Livalo

LIVALO is contraindicated in the following conditions:

• Concomitant use of cyclosporine
  [see

  7 DRUG INTERACTIONS

  Table 2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when administered concomitantly with LIVALO and instructions for preventing or managing drug interactions

  [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].

  Table 2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with LIVALO

  Cyclosporine
  Clinical Impact:	Cyclosporine significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis .
  Intervention:	Concomitant use of cyclosporine with LIVALO is contraindicated [see Contraindications (4)].
  Gemfibrozil
  Clinical Impact:	Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of gemfibrozil with statins, including LIVALO.
  Intervention:	Avoid concomitant use of gemfibrozil with LIVALO.
  Erythromycin
  Clinical Impact:	Erythromycin significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis .
  Intervention:	In patients taking erythromycin, do not exceed LIVALO 1 mg once daily [see Dosage and Administration (2.4)].
  Rifampin
  Clinical Impact:	Rifampin significantly increases peak pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis .
  Intervention:	In patients taking rifampin, do not exceed LIVALO 2 mg once daily [see Dosage and Administration (2.4)].
  Fibrates
  Clinical Impact:	Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with statins, including LIVALO.
  Intervention:	Consider if the benefit of using fibrates concomitantly with LIVALO outweighs the increased risk of myopathy and rhabdomyolysis.
  Niacin
  Clinical Impact:	The risk of myopathy and rhabdomyolysis may be increased with concomitant use of lipid-modifying doses (≥1 g/day) of niacin with LIVALO.
  Intervention:	Consider if the benefit of using lipid-modifying doses (≥1 g/day) of niacin concomitantly with LIVALO outweighs the increased risk of myopathy and rhabdomyolysis.
  Colchicine
  Clinical Impact:	Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with statins, including LIVALO.
  Intervention:	Consider the risk/benefit of concomitant use of colchicine with LIVALO.

  See full prescribing information for details regarding concomitant use of LIVALO with other drugs that increase the risk of myopathy and rhabdomyolysis.

  ].
• Acute liver failure or decompensated cirrhosis
  [see

  5.3 Hepatic Dysfunction

  Increases in serum transaminases have been reported with LIVALO

  [see Adverse Reactions (6)].

  In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including LIVALO.

  Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.

  Consider liver enzyme testing before the initiation of LIVALO and when clinically indicated thereafter

  .

  LIVALO is contraindicated in patients with acute liver failure or decompensated cirrhosis

  [see Contraindications (4)].

  If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LIVALO.

  ].
• Hypersensitivity to pitavastatin or any excipents in LIVALO. Hypersensitivity reactions including angioedema, rash, pruritus, and urticaria have been reported with LIVALO
  [see

  6 ADVERSE REACTIONS

  The following serious adverse reactions are discussed in other sections of the labeling:

  • Myopathy and Rhabdomyolysis
    [see Warnings and Precautions (5.1)]
  • Immune-Mediated Necrotizing Myopathy
    [see Warning and Precautions (5.2)]
  • Hepatic Dysfunction
    [see Warning and Precautions (5.3)]
  • Increases in HbA1c and Fasting Serum Glucose Levels
    [see Warning and Precautions (5.4)].

  The most frequent adverse reactions (rate ≥ 2%) were myalgia, constipation, , diarrhea, back pain, and pain in extremity.

  
  
  

  To report SUSPECTED ADVERSE REACTIONS, contact Kowa Pharmaceuticals America, Inc. at 1-877-334-3464 or FDA at 1-800-FDA-1088 or

  www.fda.gov/medwatch.

  6.1 Clinical Studies Experience

  Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of one drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

  Adverse Reactions in Adults with Primary Hyperlipidemia

  In 10 controlled clinical studies and 4 subsequent open-label extension studies, 3,291 adult patients with primary hyperlipidemia were administered LIVALO 1 mg to 4 mg daily. The mean continuous exposure of pitavastatin (1 mg to 4 mg) was 36.7 weeks (median 51.1 weeks). The mean age of the patients was 60.9 years (range; 18 years – 89 years) and 52% were females. Approximately 93% of the patients were White, 7% were Asian/Indian, 0.2% were African American and 0.3% were Hispanic and other.

  In controlled clinical studies and their open-label extensions, 3.9% (1 mg), 3.3% (2 mg), and 3.7% (4 mg) of LIVALO-treated patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were: elevated creatine phosphokinase (0.6% on 4 mg) and myalgia (0.5% on 4 mg).

  Adverse reactions reported in ≥ 2% of patients in controlled clinical studies and at a rate greater than or equal to placebo are shown in Table 1. These studies had treatment duration of up to 12 weeks.

  Table 1. Adverse Reactions ( ≥ 2% and ≥ placebo) in Adults with Primary Hyperlipidemia in Studies up to 12 Weeks

  Adverse Reactions	Placebo (n= 208) %	LIVALO 1 mg (n=309) %	LIVALO 2 mg (n=951) %	LIVALO 4 mg (n=1540) %
  Myalgia	1.4	1.9	2.8	3.1
  Constipation	1.9	3.6	1.5	2.2
  Diarrhea	1.9	2.6	1.5	1.9
  Back pain	2.9	3.9	1.8	1.4
  Pain in extremity	1.9	2.3	0.6	0.9

  Other adverse reactions reported from clinical studies were arthralgia, headache, influenza, and nasopharyngitis.

  Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with LIVALO.

  The following laboratory abnormalities have been reported: elevated creatine phosphokinase, transaminases, alkaline phosphatase, bilirubin, and glucose.

  Adverse Reactions in Adult HIV-Infected Patients with Dyslipidemia

  In a double-blind, randomized, controlled, 52-week trial, 252 HIV-infected patients with dyslipidemia were treated with either LIVALO 4 mg once daily (n=126) or another statin (n=126). All patients were taking antiretroviral therapy (excluding darunavir) and had HIV-1 RNA less than 200 copies/mL and CD4 count greater than 200 cell/µL for at least 3 months prior to randomization. The safety profile of LIVALO was generally consistent with that observed in the clinical trials described above. One patient (0.8%) treated with LIVALO had a peak creatine phosphokinase value exceeding 10 times the upper limit of normal (ULN), which resolved spontaneously. Four patients (3%) treated with LIVALO had at least one ALT value exceeding 3 times but less than 5 times the ULN, none of which led to drug discontinuation. Virologic failure was reported for four patients (3%) treated with LIVALO, defined as a confirmed measurement of HIV-1 RNA exceeding 200 copies/mL that was also more than a 2-fold increase from baseline.

  Adverse Reactions in Pediatric Patients Aged 8 Years and Older with HeFH

  In a 12-week, double-blind, placebo-controlled trial of LIVALO 1 mg, 2 mg, and 4 mg once daily in 82 pediatric patients 8 years to 16 years of age with HeFH and a 52-week open-label trial in 85 pediatric patients with HeFH, the safety profile was similar to that observed in the adult population.

  6.2 Postmarketing Experience

  The following adverse reactions have been identified during postapproval use of LIVALO. 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:
    abdominal discomfort, abdominal pain, dyspepsia, nausea
  • General disorders:
    asthenia, fatigue, malaise, dizziness
  • Hepatobiliary disorders:
    hepatitis, jaundice, fatal and non-fatal hepatic failure
  • Immune system disorders:
    angioedema, immune-mediated necrotizing myopathy associated with statin use
  • Metabolism and nutrition disorders:
    increases in HbA1c, fasting serum glucose levels
  • Musculoskeletal and connective tissue disorders:
    muscle spasms, myopathy, rhabdomyolysis
  • Nervous system disorders:
    hypoesthesia, peripheral neuropathy. There have been rare reports of new onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. 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:
    insomnia, depression
  • Reproductive system and breast disorders:
    erectile dysfunction
  • Respiratory, thoracic and mediastinal disorders:
    interstitial lung disease
  • Skin and subcutaneous tissue disorders:
    lichen planus

  ]
  .