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LIPITOR Atorvastatin Calcium Tablets Drug Interactions

Drug Interactions

Overview

Pharmacokinetic interaction studies conducted with drugs in healthy subjects may not detect the possibility of a potential drug interaction in some patients due to differences in underlying diseases and use of concomitant medications (see also WARNINGS AND PRECAUTIONS, Special Populations; Renal Insufficiency; Patients with Severe Hypercholesterolemia; Geriatric Use).

Concomitant Therapy with Other Lipid Metabolism Regulators: Based on post-marketing surveillance, gemfibrozil, fenofibrate, other fibrates, and lipid-modifying doses of niacin (nicotinic acid) may increase the risk of myopathy when given concomitantly with HMG-CoA reductase inhibitors (see WARNINGS, Muscle Effects; DRUG INTERACTIONS, Drug-Drug Interactions, Table 2 – Established or Potential Drug-Drug Interactions.

Cytochrome P-450-mediated Interactions: Atorvastatin is metabolized by the cytochrome P-450 isoenzyme, CYP 3A4. Interaction may occur when LIPITOR is administered with inhibitors of cytochrome P450 3A4 such as grapefruit juice, some macrolide antibiotics (i.e. erythromycin, clarithromycin), immunosuppressants (cyclosporine), azole antifungal agents (i.e. itraconazole, ketoconazole), transporter inhibitors, HIV/HCV protease inhibitors, letermovir or the antidepressant, nefazodone. Concomitant administration can lead to increased plasma concentrations of atorvastatin (see WARNINGS AND PRECAUTIONS, Pharmacokinetic Interactions, Muscle Effects, Renal Insufficiency and Endocrine Function; DRUG INTERACTIONS, Drug-Drug Interactions, Table 2 – Established or Potential Drug-Drug Interactions; REFERENCES).

Transporter Inhibitors: Atorvastatin is a substrate of the hepatic transporters (see section Pharmacokinetics).

Cyclosporine is an inhibitor of organic anion-transporting polypeptide 1B1 (OATP1B1), OATP1B3, multi-drug resistance protein 1 (MDR1), and breast cancer resistance protein (BCRP) as well as CYP3A4, thus it increases exposure to atorvastatin. Concomitant use is contraindicated (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS).

Glecaprevir and pibrentasvir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they increase exposure to atorvastatin. Co-administration of atorvastatin with products containing glecaprevir/pibrentasvir is contraindicated (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS).

Letermovir inhibits efflux transporters P-gp, BCRP, MRP2, OAT2 and hepatic transporter OATP1B1/1B3, thus it increases exposure to atorvastatin. Do not exceed 20 mg atorvastatin daily (see DRUG INTERACTIONS, Drug-Drug Interactions, Table 2 – Established or Potential Drug-Drug Interactions).

Elbasvir and grazoprevir are inhibitors of OATP1B1, OATP1B3, MDR1 and BCRP, thus they increase exposure to atorvastatin. Use with caution and lowest dose necessary.

Inducers of cytochrome P450 3A: Concomitant administration of atorvastatin with inducers of cytochrome P450 3A4 (eg efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin.

Drug-Drug Interactions

The drugs listed in this table are based on either drug interactions studies, case reports, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e. those identified as contraindicated). Interactions with other drugs have not been established.

Table 2- Established or Potential Drug-Drug Interactions

Proper name

Effect

Clinical comment

Bile Acid Sequestrants

Patients with mild to moderate HC: ↑ ­ LDL-C reduction ( -45%) when LIPITOR 10 mg and colestipol 20 g were coadministered than when either drug was administered alone (-35% for LIPITOR and -22% for colestipol).
 

Patients with severe HC:  LDL-C reduction was similar (-53%) when LIPITOR 40 mg and colestipol 20 g were coadministered when compared to that with LIPITOR 80 mg alone.  ↓ plasma atorvastatin concentration (ratio of 0.74) when LIPITOR 40 mg plus colestipol 20 g were coadministered compared with LIPITOR 40 mg alone.
 

However, the combination drug therapy was less effective in lowering TG than LIPITOR monotherapy in both types of hypercholesterolemic patients.

When LIPITOR is used concurrently with colestipol or any other resin, an interval of at least 2 hours should be maintained between the two drugs, since the absorption of LIPITOR may be impaired by the resin.

Fibric Acid Derivatives (Gemfibrozil, Fenofibrate, Bezafibrate) and Niacin (nicotinic acid)

↑ in the risk of myopathy during treatment with other drugs in this class, including atorvastatin.

Ratio of atorvastatin AUC: 1.35 and ratio of atorvastatin Cmax: 1.00 with atorvastatin 40 mg SD and Gemfibrozil 600 mg BID.

Ratio of atorvastatin AUC: 1.03 and ratio of atorvastatin Cmax: 1.02 with atorvastatin 40 mg SD and Fenobibrate 160 mg BID.

The concomitant therapy with LIPITOR and gemfibrozil should be avoided. The benefits and risks of combined therapy with LIPITOR and fenofibrate, bezafibrate and niacin should be carefully considered; lower starting and maintenance doses of atorvastatin should be considered (see WARNINGS AND

PRECAUTIONS, Muscle Effects and REFERENCES).

Coumarin Anticoagulants

No clinically significant effect on prothrombin time

LIPITOR had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy (see REFERENCES).

Digoxin

In healthy subjects, digoxin PK at steady-state were not significantly altered by coadministration of digoxin 0.25 mg and LIPITOR 10 mg daily.
 

↑ in digoxin steady-state concentrations (ratio of atorvastatin AUC:1.15 and ratio of atorvastatin Cmax: 1.20) following coadministration of digoxin 0.25 mg and LIPITOR 80 mg daily (see DETAILED PHARMACOLOGY,

Human Pharmacokinetics).

Patients taking digoxin should be monitored appropriately.

Antihypertensive
Agents:

Amlodipine




 


 

In healthy subjects, atorvastatin PK were not altered by the coadministration of LIPITOR 80 mg and amlodipine 10 mg at steady state. No apparent changes in BP or HR.
 

In healthy volunteers, co- administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no clinical significant change in the AUC or Cmax or Tmax of atorvastatin (ratio of atorvastatin AUC: 1.18 and ratio of atorvastatin Cmax: 0.91).

 

See DETAILED PHARMACOLOGY, Human Pharmacokinetics

 

 

Close monitoring is required.

QuinaprilSteady-state quinapril dosing of 80 mg QD did not significantly affect the PK profile of atorvastatin tablets 10 mg QD. 

Oral Contraceptives and Hormone Replacement Therapy

↑ plasma concentrations (AUC levels) of norethindone (ratio of atorvastatin AUC: 1.28 and ratio of atorvastatin Cmax: 1.23) and ethinyl estradiol (ratio of atorvastatin AUC: 1.19 and ratio of atorvastatin Cmax: 1.30) following coadministration of LIPITOR with an oral contraceptive containing 1 mg norethindone and 35 μg ethinyl estradiol.
 

In clinical studies, LIPITOR was used concomitantly with estrogen replacement therapy without evidence to date of clinically significant adverse interactions.

These increases should be considered when selecting an oral contraceptive.

Antacids

↓ in plasma concentrations of LIPITOR (ratio of atorvastatin AUC: 0.66 and ratio of atorvastatin Cmax: 0.67) following administration of aluminum and magnesium based antacids, such as Maalox® TC Suspension.

LDL-C reduction was not altered; TG- lowering effect of LIPITOR may be affected.

This decrease in exposure should be considered when prescribing atorvastatin with antacids.

Cimetidine

No effect on plasma concentrations (ratio of atorvastatin AUC: 1.00 and ratio of atorvastatin Cmax: 0.89) or LDL-C lowering efficacy of LIPITOR

↓ in TG-lowering effect of LIPITOR from 34% to 26%

This decrease in TG-lowering should be considered when prescribing atorvastatin with cimetidine.

Diltiazem Hydrochloride

Steady-state diltiazem increases the atorvastatin exposure, based on AUCLASTs, of a single dose of atorvastatin by approximately 50% (ratio of atorvastatin AUC: 1.51 and ratio of atorvastatin Cmax: 1.00)..

 

Antipyrine

LIPITOR had no effect on the PK of antipyrine

Ratio of antipyrine AUC: 1.03 and ratio of antipyrine Cmax: 0.89 with atorvastatin 80 mg QD and antipyrine 600 mg SD.

Antipyrine was used as a non- specific model for drugs metabolized by the microsomal hepatic enzyme system (cytochrome P-450 system).

Interactions with other drugs metabolized via the same cytochrome isozymes are not expected.

Macrolide Antibiotics (azithromycin, clarithromycin, erythromycin).

Clarithromycin and erythromycin are both CYP3A4 inhibitors

In healthy adults, coadministration of LIPITOR (10 mg QD) and azithromycin (500 mg QD) did not significantly alter the plasma concentrations of atorvastatin.
 

Ratio of atorvastatin AUC: 1.33 and ratio of atorvastatin Cmax: 1.38 with erythromycin (500 mg QID) when coadministered with atorvastatin (10 mg QD) Ratio of atorvastatin AUC: 1.82 and ratio of atorvastatin Cmax: 1.56 with clarithromycin (500 mg BID) when coadministered with atorvastatin (10 mg QD)

See WARNINGS AND
PRECAUTIONS, Muscle Effects; DETAILED PHARMACOLOGY, Human Pharmacokinetics ÷

Protease Inhibitors (nelfinavir mesylate, lopinavir/ritonavir, tipranavir/ritonavir, telaprevir, boceprevir, saquinavir/ritonavir, darunavir/ritonavir, fosamprenavir/ritonavir, fosamprenavir, glecaprevir/ pibrentasvirelbasvir/ grazoprevir, simeprevir)

↑ plasma concentrations of atorvastatin when atorvastatin 10 mg QD is coadministered with nelfinavir mesylate 1250 mg BID. Ratio of atorvastatin AUC: 1.74 and ratio of atorvastatin Cmax: 2.2.
 

Ratio of atorvastatin AUC: 5.9 and ratio of atorvastatin Cmax: 4.7 with atorvastatin 20mg QD and  Lopinavir 400mg / Ritonavir 100mg BID
 

Ratio of atorvastatin AUC: 9.4 and ratio of atorvastatin Cmax: 8.6 with atorvastatin 10mg SD and Tipranavir 500mg BID / Ritonavir 200mg           
BID, 7 days. Atorvastatin 10 mg SD had no effect on the PK of Tripanavir 500mg BID / Ritonavir 200 mg BID, 7 days
 

Ratio of atorvastatin AUC: 7.9 and ratio of atorvastatin Cmax: 10.6 with atorvastatin 20mg SD and Telaprevir 750mg q8h, 10 days
 

Ratio of atorvastatin AUC: 2.3 and ratio of atorvastatin Cmax: 2.7 with atorvastatin 40mg SD and Boceprevir 800 mg TID, 7 days
 

Ratio of atorvastatin AUC: 3.9 and ratio of atorvastatin Cmax: 4.3 with atorvastatin 40mg QD for 4 days and Ritonavir 400mg BID, 15 days / Saquinavir 400mg BID

 

Ratio of atorvastatin AUC: 3.4 and ratio of atorvastatin Cmax: 2.2 with atorvastatin 10mg QD for 4 days and Darunavir 300mg BID/Ritonavir 100 mg BID, 9 days
 

Ratio of atorvastatin AUC: 2.5 and ratio of atorvastatin Cmax: 2.8with atorvastatin 10mg QD for 4 days and Fosamprenavir 700 mg BID/ritonavir 100mg BID,14 days
 

Ratio of atorvastatin AUC: 2.3 and ratio of atorvastatin Cmax: 4.0 with atorvastatin 10mg QD for 4 days and Fosamprenavir 1400 mg BID, 14 days. Atorvastatin 10mg QD for 4 days had the following effect on the PK of Fosamprenavir 1400 mg BID, 14 days: Ratio of atorvastatin AUC: 0.73 and ratio of atorvstatin Cmax: 0.82


 

Atorvastatin 10mg QD, 4 days had no effect on the PK of Fosamprenavir 700mg BID/Ritonavir 100 mg BID, 14 days (ratio of atorvastatin AUC: 0.99 and ratio of atorvastatin Cmax: 0.94)





Ratio of atorvastatin AUC: 8.3 and ratio of atorvastatin Cmax: 22.0 with atorvastatin 10mg QD for 7 days and Glecaprevir 400mg QD/Pibrentasvir 120mg QD for 7 days

Ratio of atorvastatin AUC: 1.95 and ratio of atorvastatin Cmax: 4.3 with atorvastatin 10mg SD and Elbasvir 50mg QD/Grazoprevir 200mg QD for 13 days

Ratio of atorvastatin AUC: 2.12 and ratio of atorvastatin Cmax: 1.70 with atorvastatin 40mg SD and Simeprevir 150mg QD for 10 days

The dose of LIPITOR used in combination with nelfinavir should not exceed 40 mg daily.

 

The concomitant therapy with LIPITOR and the combination of lopinavir/ ritonavir should be used with caution and lowest LIPITOR dose necessary. (See WARNINGS AND PRECAUTIONS, Muscle Effect)

 

The concomitant therapy with LIPITOR and the combination of tipranavir/ritonavir or LIPITOR and telaprevir should be avoided.

 

The dose of LIPITOR should be restricted to 20 mg daily when used in combination with boceprevir, saquinavir/ritonavir, darunavir/ritonavir, fosamprenavir alone or fosamprenavir/ritonavir.

The dose of saquinavir/ ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study.
Therefore caution should be applied and the lowest dose necessary should be used










Concomitant therapy with LIPITOR and products containing glecaprevir/pibrentasvir is contraindicated (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS)








 

The concomitant therapy with LIPITOR and the combination of elbasvir/ grazoprevir should be used with appropriate clinical assessment and lowest atorvastatin dose necessary.

 

 

 

 

Cyclosporine

Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in an increase in exposure to atorvastatin (ratio of atorvastatin AUC: 8.7; ratio of atorvastatin Cmax: 10.7).

Concomitant use is contraindicated. (See CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS, Muscle
Effects; DETAILED
PHARMACOLOGY, Human
Pharmacokinetics);

Itraconazole

Concomitant administration of atorvastatin 20-40mg and itraconazole 200mg daily resulted in an increase in atorvastatin (ratio of atorvastatin AUC: 3.3 and ratio of atorvastatin Cmax: 1.20 for atorvastatin 40 mg only).

The dose of LIPITOR used in combination with itraconazole should not exceed 20 mg daily (see DETAILED PHARMACOLOGY, Human Pharmacokinetics);

Letermovir Concomitant administration of atorvastatin 20 mg SD and letermovir 480 mg daily resulted in an increase in exposure to atorvastatin (ratio of AUC 3.29 and ratio of atorvastatin Cmax: 2.17). The dose of LIPITOR used in combination with letermovir should not exceed 20 mg daily. Patients should be closely monitored for statin-associated adverse events such as myopathy or rhabdomyolysis (see WARNINGS AND PRECAUTIONS, Muscle Effects).

Efavirenz

Ratio of AUC: 0.59 and ratio of Cmax: 1.01 with atorvastatin 10mg and Efavirenz 600mg daily.

This decrease in exposure should be considered when prescribing atorvastatin with efavirenz.

Rifampin

Co-administration:

Ratios of AUC and Cmax are 1.12 and 2.9, respectively, for co-administered atorvastatin 40mg single dose and 7 day Rifampin 600mg daily vs. atorvastatin 40mg single dose alone.
 

Separate administration

Ratio of atorvastatin AUC: 0.20 and ratio of atorvastatin Cmax: 0.60 with atorvastatin 40mg single dose and  Rifampin 600mg daily (doses separated )

Due to the dual interaction mechanism of rifampin (cytochrome P450 3A4 induction and inhibition of hepatocyte uptake transporter OATP1B1), simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

Fusidic Acid

Although interaction studies with atorvastatin and fusidic acid have not been conducted, rhabdomyolysis resulting in fatal outcome has been reported in patients receiving a combination of statins, including atorvastatin, and fusidic acid. The mechanism of this interaction is not known.

The concurrent use of atorvastatin and fusidic acid should be avoided.
 

In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. Statin therapy may be re-introduced at least seven days after the last dose of fusidic acid.
 

Patients should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. (see WARNINGS AND PRECAUTIONS, Muscle Effects).

Colchicine

Although interaction studies with atorvastatin and colchicine have not been conducted, cases of myopathy have been reported with atorvastatin co-administrated with colchicine.

Caution should be exercised when prescribing atorvastatin with colchicine. (See WARNINGS AND PRECAUTIONS, Muscle Effects).

Legend: HC = hypercholesterolemia; TG = Triglycerides; PK = pharmacokinetics; BP = Blood Pressure; HR = Heart Rate; AUC = Area under the curve
Ratio of AUC and Cmax represent ratio treatments (co-administered drug plus atorvastatin versus atorvastatin alone).

Drug-Food Interactions

Coadministration of grapefruit juice has the potential to increase plasma concentrations of HMG CoA reductase inhibitors including LIPITOR. The equivalent of 1.2 litres per day resulted in an increase in AUC (ratio of AUC up to 2.5) and Cmax (ratio of Cmax up to 1.71) of atorvastatin. Consumption of excessive grapefruit juice with atorvastatin is not recommended.
For 240 ml of grapefruit juice, the ratio of AUC was 1.37 and the ratio of Cmax was 1.16 for atorvastatin 40 mg.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug/Laboratory Test Interactions

LIPITOR may elevate serum transaminase and creatine kinase levels (from skeletal muscle). In the differential diagnosis of chest pain in a patient on therapy with LIPITOR, cardiac and noncardiac fractions of these enzymes should be determined.

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