Atorvastatin (Dosing, Interaction, Side Effect, Administration, Etc..)

Dosing:

Adult Dose

:
Common Information:
Dosage range is 10 to 80 mg once daily; following

dose

initiation or titration; lipid level assessment should be done within 2 to 4 weeks

Disorder of cardiovascular system; in patients with multiple risk factors for coronary heart disease; Prophylaxis:
Initial; 10 to 20 mg ORALLY once daily
Initial 40 mg ORALLY once daily if reductions of greater than 45% in LDL-C are needed

Disorder of cardiovascular system; in patients with multiple risk factors for coronary heart disease; Prophylaxis - Type 2 diabetes mellitus:
Initial; 10 to 20 mg ORALLY once daily
Initial 40 mg ORALLY once daily if reductions of greater than 45% in LDL-C are needed

Disorder of cardiovascular system; Secondary; Prophylaxis:
Initial; 10 to 20 mg ORALLY once daily
Initially 40 mg ORALLY once daily if reductions of greater than 45% in LDL-C are needed

Familial hypercholesterolemia - homozygous; Adjunct:
10 to 80 mg ORALLY once daily with other lipid-lowering therapy

Familial type 3 hyperlipoproteinemia:
Initial; 10 to 20 mg ORALLY once daily; dosage range is 10 to 80 mg once daily; OR initial 40 mg ORALLY once daily if reductions of greater than 45% in LDL-C are needed.

Generalized atherosclerosis:
Arthrosclerosis regression:
80 mg orally daily with or without ezetimibe 10 mg orally daily (off-label dosage).

Hypercholesterolemia; primary (heterozygous familial and non-familial) and mixed dyslipidemia (Fredrickson types IIa and IIb):
Initial; 10 to 20 mg ORALLY once daily
Initial; 40 mg ORALLY once daily if reductions greater than 45% in LDL-C are needed; dosage range is 10 to 80 mg once daily

Hypertriglyceridemia:
Initial:
10 to 20 mg ORALLY once daily
Initial 40 mg ORALLY once daily of reductions of greater than 45% in LDL-C are needed.

Pediatric Dose

:
General Dosage Information:
Safety and efficacy not been established in pediatric patients younger than 10 years of age for the treatment of heterozygous familial hypercholesterolemia.

Hypercholesterolemia; primary (heterozygous familial and non-familial) and mixed dyslipidemia (Fredrickson types IIa and IIb):
Age 10 to 17 years:
initially 10 mg ORALLY daily; adjustments at intervals of 4-weeks or greater; up to Maximum 20 mg ORALLY daily; following

dose initiation

or titration; lipid level assessment should be done within 2 to 4 weeks
Age 6 to 10 years:
5 to 10 mg ORALLY daily has been

used in

one open-label; uncontrolled study.

Indications:
FDA-LABELED INDICATIONS:
Disorder of cardiovascular system; in patients with multiple risk factors for coronary heart disease; Prophylaxis
Disorder of cardiovascular system; in patients with multiple risk factors for coronary heart disease; Prophylaxis - Type 2 diabetes mellitus
Disorder of cardiovascular system; Secondary; Prophylaxis
Familial hypercholesterolemia - homozygous; Adjunct
Familial type 3 hyperlipoproteinemia
Hypercholesterolemia; primary (heterozygous familial and non-familial) and mixed dyslipidemia (Fredrickson types IIa and IIb)
Hypertriglyceridemia

NON-FDA LABELED INDICATIONS:
Antiviral drug adverse reaction; Antiretroviral – Hyperlipidemia
Cardiovascular event risk; Perioperative; Prophylaxis - Percutaneous coronary intervention
Diabetic retinopathy; Adjunct
Disorder of cardiovascular system; Primary; Prophylaxis
Dyslipidemia – Transplantation
Generalized atherosclerosis
Heart failure; chronic
Radiographic contrast agent nephropathy; Prophylaxis
Restenotic lesion of coronary artery; Prophylaxis
Secondary hypercholesterolemia

Mechanism Of Action

Atorvastatin calcium

selectively and competitively inhibits HMG-CoA reductase; a rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate; a sterol and cholesterol precursor.

Adverse Effect
Common:
Gastrointestinal:
Diarrhea (up to 14.1%)

Musculoskeletal:
Arthralgia (up to 11.7%)
Myalgia (up to 8.4%)

Renal:
Urinary tract infectious disease (up to 8%)

Respiratory:
Nasopharyngitis (8.3%)

Other:
Pain; in extremity (up to 9.3%)

Serious:
Dermatologic:
Dermatomyositis

Hepatic:
Increased liver enzymes (0.2% to 2.3%)
Liver failure

Immunologic:
Autoimmune disease
Systemic lupus erythematosus

Musculoskeletal:
Disorder of muscle
Rhabdomyolysis
Rupture of tendon

Neurologic:
Hemorrhagic cerebral infarction (2.3%)

Contraindication:
Active liver disease
Hypersensitivity to

atorvastatin

or any component of the product
Nursing mothers
Unexplained persistent elevation of serum transaminases
Women who are pregnant or may become pregnant; may cause fetal harm

Interaction:
The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipidmodifying

doses

of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g. clarithromycin, HIV protease inhibitors, and itraconazole)

Strong Inhibitors of CYP 3A4:
Atorvastatin calcium is metabolized by cytochrome P450 3A4. Concomitant

administration of atorvastatin

calcium with strong inhibitors of CYP 3A4 can lead to increases in

plasma concentrations of atorvastatin

. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4.

Clarithromycin:

Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin calcium alone. Therefore, in patients taking clarithromycin, caution should be

used

when the

atorvastatin calcium dose

exceeds 20 mg

Combination of Protease Inhibitors:
Atorvastatin AUC was significantly increased with concomitant administration of

atorvastatin calcium 40 mg

with ritonavir plus saquinavir (400 mg twice daily) or

atorvastatin calcium 20 mg

with lopinavir plus ritonavir (400 mg + 100 mg twice daily) compared to that of atorvastatin calcium alone .Therefore, in patients taking HIV protease inhibitors, caution should be used when the

atorvastatin calcium dose

exceeds 20 mg

Itraconazole:
Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 40 mg and itraconazole 200 mg.Therefore, in patients taking itraconazole, caution should be used when the

atorvastatin calcium dose

exceeds 20 mg

Grapefruit Juice:
Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (>1.2 liters per day).

Cyclosporine:
Atorvastatin and atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g. cyclosporine) can increase the

bioavailability of atorvastatin

. Atorvastatin AUC was significantly increased with concomitant administration of

atorvastatin calcium 10 mg

and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin calcium alone In cases where co-administration of atorvastatin calcium with cyclosporine is necessary, the

dose of atorvastatin calcium

should not exceed 10 mg

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

atorvastatin plasma concentrations

.

Digoxin:
When multiple doses of atorvastatin calcium and digoxin were co-administered, steady state plasma digoxin concentrations increased by approximately 20%

Patients taking digoxin should be monitored appropriately.
Oral Contraceptives:
Co-administration of atorvastatin calcium and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol.These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin calcium.

Warfarin:
atorvastatin calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.

Phamacokinetics:
Absorption:
Time for Maximum Plasma Concentration (Tmax) Oral: 1 to 2 hours
Bioavailability; Oral:
Absolute (atorvastatin): 14%
HMG-CoA reductase inhibitory activity: 30%

Effect of food:
Decreases the rate and extent of absorption by approximately 25% and 9%; respectively

Distribution:
Plasma Protein binding: 98% or greater
Volume of Distributor (Vd): 381 L

Metabolism:
Hepatic: Extensively metabolized through hydroxylation and beta-oxidation; does not undergo enterohepatic recirculation
Ortho-and parahydroxylated derivatives: Active; equivalent HMG-CoA reductase inhibitory activity to atorvastatin
Substrate of CYP3A4

Excretion:
Bile: Primary
Renal: Less than 2%

Dialyzable:
Hemodialysis: No
Peritoneal dialysis: No

Elimination:
Normally: 14 hours
Elderly: 19 hours
Hemodialysis: 11.8 to 14.7 hours

HMG-CoA reductase inhibitory activity:
20 to 30 hours

Ortho-hydroxy-atorvastatin (o-OH-atorvastatin):
Healthy subjects:
(40 mg): 23.6 hours
(80 mg): 32.1 hours

Hemodialysis:
(40 mg): 22.3 hours
(80 mg): 19 hours

Precaution:
Concomitant Medical Conditions:
Temporarily withhold or discontinue therapy when conditions that predispose patients to rhabdomyolysis and renal failure (e.g..; sepsis; hypotension; trauma; major surgery; uncontrolled seizures; and severe metabolic; endocrine and electrolyte disorders) are present.

Concomitant Use:
Avoid

use of

cyclosporine; gemfibrozil; telaprevir; and tipranavir/ritonavir

Elderly:

Use

caution in patients 65 years or older due to increased risk of myopathy and rhabdomyolysis.

Endocrine and Metabolic:
Uncontrolled hypothyroidism increases risk of myopathy and rhabdomyolysis
Increased HbA1c and serum glucose levels have been reported.

Hepatic:
Liver failure; with some fatal cases; has been reported; interrupt treatment if serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs; do not restart therapy if cause not identified
History of liver disease increases risk of liver dysfunction
Increases in serum transaminase levels greater than 3 times the ULN have been reported; monitoring recommended and discontinuation may be required if increased levels persist
Heavy alcohol use increases risk of liver dysfunction.

Immunologic:
Immune-mediated necrotizing myopathy; an autoimmune myopathy; has been reported; discontinue immediately if myopathy diagnosed or suspected.

Musculoskeletal:
Markedly elevated creatine phosphokinase (CPK) levels have been reported; discontinuation may be warranted
Myopathy and rhabdomyolysis with acute renal failure have been reported; especially with

higher doses

or concomitant use of cyclosporine or strong CYP3A4 inhibitors; monitoring recommended and discontinue immediately if myopathy diagnosed or suspected.

Neurologic:
Hemorrhagic stroke has been reported with greater incidence following stroke or transient ischemic attack (TIA) without cardiovascular disease within preceding 6 months Use caution in patients with preexisting amyotrophic lateral sclerosis (ALS) as rate of ALS functional decline may increase.

Renal:
Use caution in patients with history of renal impairment due to increased risk of myopathy

Pregnancy Category:
X (FDA)
D (AUS)

Breast Feeding:
Infant Risk has been demonstrated.

Monitoring:

Lipid panel; 2 to 4 weeks after initiation of atorvastatin and 2 to 4 weeks after dosage adjustment Liver function; baseline and as clinically warranted
Serum creatine kinase; although such monitoring may not prevent myopathy; patients who warrant closer monitoring are those with renal insufficiency usually as a consequence of long-standing diabetes mellitus

How To Take Or Administration:
Oral:
May be taken at any time of the day with or without food

Dosage Form:
Oral

Tablet

:
10mg
20mg
40mg
80mg

Treatment:
MANAGEMENT MILD TO MODERATE TOXICITY:
Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with vomiting or diarrhea.

MANAGEMENT OF SEVERE TOXICITY:

Treatment is symptomatic and supportive. Severe toxicity is not expected after an

overdose

.

Toxicology:
ADULTS:
LOVASTATIN:

Single doses

up to 200 mg of lovastatin have been well tolerated without significant adverse effects in adult human volunteers.

Overdoses

of up to 5 to 6 grams of lovastatin have been well tolerated; no specific symptoms occurred.

SIMVASTATIN:
The maximum reported

dose of simvastatin

ingestion is 3.6 g with no specific symptoms; recovery was complete without sequelae.

CHILDREN:
FLUVASTATIN:
Two children (a 2-year-old and a 3-year-old) ingested up to 80 mg of fluvastatin. Vomiting was induced in the children; and no capsules were present in emesis; both children recovered without any adverse effects.

Patient Counselling Or Clinical Teaching:
Instruct patient to report signs-symptoms of myopathy or rhabdomyolysis (muscle pain; tenderness; weakness; fever)
Drug may cause diarrhea; UTIs; extremity pain; nasopharyngitis; arthralgia; dyspepsia; or nausea
Advise patient to immediately report signs-symptoms of myopathy including unexplained muscle pain; tenderness; or weakness especially when accompanied by fever or malaise; or if symptoms persist after discontinuation of drug
Counsel patients to report signs-symptoms of liver injury (jaundice; dark urine; upper abdominal discomfort; anorexia; fatigue)
Counsel patient to avoid excessive quantities of alcohol to reduce risk of hepatotoxicity Instruct patient not to eat large amounts of grapefruit or drink more than 1 L-day of grapefruit juice with this drug