeding is usually unnecessary. However, on regular use or intake of high doses, breastfeeding should be discontinued early.

It is unknown whether the drug atorvastatin is excreted in the human milk. It had been observed that nursing rat pups had plasma and liver drug levels of the 50% and 40%, respectively, of that in their mother's milk. Animal breast milk drug levels might not accurately reflect human breast milk levels.

• Pediatric Use

Dosage of children aged less than 12 years have not been established.

A possible association between Reye's syndrome and the use of salicylates has been suggested but has not been established. Reye's syndrome has also occurred in many patients not exposed to salicylates. Without consulting a physician, aspirin should not be used in children and teenagers for viral infections with or without fever. In certain viral illnesses, especially influenza A, influenza B, and varicella, there is a risk of Reye's syndrome, a sporadic but possibly life-threatening condition requiring immediate medical action. The risk may be increased when Aspirin is given concomitantly. However, no causal relationship has been proven. Should persistent vomiting occur with such diseases, this may be a sign of Reye's syndrome.

Safety as well as efficacy in patients aged 10-17 years with heterozygous familial hypercholesterolemia have been evaluated in a controlled clinical trial of six months duration in adolescent boys as well as postmenarchal girls. Patients treated with atorvastatin had an adverse experience profile similar to those treated with a placebo. The most common negative experiences observed in both of the groups, regardless of the causality assessment, were found to be infections. Doses greater than 20 mg had not been studied in this patient population. This limited controlled study had no significant effect on the growth or sexual maturation in boys or menstrual cycle length in girls. Adolescent females should be counseled and advised on the appropriate contraceptive methods while on atorvastatin therapy. Atorvastatin had not been studied in controlled clinical trials involving pre-pubertal patients or patients younger than ten.

Clinical efficacy with doses of Atorvastatin up to 80 mg/day for one year had been evaluated in an uncontrolled study of patients with a homozygous FH, which including eight pediatric patients.

• Geriatric Use

In elderly populations, the risk of cardiovascular disease is higher, and Aspirin's potential benefits may be greater than in younger people. However, an increased risk of bleeding has also been observed in the elderly age group.

Limited data are available about over dosage in human subjects with Atorvastatin+ Aspirin. There is found to be no specific treatment for atorvastatin over dosage. In the event of an overdose, it is advised that the patient should be treated symptomatically as well as supportive measures instituted as required. Due to extensive drug binding of Atorvastatin to plasma proteins, hemodialysis is not expected to enhance atorvastatin clearance significantly.

A toxic dose of Aspirin is found to be 200 to 300 mg/kg (milligrams per kilogram of body weight), and the ingestion of 500 mg/kg is found to be potentially lethal. In a chronic overdose, a lower level of Aspirin in the body results in serious illness, and much lower levels can affect children.

If treatment is delayed or the overdose is found to be large enough, symptoms will continue to get worse. Breathing becomes extremely fast or may stop. Seizures, high fevers, or death may occur.

The earliest symptoms of acute aspirin poisoning might include ear ringing (tinnitus) and impaired hearing. More clinically significant signs and symptoms might include rapid breathing i.e. hyperventilation, vomiting, dehydration, fever, double vision, and faintness.

Treatment

Doctors might use gastric lavage or pump out the stomach contents to try to prevent the further absorption of the drug Aspirin into the body. The dialysis method is also sometimes used to decrease the amount of salicylate in the body. Activated charcoal is used to prevent more absorption; the doctor might give activated charcoal to absorb the salicylate from the stomach. Dehydration occurs early in aspirin poisoning. To rehydrate, the doctor will start an Intravenous infusion to provide fluids.

Specifically, in Alkaline Diuresis, sodium bicarbonate is given intravenously to make the blood and urine more alkaline. This encourages the kidneys to capture more salicylate that can leave the body through the urinary route. Sometimes, other compounds, for example, potassium, also have to be given to help with this process.

Pharmacodynamic

Atorvastatin, along with some of its metabolites, are found to be pharmacologically active in humans. The liver is said to be the primary site of action and the leading site of the cholesterol synthesis as well as LDL clearance. Drug dosage, rather than a systemic drug concentration, correlates better with the LDL-C reduction.

Acetylsalicylic acid is said to disrupt the production of the prostaglandins throughout the body by targeting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Prostaglandins are said to be potent, irritating substances that have been shown to cause headaches and pain upon injection into human subjects. Prostaglandins increase the sensitivity of the pain receptors and the substances such as histamine and bradykinin. By disrupting the production and preventing the release of prostaglandins in inflammation, this drug may stop its action at the pain receptors, preventing symptoms of the pain. Acetylsalicylic acid is called an antipyretic agent because of its ability to interfere with the production of brain prostaglandin E1. Prostaglandin E1 is reported to be a potent fever-inducing agent.

• Effects on platelet aggregation

The inhibition of platelet aggregation by Aspirin occurs because it interferes with the thromboxane A2 in platelets caused by COX-1 inhibition. Thromboxane A2 is a vital lipid responsible for platelet aggregation, which could lead to clot formation and future risk of heart attack or stroke Label.

• A note on cancer prevention

Aspirin is being studied to determine its effect on preventing various malignancies. In general, acetylsalicylic acid interferes with different cancer signaling pathways, which sometimes induces or upregulates tumor suppressor genes. The results of multiple studies suggest that there are beneficial effects of long-term use of Aspirin in preventing several types of cancer, including stomach, colorectal, pancreatic, and liver cancers. (Research is ongoing)

Pharmacokinetics

• Absorption

Absorption of Aspirin is generally rapid and complete following oral administration. Still, absorption might vary depending on the dosage form, route, and other factors, including but not limited to the tablet dissolution rate, gastric emptying time, gastric contents, and gastric pH Label.

Detailed absorption information

When ingested orally, acetylsalicylic acid is found to be rapidly absorbed in both the stomach as well as the proximal small intestine. The non-ionized acetylsalicylic acid is found to pass through the stomach lining by passive diffusion. The ideal absorption of salicylate in the stomach occurs in the pH range of about 2.15 - 4.10. Intestinal absorption of acetylsalicylic acid is found to appear at a much faster rate. At least half of the ingested dose is said to be hydrolyzed to salicylic acid in the first-hour post-ingestion by the esterases found in the gastrointestinal tract. Peak plasma salicylate concentration occurs between 1-2 hours post-administration Label.

Atorvastatin is found to be rapidly absorbed following the oral administration; maximum plasma concentrations occur within 1 to 2 hours. The extent of absorption is said to increase in proportion to that of the Atorvastatin dose. The absolute bioavailability of atorvastatin is found to be approximately 14%, and the systemic availability of HMG-CoA reductase inhibitory activity is around 30%. The low systemic availability is attributed to the presystemic clearance in gastrointestinal mucosa and/or the hepatic first-pass metabolism. Although food decreases the rate as well as the extent of drug absorption by approximately 25% and 9%, respectively, when assessed by Cmax and AUC, LDL-C reduction is found to be similar whether Atorvastatin administered before or after meals. Plasma Atorvastatin concentrations are lower (approximately 30%n for Cmax and AUC) following an evening drug administration compared with that of morning.

• Distribution

Aspirin is distributed to the body tissues shortly after administration, and Aspirin crosses the placenta. The plasma contains high salicylate levels and tissues such as peritoneal, spinal, and synovial fluids, saliva, and milk. After the dosing, the liver, heart, kidney, and lungs are also rich in salicylate concentration. Low concentrations of salicylate are usually quiet, and the minimal concentrations are found in bile, feces, and sweat.

The mean volume of distribution of the drug Atorvastatin is approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins, and a blood/plasma ratio of about 0.25 indicates poor drug penetration into the red blood cells. Based on animal data in rats, Atorvastatin is likely to be secreted in human milk.

• Metabolism

Acetylsalicylic acid is hydrolyzed in the plasma into salicylic acid. Plasma concentrations of Aspirin following administration of the extended-release form are mostly undetectable up to 4-8 hours after ingestion of a single dose of Aspirin. Salicylic acid was measured at twenty-four hours following a single amount of extended-release acetylsalicylic acid.

Salicylate is found to be mainly metabolized in the liver, although other tissues might also be involved in this process. Acetylsalicylic acid's primary metabolites are salicylic acid, ether or phenolic glucuronide, and ester or acyl glucuronide. A small portion is found to be converted to gentisic acid and other hydroxybenzoic acids.

Atorvastatin is found to be extensively metabolized to ortho- and para-hydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by the ortho- and para-hydroxylated metabolites is equivalent to that of the drug Atorvastatin. Approximately 70% of circulating inhibitory activity for of the HMG-CoA reductase is attributed to its active metabolites. In vitro studies suggest that the importance of Atorvastatin metabolism by the cytochrome P450 3A4, consistent with an increased plasma concentrations of Atorvastatin in

humans followed by co-administration with erythromycin, which is a known inhibitor of this isozyme. In animals, the ortho-hydroxy metabolite is said to undergoes further glucuronidation.

• Excretion

The Excretion of salicylates occurs mainly through the kidney, through the processes of glomerular filtration and tubular Excretion, in the form of free salicyluric acid, salicylic acid, and, additionally, phenolic and acyl glucuronides.

Salicylate is said to be found in the urine soon after administration, and the entire dose of Aspirin takes about 48 hours to be eliminated. The salicylate rate is often variable, ranging from 10% to 85% in the urine, and it heavily depends on urinary pH. Acidic urine generally aids in the reabsorption of salicylate by the renal tubules, while the alkaline urine increases Excretion.

After the administration of a typical 325 mg dose of Aspirin, the elimination of Aspirin is found to follow first-order kinetics linearly. At high concentrations, the elimination half-life increases.

Atorvastatin along with its metabolites are eliminated primarily in the bile following hepatic and/or extra-hepatic metabolism . However, Atorvastatin does not appear to undergo enterohepatic recirculation. The mean plasma elimination half-life of Atorvastatin in humans is approximately 14 hours. Still, the half-life of the inhibitory activity for HMG-CoA reductase is about 20 to 30 hours due to the contribution of active metabolites. After oral administration, less than 2% of a dose of Atorvastatin is recovered in urine.

• Therapeutic Benefits of Atorvastatin+ Aspirin Combination

The combination of Atorvastatin+Aspirin is often used for the prevention and treatment of cardiovascular disease, including:

Lowering cholesterol levels: Atorvastatin is a statin medication that works by inhibiting the production of cholesterol in the liver. By lowering cholesterol levels, it can reduce the risk of developing heart disease.

Reducing inflammation: Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) that can help reduce inflammation in the body, which is associated with the development of cardiovascular disease.

Preventing blood clots: Aspirin is also a blood thinner that can help prevent the formation of blood clots, which can cause heart attacks and strokes. By reducing blood clot formation, it can help prevent these events.

Reducing the risk of heart attacks: The combination of atorvastatin and aspirin can help reduce the risk of heart attacks in people with a history of cardiovascular disease or those at high risk for developing it.

Reducing the risk of stroke: The combination of atorvastatin and aspirin can also help reduce the risk of stroke, particularly in people with a history of transient ischemic attacks (TIAs) or previous strokes.

Treating peripheral vascular disease: The combination of atorvastatin and aspirin can be used to treat peripheral vascular disease, which is caused by narrowing or blockage of arteries that supply blood to the legs and arms.

Overall, the combination of atorvastatin and aspirin can provide a range of therapeutic benefits for people with cardiovascular disease or those at high risk for developing it. However, it's important to note that these medications may not be suitable for everyone and may have potential adverse effects or drug interactions. Therefore, it's essential to consult with a healthcare provider before starting or changing any medication regimen.

1. Kazuo Nakamura 1, Hiroshi Masuda, Hiroko Kariyazono, Junko Arima, Yoshifumi Iguro, Katsushi Yamada, Ryuzo Sakata.Effects of atorvastatin and Aspirin combined therapy on inflammatory responses in patients undergoing coronary artery bypass grafting.PMID: 17300951 DOI: 10.1016/j.cyto.2006.11.001
2. Nirmal Ghati, Sushma Bhatnagar, Manjit Mahendran, Abhishek Thakur, Kshitij Prasad, Devesh Kumar, Tanima Dwivedi, Kalaivani Mani, Pawan Tiwari, Ritu Gupta, Anant Mohan, Anita Saxena, Randeep Guleria & Siddharthan Deept.Statin and Aspirin as adjuvant therapy in hospitalized patients with SARS-CoV-2 infection: a randomized clinical trial (RESIST trial).BMC Infectious Diseases volume 22, Article number: 606 (2022)
3. Pignatelli P, Carnevale R, Cangemi R, Loffredo L, Sanguigni V, Stefanutti C, Basili S, Violi F. Atorvastatin inhibits gp91phox circulating levels in patients with hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):360-7. doi: 10.1161/ATVBAHA.109.198622. Epub 2009 Dec 3. Erratum In: Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):e20.
4. Montgomery S, Miedema MD, Dodson JAAspirin and statin therapy for primary prevention of cardiovascular disease in older adultsHeart 2022;108:1090-1097.
5. Hammill BG, Harris DF, Masoudi FA, Antman EM, Davidson DR, Edgley K, Merritt JG, Brown LS, Zemon DN, McCormick TE 3rd, Alikhaani JD, et al. Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease. N Engl J Med. 2021 May 27;384(21):1981-1990. doi: 10.1056/NEJMoa2102137. Epub 2021 May 15.
6. Ford DE, Nallamothu BK, Fintel DJ, Zhou L, et al. Rationale and Design of the Aspirin Dosing-A Patient-Centric Trial Assessing Benefits as well as Long-term Effectiveness (ADAPTABLE) Trial. JAMA Cardiol. 2020 May 1;5(5):598-607. doi: 10.1001/jamacardio.2020.0116.
7. a Mairead MacKenzie,b Lindy Berkman,c Sudeep Gupta,d C S Pramesh,e Duncan Gilbert, a,f Howard Kynaston, et al. ADD-ASPIRIN: A phase III, double-blind, placebo-controlled, randomized trial assessing the effects of Aspirin on disease recurrence and survival after primary therapy in common non-metastatic solid tumors.Contemp Clin Trials. 2016 Nov; 51: 56–64. doi: 10.1016/j.cct.2016.10.004

1. https://www.lybrate.com/medicine/atorlip-asp-10-mg-capsule
2. https://ciplamed-library.com/content/atorlip-asp-capsules#:~:text=ATORLIP ASP (atorvastatin and aspirin,stroke or peripheral vascular disease.
3. https://www.healthgrades.com/right-care/cholesterol/what-foods-to-avoid-while-taking-atorvastatin
4. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020702s056lbl.pdf
5. https://www.mims.com/philippines/drug/info/atorvastatin?mtype=generic
6. https://www.mims.com/indonesia/drug/info/aspirin?mtype=generic
7. https://www.bayer.com/sites/default/files/2020-11/aspirin-pm-en.pdf
8. https://reference.medscape.com/drug/aspirin-rectal-999329
9. https://www.drugs.com/dosage/aspirin.html
10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907695/
11. https://www.drugs.com/sfx/aspirin-side-effects.html
12. https://www.webmd.com/drugs/2/drug-1082-3/aspirin-oral/aspirin-oral/details/list-interaction-food
13. https://reference.medscape.com/drug/bayer-vazalore-aspirin-343279
14. https://www.mayoclinic.org/drugs-supplements/aspirin-oral-route/side-effects/drg-20152665?p=1
15. https://www.rxlist.com/aspirin-side-effects-drug-center.htm
16. https://pdf.hres.ca/dpd_pm/00000653.PDF
17. https://www.nursetogether.com/aspirin-nursing-considerations/#:~:text=Precautions and contraindications: Do not,of pregnancy or when breastfeeding.
18. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=28c48336-c238-0141-e054-00144ff8d46c
19. https://www.pdr.net/drug-summary/Bayer-Low-Dose-Aspirin-Regimen-aspirin-3799
20. https://www.aspirin.ca/en/
21. https://www.medicines.org.uk/emc/files/pil.8627.pdf
22. https://products.mhra.gov.uk/search/?search=aspirin&page=1
23. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203697Orig1s000lbl.pdf
24. https://go.drugbank.com/drugs/DB00945
25. https://go.drugbank.com/drugs/DB01076
26. https://pdf.hres.ca/dpd_pm/00056092.PDF
27. https://www.drugs.com/drug-interactions/aspirin-low-strength-with-atorvastatin-243-3197-276-0.html