Atorvastatin calcium 80 mg Tablet, Film Coated, 90-count

5 WARNINGS AND PRECAUTIONS • Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase when higher doses are used concomitantly with cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, human immunodeficiency virus (HIV) or hepatitis C virus (HCV) protease inhibitors). Predisposing factors include advanced age (> 65), uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported.

Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness. Atorvastatin calcium therapy should be discontinued if myopathy is diagnosed or suspected ( 2.6 , 5.1 , 8.5 ). • Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter ( 5.2 ). • A higher incidence of hemorrhagic stroke was seen in patients without CHD but with stroke or TIA within the previous 6 months in the atorvastatin calcium 80 mg group vs. placebo ( 5.5 ).

5.1Skeletal Muscle Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.

Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., clarithromycin, itraconazole, and HIV and HCV protease inhibitors) increases the risk of myopathy/rhabdomyolysis. There have been rare reports of immune-mediated necrotizing myopathy(IMNM), an autoimmune myopathy, associated with statin use.

IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing atorvastatin.

Atorvastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of the drugs listed in Table 2. Physicians considering combined therapy of atorvastatin with any of these drugs should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug.

Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the afore mentioned drugs [see Drug Interactions (7)]. Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy. Prescribing recommendations for interacting agents are summarized in Table 2 [ see Dosage and Administration (2.6), Drug Interactions (7) , and Clinical Pharmacology (12.3)].

Table 2. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting Agents Prescribing Recommendations Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir Avoid…

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Rhabdomyolysis and myopathy [ see Warnings and Precautions (5.1) ] Liver enzyme abnormalities [ see Warnings and Precautions (5.2) ] The most commonly reported adverse reactions (incidence ≥ 2%) in patients treated with atorvastatin calcium in placebo-controlled trials regardless of causality were: nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-332-1088 or www.fda.gov/medwatch.

6.1Clinical 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 clinical practice. In the atorvastatin calcium placebo-controlled clinical trial database of 16,066 patients (8755 Atorvastatin calcium vs. 7311placebo; age range 10 to 93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin calcium and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality.

The five most common adverse reactions in patients treated with atorvastatin calcium that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%). The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in patients treated with atorvastatin calcium in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection(5.7%).

Table 3 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin calcium (n=8755), from seventeen placebo-controlled trials. Table 3. Clinical adverse reactions occurring in > 2% in patients treated with any dose of atorvastatin calcium and at an incidence greater than placebo regardless of causality (% of patients).

Adverse Reaction* Any dose N=8755 10mg N=3908 20mg N=188 40mg N=604 80mg N=4055 Placebo N=7311 Nasopharyngitis 8.3 12.9 5.3 7.0 4.2

8.2Arthralgia 6.9 8.9 11.7 10.6 4.3

6.5Diarrhea 6.8 7.3 6.4 14.1 5.2

6.3Pain inextremity 6.0 8.5 3.7 9.3 3.1

5.9Urinary tract infection 5.7 6.9 6.4 8.0 4.1

5.6Dyspepsia 4.7 5.9 3.2 6.0 3.3

4.3Nausea 4.0 3.7 3.7 7.1 3.8

3.5Musculoskeletal pain 3.8 5.2 3.2 5.1 2.3

3.6Muscle Spasms 3.6 4.6 4.8 5.1 2.4

3.0Myalgia 3.5 3.6 5.9 8.4 2.7

3.1Insomnia 3.0 2.8 1.1 5.3 2.8

2.9Pharyngolaryngeal pain 2.3 3.9 1.6 2.8 0.7 2.1 * Adverse Reaction > 2% in any dose greater than placebo Other adverse reactions reported in placebo-controlled studies include: Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin and appendages: urticaria; Special senses: vision blurred, tinnitus; Urogenital system: white blood cells urine positive.

Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) In ASCOT [ see Clinical Studies (14.1) ] involving 10,305 participants (age range 40 to 80 years, 19% women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with atorvastatin calcium 10 mg daily (n=5,168) or placebo (n=5,137), the safe…

7 DRUG INTERACTIONS The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV and HCV protease inhibitors, and itraconazole) [ see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6 , 5.1 , 7 , 12.3 ) Interacting Agents Prescribing Recommendations Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir Avoid atorvastatin Clarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir Do not exceed 20 mg atorvastatin daily Nelfinavir Do not exceed 40 mg atorvastatin daily Lopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine Use with caution and lowest dose necessary • Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects.

Caution should be used when prescribing with atorvastatin calcium (7). • Digoxin: Patients should be monitored appropriately (7.9). • Oral Contraceptives: Values for norethindrone and ethinyl estradiol may be increased (7.10). • Rifampin should be simultaneously co-administered with atorvastatin calcium (7.8).

7.1Strong Inhibitors of CYP 3A4 Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin 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 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin alone [ see Clinical Pharmacology (12.3) ]. Therefore, in patients taking clarithromycin, caution should be used when the atorvastatin dose exceeds 20 mg [ see Dosage and Administration (2.6) and Warnings and Precautions (5.1) ]. Combination of Protease Inhibitors Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin with several combinations of protease inhibitors [ see Clinical Pharmacology (12.3)].

In patients taking tipranavir plus ritonavir or glecaprevir plus pibrentasvir, concomitant use of atorvastatin should be avoided. In patients taking lopinavir plus ritonavir, or simeprevir, use the lowest necessary atorvastatin dose. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, or elbasvir plus grazoprevir, the dose of atorvastatin should not exceed 20 mg.

In patients taking nelfinavir the dose of atorvastatin should not exceed 40 mg and close clinical monitoring is recommended [ see Dosage and Administration (2.6) and Warnings and Precautions (5.1)]. Itraconazole Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg [ see Clinical Pharmacology (12.3) ]. Therefore, in patients taking itraconazole, caution should be used when the atorvastatin dose exceeds 20 mg [ see Dosage and Administration (2.6) and Warnings and Precautions (5.1) ] .

7.2Grapefruit 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).

7.3Cyclosporine Atorvastatin is a substrate of the hepatic transporters. 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 10 mg…