Technivie: Indications, Dosage, Precautions, Adverse Effects
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Technivie - Product Information

Manufacture: AbbVie
Country: Canada
Condition: Hepatitis C
Class: Antiviral combinations
Form: Tablets
Ingredients: ombitasvir, paritaprevir, ritonavir, colloidal silicon dioxide/anhydrous colloidal silica, copovidone, propylene glycol monolaurate, sodium stearyl fumarate, sorbitan monolaurate, vitamin E polyethylene glycol succinate

TECHNIVIE

ombitasvir/paritaprevir/ritonavir

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal Ingredientsa
Oral ombitasvir/paritaprevir/ritonavir film-coated tablets: 12.5/75/50 mg None

a. For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

Indications and Clinical Use

TECHNIVIE (ombitasvir/paritaprevir/ritonavir) tablets with ribavirin is indicated for the treatment of adults with genotype 4 chronic hepatitis C virus infection without cirrhosis who are either treatment naïve or previously treated with peginterferon and ribavirin.

The following point should be considered when initiating treatment with TECHNIVIE.

Treatment with TECHNIVIE should be initiated and monitored by a physician experienced in the management of chronic hepatitis C.

Geriatrics (> 65 years of age)

No overall differences in safety and efficacy have been observed in a limited number of patients younger than 65 or older than 65 (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

Pediatrics (< 18 years of age)

Safety and effectiveness of TECHNIVIE in children less than 18 years of age have not been established (see WARNINGS AND PRECAUTIONS).

Contraindications

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section.
  • When TECHNIVIE (ombitasvir/paritaprevir/ritonavir) is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin Product Monograph for a list of contraindications for ribavirin.
  • The use of ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant, may be pregnant, or plan to become pregnant because of the risks for birth defects and fetal death associated with ribavirin (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).
  • TECHNIVIE is contraindicated in patients with severe hepatic impairment (Child-Pugh C) due to risk of potential toxicity.
  • TECHNIVIE is contraindicated in patients with known hypersensitivity to ritonavir (e.g. toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome).
  • The following categories of drugs are contraindicated with TECHNIVIE (See Table 1):
    • Drugs that are sensitive cytochrome P450 (CYP) 3A substrates and for which elevated plasma concentrations are associated with serious and/or life-threatening events;
    • Moderate or strong inducers of CYP3A that may lead to reduced efficacy of TECHNIVIE.
Table 1. Drugs that Are Contraindicated with TECHNIVIE
Drug Class Drug Name
Acyl-coenzyme A:cholesterol O-
acyltransferase (ACAT) inhibitor
Avasimibe*
Alpha1-adrenoreceptor antagonist Alfuzosin HCl
Antibacterial Nafcillin*
Anticonvulsants Carbamazepine, phenytoin, phenobarbital
Antihistamine Astemizole, terfenadine
Antimycobacterial Rifampin
Antiviral Efavirenz-containing regimens, including Atripla, etravirine, nevirapine
Benzodiazepines Oral midazolam, triazolam
Endothelin receptor agonist Bosentan
Ergot derivatives Ergotamine, dihydroergotamine, ergonovine*, methylergonovine*
GI Motility Agent Cisapride*
Herbal Product St. John’s Wort (Hypericum perforatum)
Hormonal Product Ethinyl estradiol-containing medications such as combined oral contraceptives
HMG-CoA Reductase Inhibitors Lovastatin, simvastatin
Long-acting beta-adrenoceptor agonist Salmeterol
Neuroleptics Pimozide
PDE5 enzyme inhibitor Sildenafil only when used for the treatment of pulmonary arterial hypertension (PAH)
Sedatives/hypnotics Triazolam, orally administered midazolam
Others Modafinil

* Drugs not sold in Canada.

Warnings and Precautions

General

When TECHNIVIE (ombitasvir/paritaprevir/ritonavir) is administered with ribavirin, the warnings and precautions for ribavirin, in particular the pregnancy avoidance warning, also apply to this combination regimen. Refer to the ribavirin Product Monograph for a full list of the warnings and precautions for ribavirin.

TECHNIVIE contains ritonavir and should not be co-administered with additional ritonavir or ritonavir-containing regimens.

As a fixed dose combination formulation, no dosage adjustments for TECHNIVIE are possible.

Retreatment of patients previously treated with TECHNIVIE or other DAAs is not recommended since the efficacy in these patients has not been established.

Transaminase Elevations

Clinically significant transaminase elevations were observed when ombitasvir, paritaprevir, ritonavir and dasabuvir were co-administered with efavirenz or with ethinyl estradiol (see CONTRAINDICATIONS and DRUG INTERACTIONS). When TECHNIVIE is co-administered with other drugs known to cause elevations of transaminases, caution should be exercised and monitoring of transaminase levels should be considered. If transaminase elevations occur, consideration should be given to whether the other drug may be discontinued. Discontinuation of TECHNIVIE should be considered if there are clinical signs of liver inflammation that are accompanied by persistent elevations in ALT, direct bilirubin or international normalized ratio (INR) (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, ALT Elevations).

Use with Fluticasone (glucocorticoids metabolized by CYP3A)

Use caution when administering TECHNIVIE with fluticasone or other glucocorticoids that are metabolized by CYP3A4 (see DRUG INTERACTIONS). Concomitant use of inhaled glucocorticoids metabolized by CYP3A can increase systemic exposures of the glucocorticoids, and cases of Cushing’s syndrome and subsequent adrenal suppression have been reported with ritonavir-containing regimens. Concomitant use of TECHNIVIE and glucocorticoids, particularly long-term use, should only be initiated if the potential benefit of treatment outweighs the risk of systemic corticosteroid effects.

Use with Rilpivirine

Concomitant use of ombitasvir, paritaprevir, ritonavir and dasabuvir with rilpivirine significantly increased rilpivirine exposure by 243%. Co-administration of TECHNIVIE with rilpivirine is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine (see DRUG INTERACTIONS, Drug-Drug Interactions).

Use with HMG-CoA Reductase Inhibitors

Simvastatin and lovastatin are contraindicated with TECHNIVIE. Concomitant use of atorvastatin with TECHNIVIE should be avoided; for patients receiving fluvastatin or pitavastatin, use the lowest dose of fluvastatin or pitavastatin or switch to low-dose pravastatin or rosuvastatin (see Table 5 and Table 7).

Hepatic/Biliary/Pancreatic

ALT Elevations

During clinical trials with ombitasvir, paritaprevir and ritonavir with or without dasabuvir and with or without ribavirin, transient, asymptomatic elevations of alanine transaminase (ALT) to greater than 5 times the upper limit of normal (ULN) occurred in approximately 1% of all patients (see ADVERSE REACTIONS, Abnormal Hematologic and Clinical Chemistry Findings, Laboratory Abnormalities). These ALT elevations were significantly more frequent in female patients who were using ethinyl estradiol-containing medications such as combined oral contraceptives, contraceptive patches or contraceptive vaginal rings (see CONTRAINDICATIONS). ALT elevations typically occurred during the first 4 weeks of treatment and declined within approximately two weeks of onset with continued dosing of ombitasvir, paritaprevir and ritonavir with or without dasabuvir and with or without ribavirin.

Ethinyl estradiol-containing medications must be discontinued prior to starting therapy with TECHNIVIE (see CONTRAINDICATIONS). Alternative contraceptive agents or methods of contraception (e.g, progestin only contraception or non-hormonal methods) are recommended during TECHNIVIE therapy. Ethinyl estradiol-containing medications can be restarted approximately 2 weeks following completion of treatment with TECHNIVIE.

During clinical trials with ombitasvir, paritaprevir and ritonavir with dasabuvir, patients using estrogens other than ethinyl estradiol, such as estradiol and conjugated estrogens used in hormone replacement therapy had a rate of ALT elevation similar to those not receiving any estrogens (1%). However, due to the limited number of patients taking these other estrogens (n=87) in clinical studies, caution is warranted for co-administration with TECHNIVIE.

Patients should be instructed to consult their health care professional without delay if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice and discolored feces. If elevated liver chemistries are identified, careful follow-up is recommended. Consider discontinuing TECHNIVIE if ALT levels remain persistently greater than 10 times the ULN. TECHNIVIE should be discontinued if there are clinical signs of liver inflammation that are accompanied by persistent elevations in ALT, conjugated bilirubin, alkaline phosphatase, direct bilirubin or international normalized ratio (INR).

Hepatic Impairment

No dose adjustment of TECHNIVIE is required in patients with mild hepatic impairment (Child-Pugh A).

The safety and efficacy of TECHNIVIE have not been established in HCV-infected patients with moderate hepatic impairment (Child-Pugh B). TECHNIVIE should not be used in patients with moderate hepatic impairment (Child-Pugh B).

TECHNIVIE is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see CONTRAINDICATIONS, DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Hepatic Impairment; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

Renal Impairment

No dose adjustment of TECHNIVIE is required in patients with mild, moderate or severe renal impairment.

TECHNIVIE has not been studied in patients on dialysis.

Since TECHNIVIE is administered with ribavirin, refer to the ribavirin Product Monograph for information regarding use in patients with renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency).

Sexual Function/Reproduction

Pregnancy and Concomitant Use with Ribavirin

Ribavirin may cause birth defects and/or death of the exposed fetus (see CONTRAINDICATIONS). Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients when TECHNIVIE is administered in combination with ribavirin as significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin.

TECHNIVIE in combination with ribavirin should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners as well as male patients and their female partners must use at least two effective forms of contraception during treatment and for at least 6 months after treatment has concluded. See additional information on specific hormonal contraceptives in CONTRAINDICATIONS;WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, ALT Elevations; and DRUG INTERACTIONS, Established and Other Potential Drug Interactions. Routine monthly pregnancy tests must be performed during this time (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women and the ribavirin Product Monograph).

Special Populations

Pregnant Women

When 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 Product Monograph for more information on use in pregnancy. See additional information on specific hormonal contraceptives in CONTRAINDICATIONS;WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, ALT Elevations; and DRUG INTERACTIONS, Drug-Drug Interactions, Established and Other Potential Drug Interactions.

There are no studies with TECHNIVIE in pregnant women.

No effects on embryo-fetal development have been noted in studies in animals with paritaprevir/ritonavir, ombitasvir and its major inactive human metabolites (M29, M36). For paritaprevir/ritonavir, the highest doses tested produced exposures equal to 143-fold (mouse) or 12-fold (rat) the exposures in humans at the recommended clinical dose. For ombitasvir, the highest dose tested produced exposures equal to 29-fold (mouse) or 4-fold (rabbit) the exposures in humans at the recommended clinical dose. The highest doses of the major, inactive human metabolites similarly tested produced exposures approximately 26 times higher in mice than in humans at the recommended clinical dose (see TOXICOLOGY, Reproduction and Teratology).

Nursing Women

It is not known whether paritaprevir/ritonavir, ombitasvir and their metabolites are excreted in human breast milk. Paritaprevir and its hydrolysis product M13, unchanged ombitasvir were the predominant components observed in the milk of lactating rats, without effect on nursing pups. A risk to the newborn cannot be excluded; therefore nursing must be discontinued prior to initiation of treatment with TECHNIVIE. Physicians prescribing ribavirin should also refer the patient to the Product Monograph for ribavirin.

Pediatrics (< 18 years of age)

Safety and effectiveness of TECHNIVIE in children less than 18 years of age have not been established.

Geriatrics (> 65 years of age)

No dose adjustment of TECHNIVIE is warranted in geriatric patients. In the clinical trial PEARL-I, 3.0% (4/135) of patients with genotype 4 chronic HCV infection were at least 65 years of age. In Phase 3 clinical trials of ombitasvir, paritaprevir and ritonavir plus dasabuvir, 8.5% (174/2053) of patients were at least 65 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

HCV-HBV Co-infection

The safety and efficacy of TECHNIVIE have not been established in patients co-infected with hepatitis B.

HCV-HIV Co-infection

The safety and efficacy of TECHNIVIE have not been established in patients co-infected with HIV. The ritonavir component of TECHNIVIE is also an HIV-1 protease inhibitor and can select for HIV-1 protease inhibitor resistance-associated substitutions. Any HCV/HIV-1 co-infected patients treated with TECHNIVIE should also be on a suppressive antiretroviral drug regimen to reduce the risk of HIV-1 protease inhibitor drug resistance.

TECHNIVIE is contraindicated with efavirenz-containing regimens (see DRUG INTERACTIONS, Drug-Drug Interactions, Drugs that Are Contraindicated with TECHNIVIE).

Drug interactions should be taken into account when treating HIV-co-infection (see Table 5).

Post-Liver Transplant

The safety and efficacy of TECHNIVIE have not been established in post liver transplant patients.

Use in Patients Who Have Failed Previous Therapy with Direct-Acting Antivirals against HCV

TECHNIVIE efficacy has not been studied in patients who have previously failed therapy with other direct-acting antiviral (DAA) agents.

Monitoring and Laboratory Tests

Refer to WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, ALT Elevations for additional information.

Adverse Reactions

Adverse Drug Reaction Overview

TECHNIVIE should be administered with ribavirin (RBV). Refer to the ribavirin Product Monograph for a list of ribavirin-associated adverse reactions.

The safety assessment of TECHNIVIE is based on data from a clinical study that included 91 genotype 4-infected patients without cirrhosis (treatment naïve or pegIFN/RBV-experienced) who received ombitasvir, paritaprevir and ritonavir with ribavirin for 12 weeks and 126 patients (of which 82 were genotype 1b-infected and either treatment naïve or null responders to previous pegIFN/RBV treatment and 44 were genotype 4-infected and treatment naïve) without cirrhosis who received ombitasvir, paritaprevir and ritonavir without ribavirin for 12 weeks (PEARL-I).

In patients receiving ombitasvir, paritaprevir and ritonavir with ribavirin, the most commonly reported treatment emergent adverse events considered related to study drug by site investigator (greater than 10% of patients) were asthenia, fatigue, and headache. No subject permanently discontinued treatment due to a related adverse event and no patient had a treatment interruption due to a related adverse event.

In patients receiving ombitasvir, paritaprevir and ritonavir without ribavirin, the most commonly reported treatment emergent adverse events considered related to study drug by site investigator (greater than 10% of patients) were asthenia and headache. No patient permanently discontinued treatment due to a related adverse event and one patient had a treatment interruption due to a related adverse event.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The adverse drug reactions of at least moderate intensity (Grades 2 to 4) and considered at least possibly or related to treatment and occurring at a frequency of ≥ 2% in the clinical trial of TECHNIVIE are presented in Table 2.

The majority of adverse events in the PEARL-I clinical trial were of grade 1 severity. The safety profile of ombitasvir, paritaprevir and ritonavir with ribavirin was consistent with the known safety profile of ribavirin.

Table 2. Tabulation of Adverse Reactions* of at Least Moderate Intensity (Grade 2 – 4) in ≥ 2% of Patients Without Cirrhosis in PEARL-I
Adverse Reaction Ombitasvir, paritaprevir,
ritonavir + RBV
12 Weeks
N = 91
n (%)
Ombitasvir, paritaprevir,
ritonavir
12 Weeks
N = 126
n (%)
Headache 3 (3.3) 3 (2.4)
Pruritus 3 (3.3) 0
Asthenia 2 (2.2) 1 (0.8)
Hyperbilirubinaemia 2 (2.2) 0
Insomnia 2 (2.2) 1 (0.8)
Fatigue 1 (1.1) 3 (2.4)

* Frequencies of adverse events are based on treatment-emergent adverse events considered at least possibly related to study drug by site investigators.

Less Common Clinical Trial Adverse Drug Reactions (< 2%)

Treatment emergent adverse events (Grades 2 to 4) considered at least possibly related to study drug by site investigators which occurred in less than 2% of patients in the PEARL-I clinical trial are listed below by system organ class (Table 3).

Table 3. Adverse Reactions (Grade 2 – 4) in < 2% of Patients in PEARL-I
Body System Adverse Events
Gastrointestinal disorders: aphthous stomatitis, diarrhoea, dyspepsia, nausea
General disorders and
administration site conditions:
chills, drug withdrawal syndrome, irritability, oedema peripheral
Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased
Metabolism and nutrition
disorders:
decreased appetite
Musculoskeletal and connective
tissue disorders:
muscle spasms
Nervous system disorders: disturbance in attention, memory impairment
Psychiatric disorders: abnormal dreams, anhedonia, anxiety, depression, libido decreased
Respiratory, thoracic and
mediastinal disorders:
epistaxis
Skin and subcutaneous tissue
disorders:
dry skin, eczema

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory Abnormalities

Changes in selected laboratory parameters are described in Table 4.

Table 4. Selected Treatment Emergent Laboratory Abnormalities of at Least Moderate Intensity (Grades 2-4) in Study PEARL-I
Laboratory Parameters Ombitasvir, paritaprevir,
ritonavir + RBV
12 Weeks
N = 91 %
Ombitasvir, paritaprevir,
ritonavir
12 Weeks
N = 126a
%
ALT
> 5-20 × ULN* (Grade 3) 0 1.6b
> 20 × ULN (Grade 4) 0 0
Hemoglobin
< 10-8 g/dL (Grade 2) 2.2 0.8
< 8-6.5 g/dL (Grade 3) 1.1 0
< 6.5 g/dL (Grade 4) 0 0
Total Bilirubin
> 3-10 × ULN (Grade 3) 3.3 0
> 10 × ULN (Grade 4) 0 0

* ULN: Upper Limit of Normal according to testing laboratory.

aPercentages were based on 125 patients with postbaseline values for the respective parameters.

bALT elevations were asymptomatic, occurred during the first 4 weeks of treatment and resolved while continuing therapy.

Serum ALT Elevations

During clinical trials with ombitasvir, paritaprevir and ritonavir with or without dasabuvir and with and without ribavirin, less than 1% of patients who were not on systemic estrogen-containing medications experienced transient serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment. These elevations were asymptomatic, generally occurred during the first 4 weeks of treatment and resolved with ongoing therapy. Increases in ALT were not associated with simultaneous increases in bilirubin levels. No specific monitoring of liver chemistries is required for the majority of patients (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, ALT Elevations).

Serum Bilirubin Elevations

Transient elevations in bilirubin (predominantly indirect) were observed in patients receiving ombitasvir, paritaprevir and ritonavir with or without dasabuvir and with ribavirin, related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced hemolysis. Bilirubin elevations occurred after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were not associated with aminotransferase elevations. The frequency of indirect bilirubin elevations was lower among patients who did not receive ribavirin.

Post-Market Adverse Drug Reactions

Hypersensitivity reactions (including angioedema) have been observed.

Drug Interactions

Overview

Drug interaction studies were conducted with a combination of the individual components of TECHNIVIE (ombitasvir + paritaprevir + ritonavir) with or without dasabuvir or with co-formulated products (ombitasvir + paritaprevir/ritonavir or ombitasvir/paritaprevir/ritonavir) with or without dasabuvir.

Drug-Drug Interactions

Potential for TECHNIVIE to Affect Other Drugs

Paritaprevir is an inhibitor of OATP1B1 and OATP1B3, and paritaprevir and ritonavir are inhibitors of OATP2B1. Paritaprevir and ritonavir are inhibitors of P-gp, BCRP. Paritaprevir and ombitasvir are inhibitors of UGT1A1, and ritonavir is an inhibitor of cytochrome P450 (CYP) 3A4. Drugs that are primarily metabolized by CYP3A, or are substrates of UGT1A1, BCRP, OATP1B1, OATP1B3 or OATP2B1 may have significantly increased plasma concentrations when co-administered with TECHNIVIE (ombitasvir/paritaprevir/ritonavir).

While ritonavir alone is shown to induce multiple CYPs (cytochrome P450) in vitro, TECHNIVIE does not significantly affect CYP2C9 at clinically relevant concentrations. In addition, TECHNIVIE is not expected to inhibit CYP2D6 and a clinically significant increase in exposures of CYP2D6 substrates is not expected during co-administration with TECHNIVIE. However, co-administration of TECHNIVIE can decrease exposures of drugs that are primarily metabolized by CYP2C19 (e.g., omeprazole) and clinical monitoring and/or dose increases might be needed for these substrates.

Paritaprevir, ombitasvir and ritonavir do not inhibit organic anion transporter (OAT1) in vivo and are not expected to inhibit organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations; therefore TECHNIVIE does not affect these active renal elimination pathways.

Paritaprevir, ombitasvir and ritonavir are not expected to inhibit organic cation transporter 1 (OCT1) at clinically relevant concentrations.

Potential for Other Drugs to Affect TECHNIVIE

Paritaprevir and ritonavir are primarily metabolized by CYP3A.

Strong inhibitors of CYP3A may significantly increase paritaprevir and ritonavir exposures when co-administered with TECHNIVIE.

Drugs that induce CYP3A are expected to decrease paritaprevir, ombitasvir and ritonavir plasma concentrations significantly and reduce their therapeutic effect.

Drugs that are moderate or strong CYP3A inducers are contraindicated with TECHNIVIE (see CONTRAINDICATIONS).

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 exposures of TECHNIVIE.

Paritaprevir is a substrate of CYP3A and transport proteins. Caution is advised if co-administering TECHNIVIE with products that are both moderate inhibitors of CYP3A4 and inhibitors of multiple transporters (P-gp, BCRP and/or OATP1B1/ OATP1B3) as it can result in clinically relevant increases in paritaprevir exposures.

Drugs that Are Contraindicated with TECHNIVIE

The drugs that are contraindicated with TECHNIVIE are summarized in Table 5.

Table 5. Drugs that Are Contraindicated with TECHNIVIE
Drug Class: Specific
Drugs
Mechanism of Action Clinical Comment
ACYL-COENZYME A: CHOLESTEROL O-ACYLTRANSFERASE (ACAT) INHBITORS
avasimibe*CYP3A4 induction by avasimibeCONTRAINDICATED since ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE.
ALPHA1-ADRENORECEPTOR ANTAGONISTS
alfuzosin HCLCYP3A inhibition by ritonavirCONTRAINDICATED due to potential for increased alfuzosin concentrations which can result in hypotension.
ANTIBACTERIAL
nafcillin*CYP3A4 induction by nafcillinCONTRAINDICATED since ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE.
ANTICONVULSANTS
carbamazepine, phenytoin, phenobarbitalCYP3A4 induction by carbamazepine, phenytoin, phenobarbitalCONTRAINDICATED since ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE.
ANTIHISTAMINES
astemizole, terfenadineCYP3A4 inhibition by ritonavirCONTRAINDICATED due to potential for cardiac arrhythmias.
ANTIMYCOBACTERIALS
rifampinCYP3A4/CYP2C8 induction by rifampinCONTRAINDICATED since ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE
ANTIVIRALS
efavirenz-containing regimens, such as Atripla, etravirineCYP3A4 induction by efavirenzCONTRAINDICATED since co-administration of efavirenz-based regimen with paritaprevir and ritonavir containing regimen was poorly tolerated and resulted in liver enzyme elevations; and during co-administration with etravirine, ombitasvir, paritaprevir and ritonavir exposures may decrease, leading to a potential loss of therapeutic activity of TECHNIVIE.
nevirapineCYP3A4 induction by nevirapineCONTRAINDICATED since ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE.
BENZODIAZEPINES
oral midazolam, triazolamCYP3A4 inhibition by ritonavirCONTRAINDICATED due to potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Co-administration of triazolam or orally administered midazolam with TECHNIVIE may cause large increases in the concentration of these benzodiazepines.
ENDOTHELIN RECEPTOR ANTAGONIST
bosentanCYP3A4 induction by bosentanCONTRAINDICATED since ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE.
ERGOT DERIVATIVES
ergotamine, dihydroergotamine, ergonovine*, methylergonovine*CYP3A4 inhibition by ritonavirCONTRAINDICATED as acute ergot toxicity characterized by vasospasm and tissue ischemia has been associated with co-administration of ritonavir and ergonovine, ergotamine, dihydroergotamine, or methylergonovine.
GI MOTILITY AGENTS
cisapride*CYP3A4 inhibition by ritonavirCONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
HERBAL PRODUCTS
St. John’s Wort (Hypericum perforatum)CYP3A4 induction by St. John's WortCONTRAINDICATED since ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE.
HORMONAL PRODUCTS
ethinyl estradiol-containing drugs (combined oral contraceptives, contraceptive vaginal rings, contraceptive patch)possibly due to UGT inhibition by ombitasvir and paritaprevirCONTRAINDICATED due to potential for ALT elevations.
HMG CoA REDUCTASE INHIBITORS
lovastatin, simvastatinCYP3A4 and OATP1B inhibition by ritonavir and paritaprevir, respectivelyCONTRAINDICATED due to potential for serious reactions such as myopathy including rhabdomyolysis.
LONG-ACTING BETA-ADRENOCEPTOR AGONISTS
salmeterolCYP3A4 inhibition by ritonavirCONTRAINDICATED as concomitant use of salmeterol and TECHNIVIE may result in increased cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
NEUROLEPTICS
pimozideCYP3A4 inhibition by ritonavirCONTRAINDICATED due to potential for cardiac arrhythmias.
PDE5 ENZYME INHIBITORS
sildenafil only at the doses used daily for the treatment of pulmonary arterial hypertensionCYP3A4 inhibition by ritonavirCONTRAINDICATED due to increased potential for sildenafil-associated adverse events such as visual disturbances, hypotension, priapism, and syncope.
OTHERS
modafinilCYP3A4 induction by modafinilCONTRAINDICATED since ombitasvir, paritaprevir and ritonavir exposures may decrease leading to a potential loss of therapeutic activity of TECHNIVIE.
* Drugs not sold in Canada

Drugs that Should not be Co-administered with TECHNIVIE

The drugs that should not be co-administered with TECHNIVIE are summarized in Table 6.

Table 6. Drugs that Should not be Co-administered with TECHNIVIE
Drug Class: Specific Drugs Clinical Comment
ANTIARRHYTHMICS
amiodarone, flecainide,
propafenone, quinidine
Should not be co-administered since these drugs are CYP3A substrates and their exposures may increase during co-administration with TECHNIVIE. Physicians considering combined therapy of TECHNIVIE with amiodarone should refer to the current amiodarone Product Monograph, carefully weigh the potential benefits and risks, and monitor patients for amiodarone-associated adverse reactions.
ANTIVIRALS
rilpivirine Should not be co-administered since rilpivirine exposures increased by up to 243% during co-administration with ombitasvir, paritaprevir and ritonavir with dasabuvir, which may lead to potential for QT interval prolongation.
ritonavir and ritonavir-containing
regimens, including
atazanavir/ritonavir,
darunavir/ritonavir,
lopinavir/ritonavir
Should not be co-administered with TECHNIVIE due to the potential for an increase in paritaprevir exposures. For administration of TECHNIVIE with atazanavir or darunavir without additional ritonavir, refer to Table 7.
IMMUNOSUPPRESSANTS
sirolimus Should not be co-administered since sirolimus is a substrate of CYP3A and P-gp and its exposure may increase during co-administration with TECHNIVIE.
OPIOID ANALGESICS
alfentanil, fentanyl Should not be co-administered since these drugs are CYP3A substrates and their exposures may increase during co-administration with TECHNIVIE.

Established and Other Potential Drug Interactions

Table 7 provides the effect of co-administration of TECHNIVIE on concentrations of concomitant drugs and effects of other drugs on TECHNIVIE.

Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug
Name
Effect on
Concentration of
Concomitant Drug
Clinical comments
ANTIARRHYTHMICS
digoxin↑ digoxinDigoxin AUC increased by 36%. Decrease digoxin dose by 30-50%. Appropriate monitoring of serum digoxin levels is recommended. Monitor P-gp substrate concentration for NTI drugs.
ANTICOAGULANTS
warfarin↓ warfarinS-warfarin and R-warfarin AUC decreased by 15%. While no dose adjustment is necessary for warfarin, appropriate monitoring of international normalized ratio (INR) is recommended.
ANTIFUNGALS
ketoconazole↑ ketoconazole
↑ paritaprevir
A single dose of ombitasvir, paritaprevir and ritonavir increased ketoconazole exposure by 105%, and paritaprevir exposure increased by nearly 2-fold. The effect of multiple doses of TECHNIVIE on ketoconazole exposure could be of much greater magnitude. Caution is warranted, and patients should be monitored for adverse reactions to ketoconazole and TECHNIVIE. Doses of ketoconazole should be reduced as appropriate.
itraconazole and posaconazole↑ itraconazole
↑ posaconazole
↑ paritaprevir
Drug interactions similar to ketoconazole are expected; monitor patients for adverse reactions and reduce the dose of the co-administered drug as appropriate.
voriconazole↓ voriconazole
↑ paritaprevir
Co-administration of TECHNIVIE with voriconazole is recommended only if the assessment of the benefit-to-risk ratio justifies the use of voriconazole.
CALCIUM CHANNEL BLOCKERS
amlodipine1↑ amlodipineAmlodipine AUC increased by 157%. When co-administering amlodipine with TECHNIVIE. Caution is warranted and a 50% reduction in the dose of amlodipine should be considered.
DIURETICS
furosemide1↑ furosemide (Cmax)Furosemide Cmax increased by 42%. Caution is warranted when co-administering furosemide with TECHNIVIE and furosemide dose may be decreased up to 50% based on clinical response.
HIV-ANTIVIRAL AGENTS
atazanaviratazanavir
administered in the
morning
↔ atazanavir
↑ paritaprevir
Atazanavir should be taken without ritonavir with TECHNIVIE since ritonavir is included in TECHNIVIE. Atazanavir plus ritonavir is not recommended with TECHNIVIE.
darunavir↓ darunavir (Ctrough)Darunavir dose should be taken without ritonavir when co-administered with TECHNIVIE. Because of decreased darunavir trough concentrations, patients should be monitored for HIV-1viral breakthrough.
HMG CoA REDUCTASE INHIBITORS
rosuvastatin↑ rosuvastatinFollowing multiple doses with ombitasvir, paritaprevir and ritonavir, rosuvastatin Cmax and AUC were increased 160% and 33%, respectively compared to rosuvastatin administered alone.
Rosuvastatin dose should not exceed 20 mg per day. Patients should be monitored for rosuvastatin side effects such as myopathy/rhabdomyolysis.
pravastatin↑ pravastatinPravastatin dose should not exceed 40 mg per day. Patients should be monitored for pravastatin side effects such as myopathy/rhabdomyolysis.
IMMUNOSUPPRESSANTS
cyclosporine↑ cyclosporine
↑ paritaprevir
Cyclosporine exposure increased by 4 -fold. When starting co-administration with TECHNIVIE , give one fifth of the total daily dose of cyclosporine once daily with TECHNIVIE. Monitor cyclosporine levels and adjust dose and/or dosing frequency as needed.
tacrolimus↑ tacrolimusTacrolimus exposure increased by > 85-fold. Tacrolimus t½ increased from 32 to 253 hours in the presence of ombitasvir, paritaprevir and ritonavir. When starting co-administration with TECHNIVIE, administer 0.5 mg tacrolimus once every week. Monitor tacrolimus levels and adjust dose and/or dosing frequency as needed.
NARCOTIC ANALGESICS
buprenorphine/naloxone↑ buprenorphine
↑ norbuprenorphine
Buprenorphine and norbuprenorphine exposures increased by 51% and 111%, respectively. However, no dose adjustment of buprenorphine/naloxone is required upon co-administration with TECHNIVIE.
PROTON PUMP INHIBITORS
omeprazole↓ omeprazoleOmeprazole AUC decreased by 54%. Use higher doses of omeprazole if clinically indicated.
SEDATIVES/HYPNOTICS
alprazolam1↑ alprazolamAlprazolam AUC increased by 34%. Caution is warranted and clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response.

1Drug interaction evaluated with ombitasvir and paritaprevir/ritonavir in combination with dasabuvir.

For the co-administered drug, 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%, ↔ = no change or change less than 20%).

Drugs with No Observed Interactions with TECHNIVIE

Drug interaction studies in patients reveal no clinically significant interaction between TECHNIVIE and the following commonly co-prescribed medications. No dose adjustments are required when co-administering these drugs with TECHNIVIE: methadone, naloxone, duloxetine, escitalopram, norethindrone, emtricitabine, raltegravir, zolpidem, tenofovir disoproxil fumarate, gemfibrozil, progestin only contraceptives, warfarin.

Note: progestin only contraceptives and zolpidem were evaluated with ombitasvir and paritaprevir/ritonavir in combination with dasabuvir.

Drug Interaction Pharmacokinetic Parameters for Clinically Relevant Interactions

Magnitude of pharmacokinetic interaction for drug interactions resulting in contraindications, dose modification or clinical monitoring is presented in Table 8 and Table 9. Table 8 provides the magnitude of interaction on the individual components of TECHNIVIE and Table 9 shows the effect on the concomitant medication. For information regarding clinical recommendations, see Table 7.

Table 8. Drug Interactions: Change in Pharmacokinetic Parameters of the Individual Components of TECHNIVIE in the Presence of Co-administered Drug
Co-administered
Drug
Dose of Co-
administered
Drug (mg)
n DAA Ratio (with/without co-administered
drug) of
DAA Pharmacokinetic Parameters
(90% CI);
No Effect = 1.00
Cmax AUC Cmin
ANTIARRHYTHMICS
Digoxin0.5 single dose11ombitasvir0.99 (0.95-1.04)1.02 (0.98-1.06)1.01 (0.98-1.05)
paritaprevir1.15 (0.97-1.36)1.12 (1.00-1.25)0.97 (0.84-1.13)
ritonavir1.06 (0.99-1.13)1.01 (0.98-1.05)0.95 (0.86-1.04)
ANTICONVULSANTS
Carbamazepinea200 once daily followed by 200 twice daily12ombitasvir0.69 (0.61, 0.78)0.69 (0.64, 0.74)NA
paritaprevir0.34 (0.25, 0.48)0.30 (0.23, 0.38)NA
ritonavir0.17 (0.12, 0.24)0.13 (0.09, 0.17)NA
ANTIFUNGALS
Ketoconazole400 once daily12ombitasvir0.98 (0.92, 1.04)1.26 (1.20, 1.32)NA
paritaprevir1.72 (1.32, 2.26)2.16 (1.76, 2.66)NA
ritonavir1.27 (1.11, 1.45)1.51 (1.36, 1.68)NA
CALCIUM CHANNEL BLOCKERS
Amlodipinea5 single dose14ombitasvir1.00 (0.95, 1.06)1.00 (0.97, 1.04)1.00 (0.97, 1.04)
paritaprevir0.77 (0.64, 0.94)0.78 (0.68, 0.88)0.88 (0.80, 0.95)
ritonavir0.96 (0.87, 1.06)0.93 (0.89, 0.98)0.95 (0.89, 1.01)
DIURETICS
Furosemidea20 single dose12ombitasvir1.14 (1.03, 1.26)1.07 (1.01, 1.12)1.12 (1.08, 1.16)
paritaprevir0.93 (0.63, 1.36)0.92 (0.70, 1.21)1.26 (1.16, 1.38)
ritonavir1,1 (0.96, 1.27)1,04 (0.92, 1.18)1,07 (0.99, 1.17)
HIV-ANTIVIRAL AGENTS
Atazanavirb300 once daily10ombitasvir0.83 (0.74, 0.94)0.91 (0.81, 1.02)0.98 (0.87, 1.11)
paritaprevir2.74 (1.76, 4.27)2.87 (2.08, 3.97)3.71 (2.87, 4.79)
ritonavir0.85 (0.72, 0.99)0.97 (0.84, 1.13)1.45 (1.29, 1.64)
Darunavirb800 once daily9ombitasvir1.01 (0.87, 1.17)1.01 (0.91, 1.11)1.06 (0.99, 1.13)
paritaprevir2.09 (1.35, 3.24)1.94 (1.36, 2.75)1.85 (1.41, 2.42)
ritonavir0.83 (0.68, 1.01)0.80 (0.73, 0.87)0.91 (0.78, 1.06)
Lopinavir/
ritonavir
400/100 twice daily18ombitasvir1.07 (1.01, 1.13)1.25 (1.19, 1.32)1.48 (1.39, 1.57)
paritaprevir4.76 (3.54, 6.39)6.10 (4.30, 8.67)12.33 (7.30, 20.84)
ritonavir1.74 (1.39, 2.17)2.78 (2.42, 3.20)10.02 (7.66, 13.11)
Lopinavir/
ritonavirc
800/200 once daily11ombitasvir0.97 (0.87, 1.08)1.09 (1.00, 1.19)1.24 (1.13, 1.35)
paritaprevir1.78 (1.26, 2.52)3.55 (2.37, 5.32)14.78 (9.41, 23.23)
ritonavir1.80 (1.30, 2.48)3.09 (2.36, 4.06)23.16 (15.55, 34.51)
Rilpivirinea25 once daily (morning)d10ombitasvir1.11 (1.02, 1.20)1.09 (1.04, 1.14)1.05 (1.01, 1.08)
paritaprevir1.30 (0.94, 1.81)1.23 (0.93, 1.64)0.95 (0.84, 1.07)
ritonavir1.10 (0.98, 1.24)1.08 (0.93, 1.27)0.97 (0.91, 1.04)
HMG CoA REDUCTASE INHIBITORS
Pravastatin10 once daily10ombitasvir0.98 (0.90, 1.06)0.94 (0.88, 1.02)0.97 (0.90, 1.03)
paritaprevir1.44 (1.15, 1.81)1.33 (1.09, 1.62)1.28 (0.83, 1.96)
ritonavir1.37 (1.05, 1.79)1.37 (0.84, 2.24)0.85 (0.76, 0.96)
HORMONAL PRODUCT
Ethinyl estradiol/ NorgestimateEthinyl estradiol 0.035 and Norgestimate 0.25 once daily7eombitasvir1.05 (0.81, 1.35)0.97 (0.81, 1.15)0.96 (0.88, 1.12)
paritaprevir0.70 (0.40, 1.21)0.66 (0.42, 1.04)0.87 (0.67, 1.14)
ritonavir0.80 (0.53, 1.21)0.71 (0.54, 0.94)0.79 (0.68, 0.93)
IMMUNOSUPPRESSANTS
Cyclosporine10 single dosef12ombitasvir1.06 (1.02, 1.11)1.10 (1.07, 1.12)1.10 (1.06, 1.14)
paritaprevir1.39 (1.10, 1.75)1.46 (1.29, 1.64)1.18 (1.08, 1.30)
ritonavir1.13 (0.94, 1.35)1.20 (1.10, 1.30)1.11 (0.89, 1.37)
Tacrolimus0.5 single doseg11ombitasvir0.94 (0.89, 1.00)0.95 (0.91, 1.00)0.95 (0.92, 0.99)
paritaprevir0.71 (0.55, 0.91)0.79 (0.69, 0.92)0.84 (0.74, 0.97)
ritonavir0.88 (0.76, 0.93)0.89 (0.85, 0.93)1.04 (0.96, 1.13)
PROTON PUMP INHIBITORS
Omeprazole40 once daily12ombitasvir0.96 (0.81, 1.14)1.00 (0.88, 1.12)0.97 (0.89, 1.107)
paritaprevir1.02 (0.64, 1.62)0.93 (0.64, 1.34)0.83 (0.67, 1.04)
ritonavir1.06 (0.95, 1.18)1.07 (0.96, 1.21)1.07 (0.97, 1.18)
SEDATIVES/HYPNOTICS
Alprazolama0.5 single dose12ombitasvir0.98 (0.93, 1.04)1.00 (0.96, 1.04)0.98 (0.93, 1.04)
paritaprevir0.91 (0.64, 1.31)0.96 (0.73, 1.27)1.12 (1.02, 1.23)
ritonavir0.92 (0.84, 1.02)0.96 (0.89, 1.03)1.01 (0.94, 1.09)

a. Study evaluated interaction with ombitasvir/paritaprevir/ritonavir plus dasabuvir; results extrapolated to ombitasvir/paritaprevir/ritonavir.

b. Atazanavir or darunavir administered with ombitasvir/paritaprevir/ritonavir in the morning was compared to atazanavir or darunavir administered with 100 mg ritonavir in the morning.

c. Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of ombitasvir/paritaprevir/ritonavir.

d. Similar changes were observed when rilpivirine was dosed in the evening with food or 4 hours after food.

e. Data shown is combined data for ombitasvir/paritaprevir/ritonavir with (N=3) and without (N=4) dasabuvir.

f. 10 mg cyclosporine was administered with ombitasvir/paritaprevir/ritonavir in the test arm and 100 mg cyclosporine was administered in the reference arm without ombitasvir/paritaprevir/ritonavir.

g. 0.5 mg tacrolimus was administered with ombitasvir/paritaprevir/ritonavir in the test arm and 2 mg tacrolimus was administered in the reference arm without ombitasvir/paritaprevir/ritonavir.

NA: not available/not applicable; DAA: Direct-acting antiviral agent; CI: Confidence interval.

Doses of ombitasvir, paritaprevir, ritonavir were 25 mg, 150 mg and 100 mg, respectively.

For studies conducted with ombitasvir/paritaprevir/ritonavir plus dasabuvir, doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures).

Ombitasvir, paritaprevir and ritonavir were dosed once daily (and where applicable, dasabuvir was dosed twice daily) in all the above studies except studies with ketoconazole and carbamazepine that used single doses.

Table 9 summarizes the effects of TECHNIVIE on the pharmacokinetics of co-administered drugs which showed clinically relevant changes. For information regarding clinical recommendations, see Table 7.

Table 9. Drug Interactions: Change in Pharmacokinetic Parameters for Co-administered Drug in the Presence of TECHNIVIE
Co-administered
Drug
Dose of Co-
administered
Drug (mg)
n Ratio (with/without TECHNIVIE) of Co-
administered Drug Pharmacokinetic
Parameters
(90% CI); No Effect = 1.00
Cmax AUC Cmin
ANTIARRHYTHMICS
Digoxin0.5 single dose111.58 (1.43-1.73)1.36 (1.21-1.53)1.24 (1.07-1.43)
ANTICONVULSANTS
Carbamazepinea200 once daily followed by 200 twice daily121.10 (1.07, 1.14)1.17 (1.13, 1.22)1.35 (1.27, 1.45)
Carbamazepine’s metabolite, carbamazepine-10,11-epoxide (CBZE)0.84 (0.82, 0.87)0.75 (0.73, 0.77)0.57 (0.54, 0.61)
ANTIFUNGALS
Ketoconazole400 once daily121.10 (1.05, 1.16)2.05 (1.93, 2.18)NA
CALCIUM CHANNEL BLOCKERS
Amlodipinea5 single dose141.26 (1.11, 1.44)2.57 (2.31, 2.86)NA
DIURETICS
Furosemidea20 single dose121.42 (1.17, 1.72)1.08 (1.00, 1.17)NA
HIV-ANTIVIRAL AGENTS
Atazanavirb300 once daily110.90 (0.83, 0.97)0.93 (0.85, 1.02)0.81 (0.72, 0.91)
Darunavirb800 once daily90.99 (0.92, 1.08)0.92 (0.84, 1.00)0.74 (0.63, 0.88)
Lopinavir/ritonavirc400/100 twice daily181.06 (0.99, 1.14)1.13 (1.09, 1.17)1.34 (1.26, 1.42)
Lopinavir/ritonavirc,d800/200 once daily121.05 (0.95, 1.17)1.17 (1.09, 1.26)3.50 (2.69, 4.56)
Rilpivirinea25 once daily (morning)e82.55 (2.08, 3.12)3.25 (2.80, 3.77)3.62 (3.12, 4.21)
HMG CoA REDUCTASE INHIBITORS
Pravastatin10 once daily101.43 (1.09, 1.88)1.76 (1.46, 2.13)NA
HORMONAL PRODUCT
Ethinyl EstradiolfEthinyl estradiol 0.035 and Norgestimate 0.25 once daily81.16 (0.90, 1.50)1.06 (0.96, 1.17)1.12 (0.94, 1.33)
Norelgestrominf92.01 (1.77, 2.29)2.60 (2.30, 2.95)3.11 (2.51, 3.85)
Norgestref92.26 (1.91, 2.67)2.54 (2.09, 3.09)2.93 (2.39, 3.57)
IMMUNOSUPPRESSANTS
Cyclosporine10 single doseg120.83 (0.72, 0.94)h4.28 (3.66, 5.01)h12.85 (10.61, 15.55)h
Tacrolimus0.5 single dosei114.27 (3.49, 5.22)h85.81 (67.88, 108.49)h24.61 (19.69, 30.77)h
PROTON PUMP INHIBITORS
Omeprazole40 once daily120.48 (0.29, 0.78)0.46 (0.27, 0.77)NA
SEDATIVES/HYPNOTICS
Alprazolama0.5 single dose121.09 (1.03, 1.15)1.34 (1.15, 1.55)NA

a. Study evaluated interaction with ombitasvir/paritaprevir/ritonavir plus dasabuvir; results extrapolated to ombitasvir/paritaprevir/ritonavir.

b. Atazanavir or darunavir administered with ombitasvir/paritaprevir/ritonavir in the morning.

c. Lopinavir parameters are reported.

d. Lopinavir/ritonavir administered in the evening, 12 hours after morning dose of ombitasvir/paritaprevir/ritonavir.

e. Similar increases were observed when rilpivirine was dosed in the evening with food or 4 hours after food.

f. Data shown are combined data for ombitasvir/paritaprevir/ritonavir with (N=3) and without (N=6, except for EE where N=5) dasabuvir.

g. 10 mg cyclosporine was administered with ombitasvir/paritaprevir/ritonavir in the test arm and 100 mg cyclosporine was administered in the reference arm without ombitasvir/paritaprevir/ritonavir.

h. Dose normalized parameters reported.

i. 0.5 mg tacrolimus was administered with ombitasvir/paritaprevir/ritonavir in the test arm and 2 mg tacrolimus was administered in the reference arm without ombitasvir/paritaprevir/ritonavir.

NA: not available/not applicable; CI: Confidence interval.

Doses of ombitasvir, paritaprevir and ritonavir were 25 mg, 150 mg and 100 mg, respectively.

For studies conducted with ombitasvir/paritaprevir/ritonavir plus dasabuvir, doses of dasabuvir were 250 mg or 400 mg (both doses showed similar exposures).

Ombitasvir, paritaprevir and ritonavir were dosed once daily (and where applicable, dasabuvir was dosed twice daily) in all the above studies except studies with ketoconazole and carbamazepine that used single doses.

Drug-Food Interactions

Food increased the exposure (AUC) of paritaprevir, ombitasvir and ritonavir by up to 211%, 82% and 49% respectively relative to the fasting state. The increase in exposure was similar regardless of meal type (e.g., high-fat versus moderate-fat) or calorie content (approximately 600 Kcal versus approximately 1000 Kcal). To maximize absorption, TECHNIVIE should be taken with food without regard to fat or calorie content (see DOSAGE AND ADMINISTRATION).

Drug-Herb Interactions

Co-administration of St. John’s Wort (Hypericum perforatum), a potent hepatic and intestinal CYP3A4 and/or P-gp inducer, may decrease TECHNIVIE plasma concentrations, which may result in loss of therapeutic effect.

St. John’s Wort (Hypericum perforatum) is contraindicated with TECHNIVIE (see CONTRAINDICATIONS).

Drug-Laboratory Interactions

Interactions of TECHNIVIE with laboratory tests have not been established.

Dosage and Administration

Dosing Considerations

TECHNIVIE is a fixed dose combination (FDC) tablet of ombitasvir/paritaprevir/ritonavir.

TECHNIVIE is used in combination with ribavirin in patients with genotype 4 chronic hepatitis C infection.

TECHNIVIE tablets should be swallowed whole, with water if required, and not chewed, broken, or crushed.

Recommended Dose and Dosage adjustment

The recommended oral dose of TECHNIVIE is two ombitasvir/paritaprevir/ritonavir 12.5/75/50 mg tablets taken once daily (in the morning) with food without regard to fat or calorie content (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption, Effects of Food on Oral Absorption).

As a fixed dose combination formulation, no dosage adjustments for TECHNIVIE are possible.

TECHNIVIE tablets should be used in combination with ribavirin (RBV).

For specific dosage instructions for ribavirin and dose modifications, refer to the prescribing information of ribavirin.

The recommended treatment regimen and duration based on patient population is provided in Table 10.

Table 10. Recommended Treatment Regimen and Treatment Duration for HCV Genotype-4 Treatment-naïvea and Treatment-experiencedb Patients Without Cirrhosis
Patient Population Treatment Duration
Genotype 4, without cirrhosis TECHNIVIEc + RBVd,e
(ombitasvir/paritaprevir/ritonavir + RBV)
Two Tablets, QD
12 weeks

a. Treatment naïve was defined as not having received any prior therapy for HCV infection.

b. Treatment-experienced patients were defined as either: prior relapsers (received at least 36 weeks of pegIFN/RBV treatment and HCV RNA was undetectable at the end of treatment, but HCV RNA was detectable within 52 weeks of treatment follow-up) or prior partial responders (received at least 20 weeks of pegIFN/RBV and achieved a greater than or equal to 2 log10 IU/mL reduction in HCV RNA at week 12, but not achieving HCV RNA undetectable at end of treatment) or prior null-responders (received at least 10 weeks of pegIFN/RBV treatment and failed to achieve a 2 log10 IU/mL reduction in HCV RNA at week 12).

c. The recommended regimen is the co-formulated combination of ombitasvir/paritaprevir/ritonavir (12.5/75/50 mg), two tablets once daily (see Recommended Dose and Dosage Adjustment of DOSAGE AND ADMINISTRATION). The clinical trial was conducted with the individual components (see CLINICAL TRIALS).

d. RBV, ribavirin. When administered with TECHNIVIE, the recommended dosage of RBV is based on weight: 1000 mg for patients subjects <75 kg and 1200 mg/day for those ≥75 kg, divided and administered twice-daily with food.

e. TECHNIVIE administered without RBV for 12 weeks may be considered for treatment-naïve patients who cannot take or tolerate ribavirin (see CLINICAL TRIALS).

TECHNIVIE should be taken as directed for the prescribed duration, without interruption. If TECHNIVIE is administered with ribavirin, ribavirin should be administered for the same duration as TECHNIVIE.

Special Populations

Pediatrics (< 18 years of age)

Safety and effectiveness of TECHNIVIE in children less than 18 years of age have not been established.

Geriatrics (≥ 65 years of age)

No dose adjustment of TECHNIVIE is warranted in geriatric patients (see INDICATIONS AND CLINICAL USE; WARNINGS AND PRECAUTIONS, Geriatric Use; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatric Use).

Hepatic Impairment

No dose adjustment of TECHNIVIE is required in patients with mild hepatic impairment (Child-Pugh A). The safety and efficacy of TECHNIVIE™ have not been established in HCV-infected patients with moderate hepatic impairment (Child-Pugh B). TECHNIVIE should not be used in patients with moderate hepatic impairment (Child-Pugh B). TECHNIVIE is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

Renal Impairment

No dose adjustment of TECHNIVIE is required in patients with mild, moderate or severe renal impairment (see WARNINGS AND PRECAUTIONS, Renal).

TECHNIVIE has not been studied in patients on dialysis.

Missed Dose

Patients should be informed that in case a dose of ombitasvir/paritaprevir/ritonavir is missed, the prescribed dose can be taken within 12 hours.

If not, the missed dose should NOT be taken and the patient should take the next dose as per the usual dosing schedule.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

The highest documented single dose administered to healthy subjects was 400 mg for paritaprevir (with 100 mg ritonavir), 200 mg for ritonavir (with 100 mg paritaprevir) and 350 mg for ombitasvir. No study related adverse reactions with paritaprevir, ritonavir, or ombitasvir were observed. Transient increases in indirect bilirubin were observed at the highest doses of paritaprevir/ritonavir. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted immediately. ECG monitoring is recommended.

Action and Clinical Pharmacology

Mechanism of Action

TECHNIVIE (ombitasvir/paritaprevir/ritonavir) combines two direct-acting hepatitis C virus antiviral agents with distinct mechanisms of action, and non-overlapping resistance profiles, to target HCV at multiple steps in the viral lifecycle (see MICROBIOLOGY, Mechanism of Action).

Paritaprevir is an inhibitor of HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. Ombitasvir is an inhibitor of HCV NS5A which is essential for viral replication. The stopping of viral replication leads to a rapid decline of HCV viral load and clearing of HCV levels in the body.

Ritonavir is not active against HCV. Ritonavir is a potent CYP3A inhibitor that increases peak and trough plasma drug concentrations of paritaprevir and overall drug exposure (i.e., area under the curve).

Pharmacodynamics

Effects on Electrocardiogram

The effect of a combination of paritaprevir, ombitasvir, ritonavir, and dasabuvir on QTc interval was evaluated in a randomized, double blind, placebo and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 60 healthy subjects. At concentrations approximately 6 and 1.8 times the therapeutic concentrations of paritaprevir and ombitasvir, the combination did not prolong QTc to any clinically relevant extent.

Pharmacokinetics

The pharmacokinetic properties of the combination of ombitasvir, paritaprevir and ritonavir have been evaluated in healthy adult subjects and in patients with chronic hepatitis C infection. Table 11 shows mean Cmax and AUC of ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily following multiple doses with food in healthy subjects (Table 11).

Table 11. Geometric Mean Steady-State Exposures of Ombitasvir/Paritaprevir/Ritonavir 25/150/100 mg Once Daily with Food in HCV GT4 Non-Cirrhotic Patients and Healthy Subjects
Compound/Population AUC (ng∙h/mL) Cmax (ng/mL) Cmin (ng/mL)
HCV-Infected Patients*
Ombitasvir 1210 78.1 20.5
Paritaprevir 2320 198 12.4
Ritonavir 5620 478 35.7
Healthy Subjects
Ombitasvir 1370 120 29
Paritaprevir 4770 807 18
Ritonavir 8090 1330 32

*Pharmacokinetic parameters in HCV-infected patients derived from population pharmacokinetic analysis of sparse samples collected from GT-4 infected patients in Study M13-393.

Paritaprevir Cmax and AUC from the ombitasvir/paritaprevir/ritonavir co-formulated tablet are 93% and 63% higher, respectively, compared to exposures of paritaprevir formulation administered in combination with ritonavir and ombitasvir formulations in PEARL-1.

Absorption

In clinical studies in healthy subjects, ombitasvir/paritaprevir/ritonavir were absorbed after oral administration with mean Tmax of approximately 4 to 5 hours. While ombitasvir exposures increased in a dose proportional manner, paritaprevir and ritonavir exposures increased in a more than dose proportional manner. Accumulation is minimal for ombitasvir and approximately 1.5- to 2-fold for ritonavir and paritaprevir. Pharmacokinetic steady state is achieved after approximately 12 days of dosing.

The absolute bioavailability of ombitasvir and paritaprevir when administered with ritonavir as TECHNIVIE was approximately 48.1 and 52.6%, respectively.

Effects of Food on Oral Absorption

A moderate fat meal (approximately 600 Kcal, 20-30% calories from fat) increased the exposure (AUC) of ombitasvir, paritaprevir and ritonavir by up to 82, 211 and 49%, respectively relative to the fasting state.

A high fat meal (approximately 900 Kcal, 60% calories from fat) increased the mean AUC of ombitasvir, paritaprevir and ritonavir with by 76, 180, and 44%, respectively relative to fasting state. The increase in exposure was similar regardless of meal type (e.g., high-fat versus moderate-fat) or calorie content (approximately 600 Kcal versus approximately 1000 Kcal).

Distribution

Ombitasvir, paritaprevir and ritonavir are highly bound to plasma proteins. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. The blood to plasma concentration ratios in humans ranged from 0.6 to 0.8, indicating that ombitasvir and paritaprevir were preferentially distributed in the plasma compartment of whole blood.

Paritaprevir

Paritaprevir was approximately 97 to 98.6% bound to human plasma proteins over a concentration range of 0.08 to 8 mcg per mL. The mean blood-to-plasma concentration ratio was 0.7. The volume of distribution (V) was 103 L.

Ritonavir

Ritonavir was greater than 99% bound to human plasma proteins over a concentration range of 0.007 to 22 mcg per mL. The mean blood-to-plasma concentration ratio was 0.6.

Ombitasvir

Ombitasvir was approximately 99.9% bound to human plasma proteins over a concentration range of 0.09 to 9 mcg per mL. The mean blood-to-plasma concentration ratio was 0.49. The volume of distribution (V) was 173 L.

In animals, paritaprevir liver levels are significantly higher than plasma levels (e.g. liver: plasma ratio of greater than 300:1 in mouse). In vitro data indicate that paritaprevir is a substrate for the human hepatic uptake transporters, OATP1B1 and OATP1B3.

Metabolism

Paritaprevir

Paritaprevir is metabolized predominantly by CYP3A4 and to a lesser extent CYP3A5. Following administration of a single 200/100 mg oral dose of 14C-paritaprevir/ritonavir to humans, the parent drug was the major circulating component accounting for approximately 90% of the plasma radioactivity. At least 5 minor metabolites of paritaprevir have been identified in circulation that accounted for approximately 10% of plasma radioactivity. These metabolites are not expected to have antiviral activity.

Ombitasvir

Ombitasvir is metabolized via amide hydrolysis followed by oxidative metabolism. Following a 25 mg single dose of 14C- ombitasvir given alone, unchanged parent drug accounted for 8.9% of total radioactivity in human plasma; a total of 13 metabolites were identified in human plasma. These metabolites are not expected to have antiviral activity or off-target pharmacologic activity.

Ritonavir

Ritonavir is predominantly metabolized by CYP3A and to a lesser extent, by CYP2D6. Nearly the entire plasma radioactivity after a single 600 mg dose of 14C-ritonavir oral solution in humans was attributed to unchanged ritonavir.

Excretion

Paritaprevir

Following a 200 mg 14C-paritaprevir dose with 100 mg ritonavir, approximately 88% of the radioactivity was recovered in feces with limited radioactivity (8.8%) in urine; unchanged paritaprevir accounted for 1.1% of the radioactivity in the feces and 0.05% in the urine. The mean plasma half-life of paritaprevir was approximately 5.5 hours.

Ombitasvir

Following a 25 mg 14C-ombitasvir dose, approximately 90.2% of the radioactivity was recovered in feces with limited radioactivity (1.91%) in urine; unchanged ombitasvir accounted for 87.8% of the radioactivity in the feces and 0.03% in the urine. The mean elimination half-life of ombitasvir was approximately 21 to 25 hours.

Ritonavir

Following dosing of paritaprevir/ritonavir/ombitasvir, mean plasma half-life of ritonavir was approximately 4 hours. Following a 600 mg dose of 14C-ritonavir oral solution, 86.4% of the radioactivity was recovered in the feces and 11.3% of the dose was excreted in the urine.

Ombitasvir, paritaprevir and ritonavir do not inhibit organic anion transporter (OAT1) in vivo and, based on in vitro data, are not expected to inhibit organic cation transporter (OCT2), organic anion transporter (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations.

Ombitasvir, paritaprevir and ritonavir are neither inhibitors nor substrates of organic cation transporter 1 (OCT1).

Special Populations and Conditions

Pediatrics

The pharmacokinetics of TECHNIVIE in pediatric patients has not been established (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics (< 18 years of age)).

Geriatrics (> 65 years of age)

Due to the limited number of patients at least 65 years of age in the clinical trial PEARL-I, the effect of age on pharmacokinetics could not be determined. Population pharmacokinetic analysis of data from Phase 3 clinical trials with ombitasvir, paritaprevir and ritonavir with dasabuvir showed that a 10 year increase or decrease in age from 54 years (median age in the Phase 3 trials) would result in approximately 10% change in ombitasvir exposures and ≤ 20% change in paritaprevir exposures. Age was not a significant predictor for ritonavir exposures. There is no pharmacokinetic information in patients at least 75 years of age. Phase 3 studies of ombitasvir, paritaprevir and ritonavir with dasabuvir included 174 patients at least 65 years of age (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics (> 65 years of age)).

Gender

Based on population pharmacokinetic analyses in HCV genotype 4-infected patients in the clinical trial PEARL-I, sex had no effect on paritaprevir or ritonavir exposures; male patients would have approximately 29 to 37% lower ombitasvir exposures (Cmax, AUCss and Cmin) than female patients. These effects do not warrant dose adjustments of ombitasvir based on sex.

Race

Based on PEARL-I population pharmacokinetic analyses, exposures of ombitasvir, paritaprevir, and ritonavir were not significantly different in HCV genotype 4-infected patients of Black race compared to patients of other races. Due to the limited number of patients enrolled in PEARL-I, the effect of other ethnicities on pharmacokinetics could not be determined. Ethnicities have been evaluated in Phase 3 studies of ombitasvir, paritaprevir and ritonavir in combination with dasabuvir. Population pharmacokinetic analysis of data from Phase 3 clinical trials with ombitasvir, paritaprevir and ritonavir with dasabuvir showed that Asian patients had 18 to 21% higher ombitasvir exposures, and 37 to 39% higher paritaprevir exposures than non-Asian patients. The ritonavir exposures were comparable between Asians and non-Asians. These differences in exposures were not clinically significant.

Hepatic Insufficiency

Pharmacokinetics of ombitasvir, paritaprevir and ritonavir were not evaluated in patients with hepatic impairment.

The single dose pharmacokinetics of the combination of paritaprevir 200 mg, ritonavir 100 mg, ombitasvir 25 mg, and dasabuvir 400 mg were evaluated in healthy subjects with mild hepatic impairment (Child-Pugh A), moderate hepatic impairment (Child-Pugh B) and severe hepatic impairment (Child-Pugh C).

In patients with mild hepatic impairment paritaprevir, ritonavir and ombitasvir mean AUC values decreased by 29, 34 and 8%, respectively compared to patients with normal hepatic function. No dose adjustment for TECHNIVIE is recommended for HCV-infected patients with mild hepatic impairment.

In patients with moderate hepatic impairment, paritaprevir mean AUC value increased by 62%, ombitasvir and ritonavir mean AUC values decreased by 30% compared to patients with normal hepatic function. The safety and efficacy of TECHNIVIE have not been established in HCV-infected patients with moderate hepatic impairment (Child-Pugh B); because paritaprevir and ritonavir exhibit time-dependent pharmacokinetics, the pharmacokinetics of each component of TECHNIVIE at steady state has not been assessed in patients with moderate hepatic impairment, hence no dosing recommendation can be made. TECHNIVIE should not be used in patients with moderate hepatic impairment.

In patients with severe hepatic impairment, paritaprevir mean AUC values increased by 945%, ritonavir mean AUC value was 13% higher and ombitasvir mean AUC value decreased by 54% compared to patients with normal hepatic function. Therefore, TECHNIVIE should not be used in patients with severe hepatic impairment.

The efficacy of TECHNIVIE have not been established in patients with mild or moderate hepatic impairment (Child-Pugh A or B). TECHNIVIE is contraindicated in patients with severe hepatic impairment (Child-Pugh C).

Renal Insufficiency

Pharmacokinetics of the combination of paritaprevir 150 mg, ombitasvir 25 mg, and ritonavir 100 mg, were evaluated in non-HCV infected patients with mild (creatinine clearance [CrCl]: 60 to 89 mL per min), moderate (CrCl: 30 to 59 mL per min) and severe (CrCl: 15 to 29 mL per min) renal impairment.

Overall, changes in exposure of ombitasvir, paritaprevir and ritonavir in non-HCV infected patients with mild-, moderate- and severe renal impairment are not expected to be clinically relevant.

In patients with mild renal impairment, the mean ritonavir AUC values increased by 40%, while ombitasvir and paritaprevir AUC values were unchanged compared to patients with normal renal function.

In patients with moderate renal impairment, the mean ritonavir AUC values increased by 76%, while ombitasvir and paritaprevir AUC values were unchanged compared to patients with normal renal function.

In patients with severe renal impairment, the mean paritaprevir and ritonavir AUC values increased by 25 and 108%, respectively, while ombitasvir AUC values were unchanged compared to patients with normal renal function.

Consult the Product Monograph of ribavirin in renal impairment patients.

Storage and Stability

Store between 2 and 30°C. Protect from moisture.

Special Handling Instructions

There are no special handling instructions.

Dosage Forms, Composition and Packaging

TECHNIVIE is a pink-colored, film-coated, oblong, biconvex-shaped tablet debossed “AV1” on one side. Each tablet contains 12.5 mg ombitasvir, 75 mg paritaprevir and 50 mg ritonavir.

TECHNIVIE is dispensed in a convenient monthly carton for a total of 28 days of therapy. Each monthly carton contains four weekly cartons. Each weekly carton contains seven daily dose packs.

Each daily dose pack contains two 12.5/75/50 mg ombitasvir/paritaprevir/ritonavir tablets.

Listing of Non-Medicinal Ingredients

Each ombitasvir/paritaprevir/ritonavir fixed dose combination tablet contains 12.5 mg ombitasvir /75 mg paritaprevir/50 mg ritonavir with the following non-medicinal ingredients: colloidal silicon dioxide/anhydrous colloidal silica, copovidone, propylene glycol monolaurate, sodium stearyl fumarate, sorbitan monolaurate, and vitamin E polyethylene glycol succinate. The film-coating ingredients include: iron oxide red, polyethylene glycol/macrogol, polyvinyl alcohol, purified water, talc, and titanium dioxide. The tablets do not contain gluten.