6 ADVERSE REACTIONS TECHNIVIE should be administered with ribavirin (RBV). Refer to the prescribing information for ribavirin for a list of ribavirin-associated adverse reactions. The following adverse reaction is described below and elsewhere in the labeling: Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis [see Warnings and Precautions (5.2)] Increased Risk of ALT Elevations [see Warnings and Precautions (5.3)] The most commonly reported adverse reactions (incidence greater than 10% of subjects, all grades) observed with treatment with ombitasvir, paritaprevir and ritonavir with ribavirin for 12 weeks in patients without cirrhosis were asthenia, fatigue, nausea and insomnia. (6.1) The most common adverse events (incidence greater than 10% of subjects, all grades) observed with treatment with TECHNIVIE and ribavirin for 12 weeks in patients in compensated cirrhosis were fatigue, asthenia, headache, musculoskeletal pain, pruritus, insomnia/sleep disorder, skin reactions, mood disorders, nausea, dizziness and dyspnea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 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, adverse reaction rates observed in clinical trials of ombitasvir, paritaprevir and ritonavir cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reaction in Subjects without Cirrhosis The safety assessment of TECHNIVIE is based on data from two clinical studies in subjects with HCV genotype 4 infection. PEARL-I was a study including 135 subjects without cirrhosis, 91 who received ombitasvir 25 mg, paritaprevir 150 mg and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily with ribavirin for 12 weeks and 44 subjects who received ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily without ribavirin for 12 weeks. Adverse reactions that occurred in subjects without cirrhosis treated with ombitasvir, paritaprevir and ritonavir with or without ribavirin for 12 weeks are listed in Table 3. The majority of adverse reactions in non-cirrhotic subjects were mild in severity, none were serious and none led to discontinuation of treatment. Table 3. Selected Adverse Reactions (All Grades) with ≥5% Frequency Reported in Subjects with HCV Genotype 4 Infection without Cirrhosis Treated with Ombitasvir, Paritaprevir and Ritonavir with or without Ribavirin for 12 Weeks PEARL-I Without Cirrhosis Adverse Reaction Ombitasvir, paritaprevir, ritonavir + RBV N = 91 % Ombitasvir, paritaprevir, ritonavir N = 44 % Asthenia 29 25 Fatigue 15 7 Nausea 14 9 Insomnia 13 5 Pruritus1 7 5 Skin reactions2,3 7 5 1Grouped term ‘pruritus’ includes the preferred terms pruritus and pruritus generalized. 2Grouped term ‘skin reactions’ includes the preferred terms rash, erythema, eczema, rash maculo-papular, rash macular, dermatitis, rash papular, skin exfoliation, rash pruritic, rash erythematous, rash generalized, dermatitis allergic, dermatitis contact, exfoliative rash, photosensitivity reaction, psoriasis, skin reaction, ulcer and urticaria. 3The majority of events were graded as mild in severity. Adverse Events in Subjects with Compensated Cirrhosis AGATE-I was a study including 120 subjects with compensated cirrhosis who received TECHNIVIE once daily with ribavirin for a total of 12 weeks (n=60) or 16 weeks (n=60). Adverse events occurring up to and including 12 weeks of treatment (≤ 84 days) from both arms were included in the analysis of adverse events and are listed in Table 4. Seven of 120 subjects (6%) experienced serious adverse events at or before 12 weeks of treatment. No adverse events led to the discontinuation of TECHNIVIE. Thirty-one subjects (26%) underwent ribavirin dose reductions; five discontinued ribavirin, three received transfusion and one received erythropoietin. Table 4. Selected Adverse Events (All Grades) with ≥5% Frequency Reported in Subjects with HCV Genotype 4 Infection with Compensated Cirrhosis Treated with TECHNIVIE and Ribavirin through 12 Weeks AGATE-I Compensated Cirrhosis Adverse Events TECHNIVIE + RBV N=120 (%) Fatigue 25 Asthenia 25 Headache 23 Musculoskeletal Pain/Changes1 17 Pruritus 16 Insomnia/Sleep Disorder2 14 Skin Reactions3 13 Dyspnea4 11 Mood Disorders5 11 Nausea 11 Dizziness 11 Cardiac Events6 9 Abdominal Pain7 9 Cough 7 Clinical Liver or Bilirubin Related Events8 7 Edema9 6 Altered Mental Status10 6 Decreased Appetite 6 Vomiting 6 1Grouped term ‘musculoskeletal pain/changes’ includes the preferred terms arthralgia, arthritis, back pain, muscle injury, muscle spasms, muscular weakness, musculoskeletal chest pain, myalgia, neck pain, and pain in extremity. 2Grouped term ‘insomnia/sleep disorder’ includes preferred terms insomnia and sleep disorder. 3Grouped term ‘skin reactions’ includes preferred terms dermatitis bullous, dermatitis psoriasiform, dry skin, eczema asteatotic, erythema, rash, skin exfoliation, skin lesion and skin toxicity. 4Grouped term ‘dyspnea’ includes preferred terms dyspnea and dyspnea exertional. 5Grouped term ‘mood disorders’ includes preferred terms affective disorder, agitation, anxiety, depressed mood, depression, irritability, mania and suicide attempt. 6Grouped term ‘cardiac events’ includes preferred terms acute coronary syndrome, angina pectoris, atrial fibrillation, chest pain, hypertension, hypotension and palpitations. 7Grouped term ‘abdominal pain’ includes preferred terms abdominal discomfort, abdominal pain, abdominal pain lower and abdominal pain upper. 8Grouped term ‘clinical liver or bilirubin related events’ includes preferred terms ascites, hepatic encephalopathy, jaundice, ocular icterus, esophageal varices hemorrhage and portal vein thrombosis. 9Grouped term ‘edema’ includes preferred terms edema and edema peripheral. 10Grouped term ‘altered mental status’ includes preferred terms disturbance in attention, memory impairment, psychomotor retardation and somnolence. Laboratory Abnormalities Serum ALT Elevations None of the 135 subjects without cirrhosis and two (2%) of the 120 subjects with compensated cirrhosis treated with TECHNIVIE experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) and ≥2 times baseline after starting treatment [see Warnings and Precautions (5.3)]. Serum Bilirubin Elevations in Patients without Cirrhosis Post-baseline elevations in bilirubin at least 2 times ULN were observed in 5% (7/134) of subjects without cirrhosis, receiving TECHNIVIE, all of whom were also receiving RBV. These bilirubin increases were predominately indirect and related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and possibly ribavirin-induced hemolysis. Bilirubin elevations occurred early after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were generally not associated with serum ALT elevations. Serum Bilirubin Elevations/Hepatic Decompensation in Patients with Compensated Cirrhosis Among the 120 subjects with compensated cirrhosis, mean total bilirubin and mean indirect bilirubin levels increased to approximately 3 fold from baseline on treatment. Mean direct bilirubin levels increased to approximately 2 fold on treatment. Mean bilirubin elevations occurred early, peaked by Week 1, remained elevated on treatment and normalized by post treatment week 4. Bilirubin elevations were generally not associated with serum ALT elevations. Over 40% (50/120) of subjects across both arms experienced elevated direct bilirubin levels (>ULN) at or before 12 weeks of treatment. Twelve percent (6/50) of these subjects experienced clinical bilirubin or liver related events including jaundice, ocular icterus and portal vein thrombosis. One subject who did not have direct bilirubin elevations also experienced liver related adverse events of esophageal varices and ascites. Anemia/Decreased Hemoglobin in Patients without Cirrhosis The mean change from baseline in hemoglobin levels in subjects without cirrhosis treated with TECHNIVIE in combination with ribavirin was -2.1 g/dL and the mean change in subjects treated with TECHNIVIE alone was -0.4 g/dL. Decreases in hemoglobin levels occurred early in treatment (Week 1-2) with further reductions through Week 3. Hemoglobin values remained low during the remainder of treatment and returned towards baseline levels by post-treatment Week 4. One subject treated with TECHNIVIE with ribavirin had a single hemoglobin level decrease to less than 8 g/dL during treatment. No subject treated with TECHNIVIE alone had hemoglobin levels less than 8 g/dL. Four percent (4/91) of subjects without cirrhosis treated with TECHNIVIE with ribavirin underwent ribavirin dose reductions to manage anemia/decreased hemoglobin levels. No subject received erythropoietin. Anemia/Decreased Hemoglobin in Patients with Compensated Cirrhosis Across both treatment arms, 4/120 cirrhotic subjects (3%) had anemia (hemoglobin less than LLN) prior to initiation of treatment. However, 88/120 (73%) had anemia (hemoglobin less than LLN) and/or a hemoglobin decrease of ≥ 2g/dl at or before 12 weeks of treatment. One subject (1%) had a single hemoglobin value less than 8.0 g/dL on treatment at or before 12 weeks of treatment. Reductions in hemoglobin are most likely primarily related to ribavirin in this population. Of 64 subjects with a history of cardiovascular disease or diabetes mellitus, 9 (14%) experienced cardiac adverse events at or before 12 weeks of treatment. These 9 subjects had a mean hemoglobin decrease of 3.9 g/dL (range 1.1 to 5.3 g/dL) from baseline and experienced cardiac events including acute coronary syndrome, angina pectoris, chest pain, atrial fibrillation, palpitations, hypotension and hypertension. Among 56 subjects without a prior history of cardiovascular disease or diabetes, 2 (4%) experienced a cardiac event (mild or moderate hypertension). 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of TECHNIVIE. 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. Immune System Disorders: Hypersensitivity reactions (including angioedema). Hepatobiliary Disorders: Hepatic decompensation, hepatic failure [see Warnings and Precautions (5.3)]. Skin and Subcutaneous Tissue Disorders: Erythema multiforme (EM).