atorvaliq

Take orally once daily, only on an empty stomach ( 2.1 ). • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating ATORVALIQ, and adjust dosage if necessary ( 2.1 ). • Adults ( 2.2 ): o Recommended starting dosage is 10 or 20 mg once daily; dosage range is 10 mg to 80 mg once daily. o Patients requiring LDL-C reduction >45% may start at 40 mg once daily. • Pediatric Patients Aged 10 Years of Age and Older with HeFH: Recommended starting dosage is 10 mg once daily; dosage range is 10 to 20 mg once daily ( 2.3 ). • Pediatric Patients Aged 10 Years of Age and Older with HoFH: Recommended starting dosage is 10 to 20 mg once daily; dosage range is 10 to 80 mg once daily ( 2.4 ). • See full prescribing information for ATORVALIQ dosage modifications due to drug interactions ( 2.5 ). 2.1 Important Dosage and Administration Information • Measure the ATORVALIQ dose using a calibrated oral syringe or other oral dosing device scored using metric units of measurements (i.e., mL). • Take ATORVALIQ orally once daily at any time of day, only on an empty stomach (1 hour before or 2 hours after a meal). • Advise patients to take a missed dose as soon as possible. If the dose was missed by more than 12 hours, patients should not take the missed dose and resume with the next scheduled dose. • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating…

The following important adverse reactions are described below and elsewhere in the labeling: • Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1) ] • Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2) ] • Hepatic Dysfunction [see Warnings and Precautions (5.3) ] • Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4) ] Most common adverse reactions (incidence ≥5%) are nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact CMP Pharma, Inc. at 1-844-321-1443, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ATORVALIQ has been established in adequate and well-controlled trials of atorvastatin calcium tablets, referenced below as “atorvastatin” [see Clinical Studies (14) ]. In the atorvastatin placebo-controlled clinical trial database of 16,066 patients (8,755 atorvastatin vs. 7,311 placebo; age range 10-93 years, 39% women, 91% White, 3% Black, 2% Asian, 4% other) with a median treatment duration of 53 weeks, the most…

ATORVALIQ is contraindicated in patients with: • Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3) ] • Hypersensitivity to atorvastatin or any excipients in ATORVALIQ. Hypersensitivity reactions, including anaphylaxis, angioneurotic edema, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported [see Adverse Reactions (6.2) ] . • Acute liver failure or decompensated cirrhosis ( 4 ). • Hypersensitivity to atorvastatin or any excipient in ATORVALIQ ( 4 ).

No specific antidotes for ATORVALIQ are known. Contact Poison Control (1-800-222-1222) for latest recommendations. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance ATORVALIQ clearance.

U.S. Poison Control: call or text 1-800-222-1222 (free, 24/7). In an emergency call 911. From the FDA label; not medical advice.

See full prescribing information for details regarding concomitant use of ATORVALIQ with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis ( 2.5 , 7.1 ). • Rifampin: May reduce atorvastatin plasma concentrations. Administer simultaneously with ATORVALIQ ( 7.2 ). • Oral Contraceptives: May increase plasma levels of norethindrone and ethinyl estradiol; consider this effect when selecting an oral contraceptive ( 7.3 ). • Digoxin: May increase digoxin plasma levels; monitor patients appropriately ( 7.3 ). 7.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with ATORVALIQ Atorvastatin is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters. Table 2 includes a list of drugs that may increase exposure to atorvastatin and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . Table 2: Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with ATORVALIQ Cyclosporine or Gemfibrozil Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 [see Clinical Pharmacology (12.3) ] . Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with ATORVALIQ. Intervention: Concomitant use of cyclosporine or gemfibrozil with ATORVALIQ is not recommended. Anti-Viral Medications Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of ATORVALIQ with many anti-viral medications, which are inhibitors of CYP3A4 and/or transporters (e.g., BCRP, OATP1B1/1B3, P-gp, MRP2, and/or OAT2) [see Clinical Pharmacology (12.3) ] . Cases of myopathy and rhabdomyolysis have been reported with concomitant use of ledipasvir plus sofosbuvir with atorvastatin. Intervention: • Concomitant use of tipranavir plus ritonavir or glecaprevir plus pibrentasvir with ATORVALIQ is not recommended. • In patients taking lopinavir plus ritonavir, or simeprevir, consider the risk/benefit of concomitant use with ATORVALIQ. • In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir or letermovir, do not exceed ATORVALIQ 20 mg. • In patients taking nelfinavir, do not exceed ATORVALIQ 40 mg [see Dosage and Administration (2.5) ]. • Consider the risk/benefit of concomitant use of ledipasvir plus sofosbuvir with ATORVALIQ. • Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Tipranavir plus ritonavir, glecaprevir plus pibrentasvir, lopinavir plus ritonavir, simeprevir, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir, nelfinavir, and ledipasvir plus sofosbuvir. Select Azole Antifungals or Macrolide Antibiotics Clinical Impact: Atorvastatin plasma levels were significantly increased with concomitant administration of ATORVALIQ with select azole antifungals or macrolide antibiotics, due to inhibition of CYP3A4 and/or transporters [see Clinical Pharmacology (12.3) ] . Intervention: In patients taking clarithromycin or itraconazole, do not exceed ATORVALIQ 20 mg [see Dosage and Administration (2.5) ] . Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with ATORVALIQ. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. Niacin Clinical Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin (≥1 gram/day niacin) with atorvastatin [see Warnings and Precaustions (5.1) ] . Intervention: Consider if the benefit of using lipid modifying dosages of niacin concomitantly with ATORVALIQ outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil) Clinical Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with ATORVALIQ. Intervention: Consider if the benefit of using fibrates concomitantly with ATORVALIQ outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Colchicine Clinical Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with atorvastatin. Intervention: Consider the risk/benefit of concomitant use of colchicine with ATORVALIQ. If concomitant use is decided, monitor patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug. Grapefruit Juice Clinical Impact: Grapefruit juice consumption, especially excessive consumption, more than 1.2 liters/daily, can raise the plasma levels of atorvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid intake of large quantities of grapefruit juice, more than 1.2 liters daily, when taking ATORVALIQ. 7.2 Drug Interactions that may Decrease Exposure to ATORVALIQ Table 3 presents drug interactions that may decrease exposure to ATORVALIQ and instructions for preventing or managing them. Table 3: Drug Interactions that may Decrease Exposure to ATORVALIQ Rifampin Clinical Impact: Concomitant administration of atorvastatin with rifampin, an inducer of cytochrome P450 3A4 and inhibitor of OATP1B1, can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, delayed administration of ATORVALIQ after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations. Intervention: Administer ATORVALIQ and rifampin simultaneously. 7.3 ATORVALIQ Effects on Other Drugs Table 4 presents atorvastatin’s effect on other drugs and instructions for preventing or managing them. Table 4: ATORVALIQ Effects on Other Drugs Oral Contraceptives Clinical Impact: Co-administration of atorvastatin and an oral contraceptive increased plasma concentrations of norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3) ]. Intervention: Consider this when selecting an oral contraceptive for patients taking ATORVALIQ. Digoxin Clinical Impact: When multiple doses of atorvastatin and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology (12.3) ]. Intervention: Monitor patients taking digoxin appropriately. Drug Interactions Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin. Table 5: Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and dosing regimen Atorvastatin Dose (mg) Ratio of AUC Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone). Ratio of Cmax See Sections 5.1 and 7 for clinical significance. Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD Once daily for 28 days 8.69 10.66 Tipranavir 500 mg BID Twice daily /ritonavir 200 mg BID , 7 days 10 mg SD Single dose 9.36 8.58 Glecaprevir 400 mg QD /pibrentasvir 120 mg QD , 7 days 10 mg QD for 7 days 8.28 22.00 Telaprevir 750 mg q8h Every 8 hours , 10 days 20 mg SD 7.88 10.60 , The dose of saquinavir plus 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. Saquinavir 400 mg BID /ritonavir 400 mg BID , 15 days 40 mg QD for 4 days 3.93 4.31 Elbasvir 50 mg QD /grazoprevir 200 mg QD , 13 days 10 mg SD 1.94 4.34 Simeprevir 150 mg QD , 10 days 40 mg SD 2.12 1.70 Clarithromycin 500 mg BID , 9 days 80 mg QD for 8 days 4.54 5.38 Darunavir 300 mg BID /ritonavir 100 mg BID , 9 days 10 mg QD for 4 days 3.45 2.25 Itraconazole 200 mg QD , 4 days 40 mg SD 3.32 1.20 Letermovir 480 mg QD , 10 days 20 mg SD 3.29 2.17 Fosamprenavir 700 mg BID /ritonavir 100 mg BID , 14 days 10 mg QD for 4 days 2.53 2.84 Fosamprenavir 1400 mg BID , 14 days 10 mg QD for 4 days 2.3 4.04 Nelfinavir 1250 mg BID , 14 days 10 mg QD for 28 days 1.74 2.22 Grapefruit Juice, 240 mL QD , Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL-1.2 liters per day). 40 mg SD 1.37 1.16 Diltiazem 240 mg QD , 28 days 40 mg SD 1.51 1.00 Erythromycin 500 mg QID Four times daily , 7 days 10 mg SD 1.33 1.38 Amlodipine 10 mg, single dose 80 mg SD 1.18 0.91 Cimetidine 300 mg QID , 2 weeks 10 mg QD for 2 weeks 1.00 0.89 Colestipol 10 g BID , 24 weeks 40 mg QD for 8 weeks NA 0.74 Ratio based on a single sample taken 8-16 h post dose. Maalox TC ® 30 mL QID , 17 days 10 mg QD for 15 days 0.66 0.67 Efavirenz 600 mg QD , 14 days 10 mg for 3 days 0.59 1.01 Rifampin 600 mg QD , 7 days (co‑administered) Due to the dual interaction mechanism of rifampin, 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. 40 mg SD 1.12 2.90 Rifampin 600 mg QD , 5 days (doses separated) 40 mg SD 0.20 0.60 Gemfibrozil 600 mg BID , 7 days 40 mg SD 1.35 1.00 Fenofibrate 160 mg QD , 7 days 40 mg SD 1.03 1.02 Boceprevir 800 mg TID Three times daily , 7 days 40 mg SD 2.32 2.66 Table 6: Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs Atorvastatin Co-administered drug and dosing regimen Drug/Dose (mg) Ratio of AUC Ratio of Cmax 80 mg QD Once daily for 15 days Antipyrine, 600 mg SD Single dose 1.03 0.89 80 mg QD for 10 days See Section 7 for clinical significance. Digoxin 0.25 mg QD , 20 days 1.15 1.20 40 mg QD for 22 days Oral contraceptive QD , 2 months - norethindrone 1 mg - ethinyl estradiol 35 µg 1.28 1.19 1.23 1.30 10 mg SD Tipranavir 500 mg BID Twice daily /ritonavir 200 mg BID , 7 days 1.08 0.96 10 mg QD for 4 days Fosamprenavir 1400 mg BID , 14 days 0.73 0.82 10 mg QD for 4 days Fosamprenavir 700 mg BID /ritonavir 100 mg BID , 14 days 0.99 0.94 Atorvastatin had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.