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Amlodipine Experience

Amlodipine is well tolerated. In placebo controlled clinical trials involving patients with hypertension or angina, the most commonly observed side effects were:

Autonomic Nervous System: flushing

Body As A Whole: fatigue

Cardiovascular, General: edema

Central & Peripheral Nervous system: dizziness, headache

Gastrointestinal: abdominal pain, nausea

Heart Rate/Rhythm: palpitations

Psychiatric: somnolence

In these clinical trials no pattern of clinically significant laboratory test abnormalities related to amlodipine has been observed. In post-marketing experience, the following additional undesirable effects have been reported with amlodipine:

Autonomic Nervous: dry mouth, increased sweating, Body As A Whole: asthenia, back pain, malaise, pain, weight increase/decrease, Cardiovascular, General: hypotension, syncope, Central & Peripheral Nervous: hypertonia, hypoesthesia/paresthesia, peripheral neuropathy, tremor, Endocrine: gynecomastia, Gastrointestinal: altered bowel habits, dyspepsia (including gastritis), gingival hyperplasia, pancreatitis, vomiting, Metabolic/Nutritional: hyperglycemia, Musculoskeletal: arthralgia, muscle cramps, myalgia, Platelet/Bleeding/Clotting: purpura, thrombocytopenia, Psychiatric: impotence, insomnia, mood changes, Respiratory: coughing, dyspnea, rhinitis, Skin/Appendages: alopecia, skin discoloration, urticaria, Special senses: taste perversion, tinnitus, Urinary: increased urinary frequency, micturition disorder, nocturia, Vascular (Extracardiac): vasculitis, Vision: visual disturbances, White Blood Cell/R.E.S.: leucopenia, Hepatobiliary: hepatitis, jaundice and hepatic enzyme elevations have also been reported very infrequently (mostly consistent with cholestasis). Some cases severe enough to require hospitalization have been reported in association with use of amlodipine. In many instances, causal association is uncertain, and Rarely: allergic reaction including pruritus, rash, angioedema, and erythema multiforme. As with other calcium channel blockers the following adverse events have been rarely reported and cannot be distinguished from the natural history of the underlying disease: myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atria) fibrillation) and chest pain.

Atorvastatin Experience

Atorvastatin is generally well-tolerated. Adverse reactions have usually been mild and transient. Less than 2% of patients were discontinued from clinical trials due to side effects attributed to atorvastatin. The most frequent (≥1%) adverse effects associated with atorvastatin therapy, in patients participating in controlled clinical studies were:

Psychiatric Disorders: insomnia

Nervous System Disorders: headache

Gastrointestinal Disorders: nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence

Musculoskeletal and Connective Tissue Disorders: myalgia

General Disorders and Administration Site Conditions: asthenia

The following additional adverse effects have been reported in atorvastatin clinical trials:

Metabolism and Nutrition Disorders: hypoglycemia, hyperglycemia, anorexia

Nervous System Disorders: peripheral neuropathy, paresthesia

Gastrointestinal Disorders: pancreatitis, vomiting

Hepatobiliary Disorders: hepatitis, cholestatic jaundice

Skin and Subcutaneous Tissue Disorders: alopecia, pruritus, rash

Musculoskeletal and Connective Tissue Disorders: myopathy, myositis, muscle cramps

Reproductive System and Breast Disorders: impotence

Not all effects listed above have been causally associated with atorvastatin therapy. In post-marketing experience, the following additional undesirable effects have been reported with atorvastatin:

Blood and Lymphatic System Disorders: thrombocytopenia, Immune System Disorders: allergic reactions (including anaphylaxis), Metabolism and Nutrition Disorders: weight gain, Nervous System Disorders: hypoesthesia, amnesia, dizziness, Ear and Labyrinth Disorders: tinnitus, Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, bullous rashes, urticaria, Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, arthralgia, back pain, General Disorders and Administration Site Conditions: chest pain, peripheral edema, malaise, fatigue.

4.9 Overdosage

There is no information on overdosage with amlodipine/atorvastatin in humans. Due to amlodipine's and atorvastatin's extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance amlodipine/atorvastatin clearance (see also section 5.2 Pharmacokinetic Properties - Renal Insufficiency). Additional data on amlodipine ingestion, suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine 10 mg has been shown to significantly decrease amlodipine absorption. Gastric lavage may be worthwhile in some cases. Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Additional data on atorvastatin ingestion, suggest that there is no specific treatment for atorvastatin overdosage. Should an overdose occur, the patient should be treated symptomatically and supportive measures instituted, as required.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

Amlodipine/Atorvastatin Pharmacodynamics

The amlodipine besylate component of amlodipine/atorvastatin is chemically described as (R.S.)3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4(2-chlorophenyl)-1, 4-dihydro-6-methyl-3,  5-pyridinedicarboxylate benzenesulphonate. Its empirical formula is C₂₀H₂₅CIN₂O₅•C₆H₆O₃S. The atorvastatin calcium component of amlodipine/atorvastatin is chemically described as [R-(R*,R*)]-2(4-fluorophenyl)-[β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is (C₃₃H₃₄FN₂O₅)₂Ca•3H₂O. The structural formulae are shown below:

Mechanism of Amlodipine/Atorvastatin

Amlodipine/atorvastatin combines two mechanisms of action: the dihydropyridine calcium antagonist (calcium ion antagonist or slow channel bin ken) action of amlodipine and the HMG-Cob reductase inhibition of atorvastatin. The amlodipine component of amlodipine/atorvastatin inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of amlodipine/atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate limiting enzyme that converts 3 hydroxy-3 methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

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