Atorvastatin Calcium (Page 3 of 8)
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of atorvastatin calcium tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders: pancreatitis
General disorders: fatigue
Hepatobiliary Disorders: fatal and non-fatal hepatic failure
Immune system disorders: anaphylaxis Injury: tendon rupture
Musculoskeletal and connective tissue disorders: rhabdomyolysis, myositis.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use.
Nervous system disorders: dizziness, peripheral neuropathy.
There have been rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins. Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Psychiatric disorders: depression
Respiratory disorders: interstitial lung disease
Skin and subcutaneous tissue disorders: angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis)
7 DRUG INTERACTIONS
7.1 Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with atorvastatin calcium tablets
Atorvastatin calcium tablets is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin calcium tablets 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 calcium tablets 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 atorvastatin calcium tablets
| Cyclosporine or Gemfibrozil | |
| Clinical Impact: | Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium tablets 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 atorvastatin calcium tablets. |
| Intervention: | Concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium tablets are not recommended. |
| Anti-Viral Medications | |
| Clinical Impact: | Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium tablets 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 calcium tablets. |
| Intervention: |
|
| 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 atorvastatin calcium tabletswith 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 atorvastatin calcium tablets 20 mg [see Dosage and Administration ( 2.5)]. Consider the risk/benefit of concomitant use of other azole antifungals or macrolide antibiotics with atorvastatin calcium tablets. 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 calcium tablets. |
| Intervention: | Consider if the benefit of using lipid modifying dosages of niacin concomitantly with atorvastatin calcium tablets 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 atorvastatin calcium tablets. |
| Intervention: | Consider if the benefit of using fibrates concomitantly with atorvastatin calcium tablets 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 calcium tablets. |
| Intervention: | Consider the risk/benefit of concomitant use of colchicine with atorvastatin calcium tablets. 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 atorvastatin calcium tablets. |
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