TECHNIVIE (fixed-dose combination of ombitasvir, paritaprevir, and ritonavir) label was updated to expand the indication

On February 27, 2017 the TECHNIVIE  (fixed-dose combination of ombitasvir, paritaprevir, and ritonavir) label was updated to  expand the indication to patients with genotype 4 chronic hepatitis C virus infection (HCV) with compensated cirrhosis. Below is a summary of the major changes to the label based on the results of the AGATE-1 trial in HCV genotype 4 infected adults with compensated cirrhosis who are either treatment-naïve or pegylated interferon/ribavirin treatment experienced. Other minor revisions were made to the table including updates to section 8.1 Pregnancy and 8.2 Lactation.

Section 1: INDICATIONS AND USAGE
TECHNIVIE is indicated in combination with ribavirin for the treatment of patients with genotype 4 chronic hepatitis C virus (HCV) infection without cirrhosis or with compensated cirrhosis.

Section 2: DOSAGE AND ADMINISTRATION
2.1 Testing Prior to the Initiation of Therapy
Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with TECHNIVIE)].

Prior to initiation of TECHNIVIE, assess hepatic laboratory and clinical evidence of hepatic decompensation. Prior to initiation of ribavirin, assess for underlying cardiac disease and refer to the ribavirin prescribing information.

2.2 Recommended Dosage in Adults
Table 1 shows the recommended TECHNIVIE treatment regimen and duration for HCV genotype 4 patients without cirrhosis or with compensated cirrhosis.

Table 1. Treatment Regimen and Duration for Patients with HCV Genotype 4 without Cirrhosis or with Compensated Cirrhosis

Patient Population	Treatment	Duration
Genotype 4 without cirrhosis or with compensated cirrhosis (Child-Pugh A)	TECHNIVIE + ribavirin*	12 weeks
*TECHNIVIE administered without RBV for 12 weeks may be considered for treatment-naïve patients without cirrhosis who cannot take or tolerate ribavirin

Section 5: WARNINGS AND PRECAUTIONS
5.2 Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis
For patients with compensated cirrhosis:

• Monitor for clinical signs and symptoms of hepatic decompensation (such as ascites, hepatic encephalopathy, variceal hemorrhage).
• Hepatic laboratory testing including direct bilirubin levels should be performed at baseline and during the first 4 weeks of starting treatment and as clinically indicated.
• Discontinue TECHNIVIE in patients who develop evidence of hepatic decompensation.

Section 6: ADVERSE REACTIONS
6.1 Clinical Trials Experience

• 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.

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 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).

12.4 Microbiology
The presence of NS5A L30S and Y93H polymorphisms in a genotype 4b clinical isolate was associated with approximately 200-fold reduced activity of ombitasvir.
In Clinical Studies

In the clinical study AGATE-I, one subject experienced on-treatment virologic failure and a second subject experienced virologic relapse at the Post-Treatment Week 24 timepoint. Treatment-emergent resistance-associated substitutions detected in these subjects included NS3 substitutions A156K or D168V, and NS5A substitutions K24Q, L28I/M, M31I or Y93H.

Phylogenetic analysis of HCV nucleotide sequences from subjects who received ombitasvir/paritaprevir/ritonavir plus ribavirin for 12 weeks in the clinical study AGATE-I, identified 11 HCV genotype 4 subtypes (4a, 4c, 4d, 4e, 4f,  4k,  4n,  4p, 4q, 4r, 4t). Most subjects were infected with either subtype 4a (58%) or 4d (20%); 1 to 2 subjects were infected with each of the other genotype 4 subtypes. Two subjects who experienced virologic failure in AGATE-I were infected with HCV subtype 4a or 4d.

Baseline HCV polymorphisms are not expected to impact the likelihood of achieving SVR when TECHNIVIE is used as recommended to treat HCV genotype 4 infected patients, based on the low virologic failure rrates observed in PEARL-I and AGATE-I, although limited data are available for genotype 4 subtypes other than 4a and 4d.

Section 14: Description of Clinical Studies
14.3 Clinical Trial Results in Adults with Chronic GT4 HCV Infection with Compensated Cirrhosis
AGATE-I was a global multicenter, open-label trial in 120 HCV genotype 4 infected adults with compensated cirrhosis who were either treatment-naïve or pegIFN/RBV treatment-experienced and were treated for 12 weeks (n=59) or 16 weeks (n=61) with TECHNIVIE given once daily with weight based RBV. TECHNIVIE was administered as coformulated ombitasvir, paritaprevir, ritonavir tablets.

Of the 59 subjects in the 12 week arm, median age was 56 years (range: 43 to 81); 51% were treatment-naïve, 29% were prior pegIFN/RBV null responders; 8% were prior pegIFN/RBV partial responders, 12% were prior pegIFN/RBV relapsers; 76% were male; 17% were Black; 29% had a body mass index of at least 30 kg/m2; 76% had baseline HCV RNA levels of at least 800,000 IU per mL; 86% had IL28B (rs12979860) non‑CC genotype; 12% had platelet counts of less than 90 x 109 per L; and 5% had albumin less than 3.5 mg per dL.

Table 11 presents the SVR12 rates for HCV genotype 4 infected subjects with compensated cirrhosis treated with TECHNIVIE with RBV for 12 weeks. Treatment with 16 weeks was not shown to increase SVR12 rates therefore, TECHNIVIE with RBV for 16 week arm is not presented in Table 11.

Table 11. AGATE-I: SVR12 for HCV Genotype 4-Infected Subjects with Compensated Cirrhosis

Treatment outcome	TECHNIVIE with RBV for 12 Weeks
	% (n/N)
SVR12, % (n/N)	97% (57/59)
Outcome for subjects without SVR12
On-treatment VFa	2% (1/59)
Relapseb	0 (0/57)
Otherc	2% (1/59)
a.    On-treatment virologic failure (VF) was defined as confirmed HCV ≥ 25 IU/mL after HCV RNA < 25 IU/mL during treatment, confirmed increase from nadir in HCV RNA > 1 log10 IU/mL during treatment, or HCV RNA ≥ 25 IU/mL persistently during treatment with at least 6 weeks of treatment. b.    Relapse was defined as confirmed HCV RNA ≥ 25 IU/mL post-treatment before or during SVR12 window among subjects with HCV RNA less than 25 IU/mL at last observation during at least 11 weeks of treatment. c.    Other includes subjects not achieving SVR12 but not experiencing on-treatment virologic failure or relapse (i.e premature discontinuation due to noncompliance).

You will be able to view the updated labels at drugs@fda or dailymed.

Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

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