Data from FDA - Curated by EPG Health - Last updated 05 December 2017

Indication(s)

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 [see Clinical Studies (14)]. TECHNIVIE is a fixed-dose combination of ombitasvir, a hepatitis C virus NS5A inhibitor, paritaprevir, a hepatitis C virus NS3/4A protease inhibitor, and ritonavir, a CYP3A inhibitor and 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. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS The contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin prescribing information for a list of contraindications for ribavirin. TECHNIVIE is contraindicated: In patients with moderate to severe hepatic impairment (Child-Pugh B and C) due to risk of potential toxicity [see Warnings and Precautions (5.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. With drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. With drugs that are moderate or strong inducers of CYP3A and may lead to reduced efficacy of TECHNIVIE. In patients with known hypersensitivity to ritonavir (e.g. toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome). Table 2 lists drugs that are contraindicated with TECHNIVIE [see Drug Interactions (7)]. Table 2. Drugs that are Contraindicated with TECHNIVIE Drug Class Drug(s) within Class that are Contraindicated Clinical Comments Alpha1-adrenoreceptor antagonist Alfuzosin HCl Potential for hypotension. Anti-gout Colchicine Potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment. Anti-anginal Ranolazine Potential for serious and/or life-threatening reactions. Antiarrhythmic Dronedarone Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Anticonvulsants Carbamazepine, phenytoin, phenobarbital Ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE. Antimycobacterial Rifampin Ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE. Antipsychotic Lurasidone Pimozide Potential for serious and/or life-threatening reactions. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Ergot derivatives Ergotamine, dihydroergotamine, methylergonovine Acute ergot toxicity characterized by vasospasm and tissue ischemia has been associated with co-administration of ritonavir and ergonovine, ergotamine, dihydroergotamine, or methylergonovine. Ethinyl estradiol- containing products Ethinyl estradiol-containing medications such as combined oral contraceptives Potential for ALT elevations [see Warnings and Precautions (5.3)]. GI Motility Agent Cisapride Potential for serious and/or life threatening reactions such as cardiac arrhythmias Herbal Product St. John’s Wort (Hypericum perforatum) Ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE. HMG-CoA Reductase Inhibitors Atorvastatin Lovastatin, simvastatin Potential for myopathy including rhabdomyolysis. Immunosuppressants Everolimus Sirolimus Tacrolimus Increased potential for serious and/or life threatening immunosuppressant-associated adverse events. Non-nucleoside reverse transcriptase inhibitor Efavirenz Co-administration of efavirenz based regimens with paritaprevir, ritonavir was poorly tolerated and resulted in liver enzyme elevations. Phosphodiesterase-5 (PDE5) inhibitor Sildenafil when dosed as Revatio for the treatment of pulmonary arterial hypertension (PAH) There is increased potential for sildenafil-associated adverse events such as visual disturbances, hypotension, priapism, and syncope. Sedatives/hypnotics Triazolam Orally administered midazolam Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with TECHNIVIE may cause large increases in the concentration of these benzodiazepines. The potential exists for serious and/or life threatening events such as prolonged or increased sedation or respiratory depression. The contraindications to ribavirin also apply to this combination regimen. (4) Patients with moderate to severe hepatic impairment. (4, 5.2, 8.6, 12.3) Co-administration with drugs that are: highly dependent on CYP3A for clearance; moderate and strong inducers of CYP3A. (4) Known hypersensitivity to ritonavir (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome). (4)
Adverse reactions
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).

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Testing Prior to the Initiation of Therapy: Test all patients for HBV infection by measuring HBsAg and anti-HBc. (2.1) Assess hepatic laboratory and clinical evidence of hepatic decompensation. Prior to initiation of ribavirin, assess for underlying cardiac disease. (2.1) Recommended dosage: Two tablets taken orally once daily (in the morning) with a meal without regard to fat or calorie content. TECHNIVIE is recommended to be used in combination with ribavirin. (2.2) Patient Population Treatment Duration Genotype 4 without cirrhosis or with compensated cirrhosis TECHNIVIE + ribavirin* 12 weeks *TECHNIVIE administered without ribavirin for 12 weeks may be considered for treatment-naïve patients without cirrhosis who cannot take or tolerate ribavirin [see Microbiology (12.4) and Clinical Studies (14)]. 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 [see Warnings and Precautions (5.1)]. 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 [see Contraindications (4) and Warnings and Precautions (5.1 and 5.2)]. 2.2 Recommended Dosage in Adults TECHNIVIE is ombitasvir, paritaprevir and ritonavir fixed dose combination tablets. The recommended dosage of TECHNIVIE is two tablets taken orally once daily (in the morning). Take TECHNIVIE with a meal without regard to fat or calorie content [see Clinical Pharmacology (12.3)]. TECHNIVIE is used in combination with ribavirin (RBV). When administered with TECHNIVIE, the recommended dosage of RBV is based on weight: 1000 mg per day for subjects less than 75 kg and 1200 mg per day for those weighing at least 75 kg, divided and administered twice-daily with food. For ribavirin dosage modifications, refer to the ribavirin prescribing information. 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 [see Microbiology (12.4) and Clinical Studies (14)]. 2.3 Dosage in Patients with Hepatic Impairment TECHNIVIE is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) [see Contraindications (4), Warnings and Precautions (5.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary If TECHNIVIE is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on use in pregnancy. No adequate human data are available to establish whether or not TECHNIVIE poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when the components of TECHNIVIE were administered separately during organogenesis and lactation. During organogenesis, the exposures were up to 29 and 4 times (mice and rabbits, respectively; ombitasvir), 143 and 12 times (mice and rats, respectively; paritaprevir, ritonavir) exposures at the recommended clinical dose of TECHNIVIE. In rodent pre/postnatal developmental studies, maternal systemic exposures (AUC) to ombitasvir and paritaprevir were approximately 26 and 24 times, respectively, the exposure in humans at the recommended clinical dose [see Data]. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal data Ombitasvir Ombitasvir was administered orally to pregnant mice (0, 15, 50, or 150 mg/kg/day) and rabbits (0, 10 or 60 mg/kg/day) during the period of organogenesis (on gestation days (GD) 6 to 15, and GD 7 to 19, respectively). There were no ombitasvir-related maternal or embryofetal effects (malformations or fetal toxicity) at any dose level in either species. The systemic exposures at the highest doses were 29-times higher (mice) and 4-times higher (rabbits) than the exposures in humans at the recommended clinical dose. In a pre- and postnatal developmental study in mice, ombitasvir was administered orally at 0, 10, 40, or 200 mg/kg/day from GD 6 to lactation day 20. There were no ombitasvir-related effects at maternal exposures 26-times higher than exposures in humans at the recommended clinical dose. The major human metabolites of ombitasvir, M29 and M36, were tested in pregnant mice during the period of organogenesis from GD 6 to 15. M29 was administered orally at doses of 0, 1, 2.5 or 4.5 mg/kg/day. M36 was dosed orally at doses 1.5, 3, or 6 mg/kg/day. In both cases, there were no treatment related maternal effects or embryofetal effects (malformations or fetal toxicity) at any dose level. The highest doses produced exposures approximately 26-times higher than the exposures in humans at the recommended clinical dose. Paritaprevir/ritonavir Paritaprevir/ritonavir was administered orally to pregnant rats (0/0, 30/15, 100/15, 450/45 mg/kg/day) and mice (0/0, 30/30, 100/30, or 300/30 mg/kg/day) during the period of organogenesis (on GD 6 to 17, and GD 6 to 15, respectively). There were no test article-related maternal or embryofetal effects (malformations or fetal toxicity) at any dose level in either species. The highest systemic exposure of paritaprevir was 12-times higher (rats) and 143-times higher (mice) than the exposures in humans at the recommended clinical dose. In a pre- and postnatal developmental study in rats, paritaprevir/ritonavir were administered orally at 0/0, 6/30, 30/30, or 300/30 mg/kg/day from GD 7 to lactation day 20. There were no treatment related effects at maternal exposures 24-times higher than exposures in humans at the recommended clinical dose. 8.2 Lactation It is not known whether TECHNIVIE and its metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant. Unchanged ombitasvir, paritaprevir and its hydrolysis product M13 were the predominant components observed in the milk of lactating rats, without effect on nursing pups [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TECHNIVIE and any potential adverse effects on the breastfed child from TECHNIVIE or from the underlying maternal condition. If TECHNIVIE is administered with ribavirin, the nursing mother’s information for ribavirin also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use during lactation. Data Animal Data Ombitasvir No effects of ombitasvir on growth and postnatal development were observed in nursing pups at the highest dose tested, 200 mg/kg/day [see Data in (8.1)]. Maternal systemic exposure (AUC) to ombitasvir was approximately 26 times the exposure in humans at the recommended clinical dose. Although not measured directly, ombitasvir was likely present in the milk of lactating mice in this study, since systemic exposure was observed in nursing pups on post-natal day 21 (approximately 3-16 % of the maternal exposure). When administered to lactating rats 10 to 11 days after parturition at a dose of 5 mg/kg, the 24 hr AUC in milk was 4 times higher than in plasma and the majority of the radioactivity in the milk was unchanged parent drug (91%). Paritaprevir/ritonavir No effects of paritaprevir/ritonavir on growth and postnatal development were observed in nursing pups at the highest dose tested 300/30 mg/kg/day paritaprevir/ritonavir [see Data in (8.1)]. Maternal systemic exposure (AUC) to paritaprevir was approximately 24 times the exposure in humans at the recommended clinical dose. Although not measured directly, paritaprevir was likely present in the milk of lactating rats at the high dose in this study, since systemic exposure was observed in nursing pups on post-natal day 15 (approximately 0.3 % of the maternal exposure). When administered to lactating rats 10 to 11 days after parturition at a dose of 30/15 mg/kg paritaprevir/ritonavir, the 24 hr AUC in milk was half that in plasma and the majority of the radioactivity in the milk was the hydrolysis product M13 (84%) followed by unchanged parent drug (16%). 8.3 Females and Males of Reproductive Potential If TECHNIVIE is administered with ribavirin, the information for ribavirin with regard to pregnancy testing, contraception, and infertility also applies to this combination regimen. Refer to ribavirin prescribing information for additional information. 8.4 Pediatric Use Safety and effectiveness of TECHNIVIE in pediatric patients less than 18 years of age have not been established. 8.5 Geriatric Use No dosage adjustment of TECHNIVIE is warranted in geriatric patients. Clinical studies PEARL-I and AGATE-1 did not include sufficient numbers of patients older than 65 years of age to assess safety or efficacy, or to determine if they responded differently than younger patients. 8.6 Hepatic Impairment No dosage adjustment of TECHNIVIE is required in patients with mild hepatic impairment (Child-Pugh A). TECHNIVIE is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B and C) [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dosage adjustment of TECHNIVIE is required in patients with mild, moderate or severe renal impairment. TECHNIVIE has not been studied in patients on dialysis. For patients that require ribavirin, refer to the ribavirin prescribing information for information regarding use in patients with renal impairment [see Clinical Pharmacology (12.3)].
Pregnancy and lactation
8.2 Lactation It is not known whether TECHNIVIE and its metabolites are present in human breast milk, affect human milk production or have effects on the breastfed infant. Unchanged ombitasvir, paritaprevir and its hydrolysis product M13 were the predominant components observed in the milk of lactating rats, without effect on nursing pups [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TECHNIVIE and any potential adverse effects on the breastfed child from TECHNIVIE or from the underlying maternal condition. If TECHNIVIE is administered with ribavirin, the nursing mother’s information for ribavirin also applies to this combination regimen. Refer to the ribavirin prescribing information for more information on use during lactation. Data Animal Data Ombitasvir No effects of ombitasvir on growth and postnatal development were observed in nursing pups at the highest dose tested, 200 mg/kg/day [see Data in (8.1)]. Maternal systemic exposure (AUC) to ombitasvir was approximately 26 times the exposure in humans at the recommended clinical dose. Although not measured directly, ombitasvir was likely present in the milk of lactating mice in this study, since systemic exposure was observed in nursing pups on post-natal day 21 (approximately 3-16 % of the maternal exposure). When administered to lactating rats 10 to 11 days after parturition at a dose of 5 mg/kg, the 24 hr AUC in milk was 4 times higher than in plasma and the majority of the radioactivity in the milk was unchanged parent drug (91%). Paritaprevir/ritonavir No effects of paritaprevir/ritonavir on growth and postnatal development were observed in nursing pups at the highest dose tested 300/30 mg/kg/day paritaprevir/ritonavir [see Data in (8.1)]. Maternal systemic exposure (AUC) to paritaprevir was approximately 24 times the exposure in humans at the recommended clinical dose. Although not measured directly, paritaprevir was likely present in the milk of lactating rats at the high dose in this study, since systemic exposure was observed in nursing pups on post-natal day 15 (approximately 0.3 % of the maternal exposure). When administered to lactating rats 10 to 11 days after parturition at a dose of 30/15 mg/kg paritaprevir/ritonavir, the 24 hr AUC in milk was half that in plasma and the majority of the radioactivity in the milk was the hydrolysis product M13 (84%) followed by unchanged parent drug (16%).

Interactions

7 DRUG INTERACTIONS Co-administration of TECHNIVIE can alter the plasma concentrations of some drugs and some drugs may alter the plasma concentrations of TECHNIVIE. The potential for drug-drug interactions must be considered before and during treatment. Consult the full prescribing information prior to and during treatment for potential drug interactions. (4, 5.5, 7, 12.3) Frequent monitoring of international normalized ratio (INR) values is recommended in patients receiving warfarin. (7.1) 7.1 Potential for TECHNIVIE to Affect Other Drugs Paritaprevir is an inhibitor of OATP1B1 and OATP1B3 and paritaprevir and ritonavir are inhibitors of BCRP and P-gp. Ritonavir is an inhibitor of CYP3A4. Co-administration of TECHNIVIE with drugs that are substrates of CYP3A, P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs [see also Contraindications (4), Warnings and Precautions (5.5), and Clinical Pharmacology (12.3)]. Fluctuations in INR values may occur in patients receiving warfarin concomitant with HCV treatment, including treatment with TECHNIVIE. If TECHNIVIE is coadministered with warfarin, close monitoring of INR values is recommended during treatment and post-treatment follow-up. 7.2 Potential for Other Drugs to Affect One or More Components of TECHNIVIE Paritaprevir and ritonavir are primarily metabolized by CYP3A enzymes. Co-administration of TECHNIVIE with strong inhibitors of CYP3A may increase paritaprevir and ritonavir concentrations. Ombitasvir is primarily metabolized via amide hydrolysis while CYP enzymes play a minor role in its metabolism. Ombitasvir, paritaprevir and ritonavir are substrates of P-gp. Paritaprevir is a substrate of BCRP, OATP1B1 and OATP1B3. Inhibition of P-gp, BCRP, OATP1B1 or OATP1B3 may increase the plasma concentrations of the various components of TECHNIVIE. 7.3 Established and Other Potential Drug Interactions If dosage adjustments of concomitant medications are made due to treatment with TECHNIVIE, dosages should be re-adjusted after administration of TECHNIVIE is completed. Dosage adjustment is not required for TECHNIVIE. Table 5 provides the effect of co-administration of TECHNIVIE on concentrations of concomitant drugs and the effect of concomitant drugs on the various components of TECHNIVIE. See Contraindications (4) for drugs that are contraindicated with TECHNIVIE. Refer to the ritonavir prescribing information for other potentially significant drug interactions with ritonavir. Table 5. Established Drug Interactions Based on Drug Interaction Trials Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comments ANGIOTENSIN RECEPTOR BLOCKERS e.g. valsartan*, losartan*, candesartan* ↑ angiotensin receptor blockers Decrease the dose of the angiotensin receptor blockers and monitor patients for signs and symptoms of hypotension and/or worsening renal function. If such events occur, consider further dose reduction of the angiotensin receptor blocker or switching to an alternative to the angiotensin receptor blocker. ANTIARRHYTHMICS digoxin ↑ digoxin For contraindicated antiarrhythmics [see Contraindications (4)]. Decrease digoxin dose by 30-50%. Appropriate monitoring of serum digoxin levels is recommended. amiodarone*, bepridil*, disopyramide*, flecainide*, lidocaine (systemic)*, mexiletine*, propafenone*, quinidine* ↑ antiarrhythmics Therapeutic monitoring (if available) is recommended for antiarrhythmics when co-administered with TECHNIVIE. ANTIDIABETIC DRUGS metformin ↔ metformin Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Concomitant metformin use in patients with renal insufficiency or hepatic impairment is not recommended. Refer to the prescribing information of metformin for further guidance. ANTIFUNGALS ketoconazole ↑ ketoconazole When TECHNIVIE is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day. voriconazole* ↓ voriconazole Co-administration of TECHNIVIE with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole. ANTIPSYCHOTICS quetiapine* ↑ quetiapine For contraindicated antipsychotics [see Contraindications (4)]. Initiation of TECHNIVIE in patients taking quetiapine: Consider alternative anti-HCV therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6th of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking TECHNIVIE: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. CALCIUM CHANNEL BLOCKERS amlodipine, nifedipine*, diltiazem*, verapamil* ↑ calcium channel blockers Decrease the dose of the calcium channel blocker. The dose of amlodipine should be decreased by at least 50%. Clinical monitoring of patients is recommended for edema and/or signs and symptoms of hypotension. If such events occur, consider further dose reduction of the calcium channel blocker or switching to an alternative to the calcium channel blocker. CORTICOSTEROIDS (INHALED/NASAL) fluticasone* ↑ fluticasone Concomitant use of TECHNIVIE with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use. DIURETICS furosemide ↑ furosemide (Cmax) Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response. HIV-ANTIVIRAL AGENTS atazanavir or atazanavir/ritonavir ↑ paritaprevir Co-administration of TECHNIVIE with atazanavir or atazanavir/ritonavir is not recommended. darunavir/ritonavir ↓ darunavir (Ctrough) Treatment naïve patients or treatment experienced patients with no darunavir-associated mutations: Darunavir 800 mg once daily (without ritonavir) can be co-administered with TECHNIVIE. lopinavir/ritonavir ↑ paritaprevir Co-administration of TECHNIVIE with lopinavir/ritonavir is not recommended. rilpivirine ↑ rilpivirine For contraindicated non-nucleoside reverse transcriptase inhibitors [see Contraindications (4)]. Co-administration of TECHNIVIE with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine. HMG CoA REDUCTASE INHIBITORS pravastatin ↑ pravastatin For contraindicated HMG CoA Reductase Inhibitors [see Contraindications (4)]. When TECHNIVIE is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day. IMMUNOSUPPRESSANTS cyclosporine ↑ cyclosporine For contraindicated immunosuppressants [see Contraindications (4)]. When initiating therapy with TECHNIVIE, reduce cyclosporine dose to 1/5th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of TECHNIVIE therapy, the appropriate time to resume pre-TECHNIVIE dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended. LONG ACTING BETA-ADRENOCEPTOR AGONIST salmeterol* ↑ salmeterol Concurrent administration of TECHNIVIE and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. MUSCLE RELAXANTS carisoprodol ↓ carisoprodol ↔ mepobramate (metabolite of carisoprodol) Increase dose if clinically indicated. cyclobenzaprine ↓cyclobenzaprine ↓norcyclobenzaprine (metabolite of cyclobenzaprine) Increase dose if clinically indicated. NARCOTIC ANALGESICS buprenorphine/naloxone ↑ buprenorphine ↑ norbuprenorphine (metabolite of buprenorphine) Patients should be closely monitored for sedation and cognitive effects. Hydrocodone/ acetaminophen ↑ hydrocodone ↔ acetaminophen Reduce the dose of hydrocodone by 50% and monitor patients for respiratory depression and sedation at frequent intervals. Upon completion of TECHNIVIE therapy, adjust the hydrocodone dose and monitor for signs of opioid withdrawal. PROTON PUMP INHIBITORS omeprazole ↓ omeprazole Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole. SEDATIVES/HYPNOTICS alprazolam ↑ alprazolam For contraindicated Sedatives/Hypnotics [see Contraindications (4)]. Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response. diazepam ↓ diazepam ↓ nordiazepam (metabolite of diazepam) Increase dose if clinically indicated. *Not studied. See Clinical Pharmacology, Tables 7 and 8 . The direction of the arrow indicates the direction of the change in exposures (Cmax and AUC) (↑ = increase of more than 20%, ↓ = decrease of more than 20%). 7.4 Drugs without Clinically Significant Interactions with TECHNIVIE No dosage adjustments are recommended when TECHNIVIE is co-administered with the following medications: abacavir, dolutegravir, duloxetine, emtricitabine/tenofovir disoproxil fumarate, escitalopram, gemfibrozil, lamivudine, methadone, progestin only contraceptives, raltegravir, sofosbuvir, sulfamethoxazole, trimethoprim, rosuvastatin, and zolpidem.

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Category Value
Authorisation number NDA207931
Orphan designation No
Product NDC 0074-3082
Date Last Revised 20-11-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1597379
Marketing authorisation holder AbbVie Inc.
Warnings WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV Test all patients for evidence of current or prior hepatitis B virus (HBV) infection before initiating treatment with TECHNIVIE. HBV reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct acting antivirals and were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated [see Warnings and Precautions (5.1)] . WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV See full prescribing information for complete boxed warning. Hepatitis B virus (HBV) reactivation has been reported, in some cases resulting in fulminant hepatitis, hepatic failure, and death. (5.1)