Holkira Pak: Indications, Dosage, Precautions, Adverse Effects
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Holkira Pak - Product Information

Manufacture: AbbVie
Country: Canada
Condition: Hepatitis C, Hepatitis C, Chronic (Hepatitis C)
Class: Antiviral agents
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, iron oxide red, polyethylene glycol/macrogol, polyvinyl alcohol, purified water, talc, and titanium dioxide

HOLKIRA PAK

ombitasvir/paritaprevir/ritonavir and dasabuvir

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Non-medicinal Ingredients
Oral ombitasvir/paritaprevir
/ritonavir film-coated
tablets: 12.5/75/50 mg
None
dasabuvir film-coated
tablets: 250 mg (as
dasabuvir sodium
monohydrate)
Lactose monohydrate
For a complete listing see Dosage Forms,
Composition and Packaging
Section

Indications and Clinical Use

HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir) is indicated for the treatment of adults with genotype 1 chronic hepatitis C (CHC) infection, including those with compensated cirrhosis:

  • with ribavirin in non-cirrhotic patients with genotype 1a infection;
  • without ribavirin in non-cirrhotic patients with genotype 1b infection;
  • with ribavirin in patients with compensated cirrhosis.

Geriatrics (> 65 years of age)

In Phase 3 clinical trials, 8.5% (174/2053) of subjects were age 65 or over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects (see WARNINGS AND PRECAUTIONS).

Pediatrics (< 18 years of age)

Safety and effectiveness of HOLKIRA PAK 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.
  • If HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir) 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).
  • Patients with severe hepatic impairment (Child-Pugh C).
  • The following categories of drugs are contraindicated with HOLKIRA PAK:
    • Drugs for which elevated plasma concentrations are associated with serious adverse events and that are sensitive cytochrome P450 (CYP) 3A substrates.
    • Drugs that are strong CYP2C8 inhibitors, which may increase dasabuvir plasma concentrations.
    • Drugs that are moderate or strong inducers of CYP3A, which may result in substantial lowering of plasma concentrations of paritaprevir, ombitasvir and dasabuvir.
    • Drugs that are strong inducers of CYP2C8, which may result in substantial lowering of plasma concentrations of dasabuvir.
Table 1. Drugs that Are Contraindicated with HOLKIRA PAK
Drug Class Drug Name
Acyl-coenzyme A:cholesterol O-
acyltransferase (ACAT) inhibitor
Avasimibe*
Alpha1-adrenoreceptor antagonist Alfuzosin HCl
Antibacterial Nafcillin*
Antibiotic Fusidic acid (oral formulation)*
Anticonvulsants Carbamazepine, phenytoin, phenobarbital
Antihistamine Astemizole, terfenadine
Antihyperlipidemic Gemfibrozil
Antimycobacterial Rifampin
Antiviral Efavirenz-containing regimens, including Atripla, etravirine
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)
Others Modafinil

* Drugs not sold in Canada.

Warnings and Precautions

General

If HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir) is administered with ribavirin, the warnings and precautions for ribavirin also apply to this combination regimen. Refer to the ribavirin Product Monograph for a full list of the warnings and precautions for ribavirin.

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

Co-administration of HOLKIRA PAK with other direct-acting antivirals against HCV has not been studied and therefore cannot be recommended.

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

Transaminase Elevations

Clinically significant transaminase elevations were observed when HOLKIRA PAK was co-administered with efavirenz or with ethinyl estradiol (see CONTRAINDICATIONS and DRUG INTERACTIONS). When HOLKIRA PAK 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 HOLKIRA PAK 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 HOLKIRA PAK 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 HOLKIRA PAK 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 Quetiapine

The use of HOLKIRA PAK with quetiapine is not recommended due to increases in quetiapine exposure. If co-administration is necessary, reduce the quetiapine dose to 1/6th of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine Product Monograph for the recommendations on adverse reaction monitoring.

Use with Rilpivirine

Concomitant use of HOLKIRA PAK with rilpivirine significantly increased rilpivirine exposure by 243%. Co-administration of HOLKIRA PAK with rilpivirine is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine (see DRUG INTERACTIONS, Drug-Drug Interactions, Drugs that Should not be Co-administered with HOLKIRA PAK; DETAILED PHARMACOLOGY, Pharmacokinetics, Drug Interactions).

Use with HMG-CoA Reductase Inhibitors

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

Cardiovascular

QTc Prolongation

HOLKIRA PAK was associated with concentration-dependent QTc prolongation. At therapeutic plasma concentrations, the maximum mean difference from placebo in the QTc interval was reported to be < 5 ms, with a 95% CI upper limit of < 10 ms (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, Effects on Electrocardiogram and DRUG INTERACTIONS, Drug-Drug Interactions).

Caution should be exercised when drugs that prolong QTc are co-administered with HOLKIRA PAK.

Hepatic/Biliary/Pancreatic

ALT Elevations

During clinical trials with HOLKIRA PAK 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 subjects (see ADVERSE REACTIONS, Abnormal Hematologic and Clinical Chemistry Findings, Laboratory Abnormalities). These ALT elevations were significantly more frequent in female subjects who were using ethinyl estradiol-containing medications such as combined oral contraceptives 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 HOLKIRA PAK with or without ribavirin.

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

Subjects 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 subjects taking these other estrogens (n=87), caution is warranted for co-administration with HOLKIRA PAK.

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. HOLKIRA PAK should be discontinued if there are clinical signs of liver inflammation that are accompanied by persistent elevations in ALT, direct bilirubin or international normalized ratio (INR).

Hepatic Impairment

No dose adjustment of HOLKIRA PAK is required in patients with mild hepatic impairment (Child-Pugh A). The safety and efficacy of HOLKIRA PAK have not been established in HCV-infected patients with moderate hepatic impairment (Child-Pugh B). HOLKIRA PAK should not be used in patients with moderate (Child-Pugh B). HOLKIRA PAK 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

No dose adjustment of HOLKIRA™ PAK is required in patients with mild, moderate, or severe renal impairment. HOLKIRA PAK has not been studied in patients on dialysis. For patients that require 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 HOLKIRA PAK is administered in combination with ribavirin as significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin.

HOLKIRA PAK 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

HOLKIRA PAK with Ribavirin

Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients when HOLKIRA PAK is used with ribavirin. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin; therefore, ribavirin is contraindicated in women who are pregnant and in men whose female partners are pregnant. Women of childbearing potential and their male partners should not receive ribavirin unless they are using two reliable forms of contraception during treatment with ribavirin and for 6 months after treatment. See additional information on specific hormonal contraceptives in CONTRAINDICATIONS;WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, ALT Elevations and Sexual Function/Reproduction; and DRUG INTERACTIONS, Drug-Drug Interactions, Established and Other Potential Drug Interactions.

HOLKIRA PAK

There are no studies with HOLKIRA PAK 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) or dasabuvir. For paritaprevir/ritonavir, the highest doses tested produced exposures equal to 98-fold (mouse) or 8-fold (rat) the exposures in humans at the recommended clinical dose. For ombitasvir, the highest dose tested produced exposures equal to 28-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. For dasabuvir, the highest dose tested produced exposures equal to 48-fold (rat) or 12-fold (rabbit) the exposures in humans at the recommended clinical dose (see TOXICOLOGY, Reproduction and Teratology).

Nursing Women

It is not known whether paritaprevir/ritonavir, ombitasvir or dasabuvir and their metabolites are excreted in human breast milk. Paritaprevir and its hydrolysis product M13, unchanged ombitasvir and dasabuvir 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 HOLKIRA PAK. Physicians prescribing ribavirin should also refer the patient to the Product Monograph for ribavirin.

Pediatrics (< 18 years of age)

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

Geriatrics (> 65 years of age)

No dose adjustment of HOLKIRA PAK is needed in geriatric patients. In Phase 3 clinical trials, 8.5% (174/2053) of subjects were age 65 or over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

HIV or HBV Co-infection

The safety and efficacy of HOLKIRA PAK have not been established in patients co-infected with HIV or hepatitis B.

HOLKIRA PAK is contraindicated with efavirenz-containing regimens.

Post-Liver Transplant

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

Other HCV Genotypes

The safety and efficacy of HOLKIRA PAK has not been established in patients with HCV genotypes other than genotype 1.

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

HOLKIRA PAK 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.

Adverse Reactions

Adverse Drug Reaction Overview

The safety summary is based on pooled data from phase 2 and 3 clinical trials in more than 2,600 subjects who received HOLKIRA PAK with or without ribavirin.

In subjects receiving HOLKIRA PAK with ribavirin, the most commonly reported treatment emergent adverse events considered related to study drug by site investigator (greater than 10% of subjects) were fatigue, headache, nausea, pruritus and insomnia. The proportion of subjects who permanently discontinued treatment due to related adverse events was 0.8% (17/2,044).

0.5% (11/2,044) of subjects interrupted treatment due to related adverse events. 3.5% (72/2,044) of subjects had ribavirin dose reductions due to related adverse events.

The safety profile of HOLKIRA PAK and ribavirin in subjects with cirrhosis was similar to that of subjects without cirrhosis.

In subjects receiving HOLKIRA PAK without ribavirin, the most commonly reported treatment emergent adverse events considered related to study drug by site investigator (greater than 10% of subjects) were fatigue and headache. No subject permanently discontinued treatment due to a related adverse events and no subject 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.

Table 2 lists adverse drug reactions (Grades 2 to 4) observed in ≥ 3% of patients in the Phase 3 trials.

The majority of adverse events in the Phase 3 clinical trials were of grade 1 severity. The safety profile of HOLKIRA PAK with ribavirin was consistent with the known safety profile of ribavirin.

Table 2. Side-by-Side Tabulation of Adverse Reactions (Grade 2 – 4) in ≥ 3% of Subjects in Phase 3*
SAPPHIRE I and II PEARL II, III and IV TURQUOISE II
(subjects with
cirrhosis)
Adverse
Reaction
HOLKIRA PAK
+ RBV
12 Weeks
N = 770
n (%)
Placebo
12 Weeks
N = 255
n (%)
HOLKIRA
PAK + RBV
12 Weeks
N = 401
n (%)
HOLKIRA PAK
12 Weeks
N = 509
n (%)
HOLKIRA PAK
+ RBV
12 or 24 Weeks
N = 380
n (%)
Fatigue 29 (3.8) 4 (1.6) 26 (6.5) 22 (4.3) 15 (3.9)
Nausea 26 (3.4) 2 (0.8) 2 (0.5) 2 (0.4) 8 (2.1)
Asthenia 22 (2.9) 3 (1.2) 6 (1.5) 1 (0.2) 12 (3.2)
Headache 35 (4.5) 6 (2.3) 10 (2.5) 12 (2.4) 12 (3.2)

* 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 Events (< 3%)

Treatment emergent adverse events (Grades 2 to 4) considered at least possibly related to study drug by site investigators which occurred in less than 3% of subjects in Phase 3 trials are listed below by system organ class (Table 3).

Table 3. Adverse Events (Grade 2 – 4) in < 3% of Subjects in Phase 3
Body System Adverse Events
Blood and lymphatic system
disorders:
anaemia, leukopenia, neutropenia
Cardiac disorders: extrasystoles, palpitations, sinus tachycardia, tachycardia, ventricular extrasystoles
Ear and labyrinth disorders: tinnitus
Endocrine disorders: goitre, hypothyroidism, thyroiditis, adrenal insufficiency
Gastrointestinal disorders: abdominal discomfort, abdominal pain, abdominal pain upper, anorectal discomfort, constipation, dental caries, diarrhoea, dry mouth, dyspepsia, dysphagia, frequent bowel movements, gastrointestinal disorder, gastrooesophageal reflux disease, haemorrhoids, hyperchlorhydria, lip ulceration, pancreatitis, retching, vomiting
General disorders and
administration site conditions:
chest discomfort, chills, energy increased, exercise tolerance decreased, hunger, inflammation, influenza like illness, irritability, malaise, oedema peripheral, pain, pre-existing condition improved, product taste abnormal, pyrexia, swelling
Hepatobiliary disorders: hyperbilirubinaemia, jaundice
Immune system disorders: seasonal allergy
Infections and infestations: abscess, bronchitis, cellulitis, ear infection, gastroenteritis, gingival infection, herpes simplex, lower respiratory tract infection, nasopharyngitis, oral herpes, sinusitis, skin infection, upper respiratory tract infection, tooth abscess
Investigations: alanine aminotransferase increased, blood bilirubin increased, blood bilirubin unconjugated increased, irritability, malaise, electrocardiogram abnormal, haemoglobin decreased, neutrophil count increased, reticulocyte count increased, transaminases increased, weight decreased, white blood cell count decreased
Metabolism and nutrition
disorders:
decreased appetite, diabetes mellitus, gout, hyperphosphataemia, hypertriglyceridaemia, hypophosphataemia, increased appetite, lactic acidosis
Musculoskeletal and connective
tissue disorders:
arthralgia, arthritis, axillary mass, back pain, bone pain, bursitis, muscle spasms, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, neck pain, pain in extremity, sensation of heaviness, tendonitis
Nervous system disorders: ataxia, cerebrovascular accident, disturbance in attention, dizziness, dysgeusia, hyperaesthesia, intention tremor, lethargy, memory impairment, migraine, neuralgia, paraesthesia, presyncope, restless legs syndrome, somnolence, syncope, tension headache, tremor
Psychiatric disorders: abnormal dreams, affect lability, agitation, anger, anxiety, anxiety disorder, depressed mood, depression, emotional disorder, euphoric mood, insomnia, libido decreased, mental status changes, mood altered, mood swings, nervousness, nightmare, sleep disorder, suicidal ideation, tearfulness, terminal insomnia
Reproductive system and breast
disorders:
amenorrhoea, menorrhagia, metrorrhagia
Respiratory thoracic and
mediastinal disorders:
acute respiratory failure, chronic obstructive pulmonary disease, cough, dyspnoea, dyspnoea exertional, hypoxia, respiratory depression, sleep apnoea syndrome
Skin and subcutaneous tissue
disorders:
alopecia, blister, cold sweat, dandruff, dry skin, erythema, night sweats, photodermatosis, photosensitivity reaction, pruritus, pruritus generalised, rash, rash erythematous, rash generalised, rash papular, rash pruritic, skin odour abnormal, skin reaction
Vascular disorders: flushing, hot flush, hypertension, hypotension

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory Abnormalities

Changes in selected laboratory parameters are described in Table 4. A side-by-side tabulation is provided to simplify presentation; direct comparisons should not be made across trials that differ in design.

Table 4. Selected Treatment Emergent Laboratory Abnormalities
Laboratory
Parameters
SAPPHIRE I and II PEARL II, III and IV TURQUOISE II
(subjects with
cirrhosis)
HOLKIRA PAK
+ RBV
12 Weeks
N = 770
n (%)
Placebo
12 Weeks
N = 255
n (%)
HOLKIRA
PAK + RBV
12 Weeks
N = 401
n (%)
HOLKIRA PAK
12 Weeks
N = 509
n (%)
HOLKIRA PAK
+ RBV
12 or 24 Weeks
N = 380
n (%)
ALT
> 5-20 × ULN* (Grade 3) 6/765 (0.8%) 10/254 (3.9%) 3/401 (0.7%) 1/509 (0.2%) 4/380 (1.1%)
> 20 × ULN (Grade 4) 3/765 (0.4%) 0 0 0 2/380 (0.5%)
Hemoglobin
< 10-8 g/dL (Grade 2) 41/765 (5.4%) 0 23/401 (5.7%) 0 30/380 (7.9%)
< 8-6.5 g/dL (Grade 3) 1/765 (0.1%) 0 2/401 (0.5%) 0 3/380 (0.8%)
< 6.5 g/dL (Grade 4) 0 0 0 0 1/380 (0.3%)
Total Bilirubin
> 3-10 × ULN (Grade 3) 19/765 (2.5%) 0 23/401 (5.7%) 2/509 (0.4%) 37/380 (9.7%)
> 10 × ULN (Grade 4) 1/765 (0.1%) 0 0 0 0

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

Serum ALT Elevations

During clinical trials with HOLKIRA PAK with and without ribavirin, less than 1% of subjects who were not on ethinyl estradiol-containing medications experienced transient serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment (see CONTRAINDICATIONS). 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. Cirrhosis was not a risk factor for elevated ALT. 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 subjects receiving HOLKIRA PAK 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 subjects who did not receive ribavirin.

Post-Market Adverse Drug Reactions

Hypersensitivity reactions (including tongue and lip swelling) have been observed.

Drug Interactions

Drug-Drug Interactions

Potential for HOLKIRA PAK to Affect Other Drugs

Paritaprevir is an inhibitor of the hepatic uptake transporters OATP1B1 and OATP1B3, and paritaprevir and ritonavir are inhibitors of OATP2B1. Paritaprevir, ritonavir and dasabuvir are inhibitors of BCRP in vivo. Paritaprevir, ombitasvir, and dasabuvir 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 HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir). Paritaprevir, ritonavir and dasabuvir are in vitro inhibitors of P-gp, however, no significant change was observed in the exposure of the P-gp substrate, digoxin, when administered with HOLKIRA PAK.

While ritonavir alone is shown to induce multiple CYPs (cytochrome P450) in vitro, HOLKIRA PAK does not significantly affect CYP2C9 at clinically relevant concentrations. In addition, HOLKIRA PAK is not expected to inhibit CYP2D6 and a clinically significant increase in exposures of CYP2D6 substrates is not expected during co-administration with HOLKIRA PAK. However, co-administration of HOLKIRA PAK 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, ritonavir, and dasabuvir 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 HOLKIRA PAK does not affect these active renal elimination pathways.

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

Caution should be exercised when drugs that prolong QTc are co-administered with HOLKIRA PAK.

Potential for Other Drugs to Affect HOLKIRA PAK

Paritaprevir and ritonavir are primarily metabolized by CYP3A, and dasabuvir is primarily metabolized by CYP2C8.

Strong inhibitors of CYP3A may significantly increase paritaprevir and ritonavir exposures when co-administered with HOLKIRA PAK. Drugs that inhibit CYP2C8 may significantly increase dasabuvir plasma concentrations.

Drugs that induce CYP3A are expected to decrease dasabuvir, paritaprevir, ombitasvir and ritonavir plasma concentrations significantly and reduce their therapeutic effect. Drugs that induce CYP2C8 are expected to decrease dasabuvir plasma concentrations significantly and reduce its therapeutic effect.

Drugs that are strong CYP2C8 inhibitors, CYP3A inducers or CYP2C8 inducers are contraindicated with HOLKIRA PAK (see CONTRAINDICATIONS).

Paritaprevir, dasabuvir, ritonavir and ombitasvir are substrates of P-gp. Paritaprevir and dasabuvir are substrates of BCRP. Paritaprevir is a substrate of OATP1B1 and OATP1B3.

Inhibition of P-gp, BCRP, OATP1B1 or OATP1B3 may significantly increase exposures of the various components of HOLKIRA PAK.

Paritaprevir is a substrate of CYP3A and transport proteins. Caution is advised if co-administering HOLKIRA PAK 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 HOLKIRA PAK

The drugs that are contraindicated with HOLKIRA PAK are summarized in Table 5.

Table 5. Drugs that Are Contraindicated with HOLKIRA PAK
Drug Class: Specific Drugs Clinical Comment
ACYL-COENZYME A: CHOLESTEROL O-ACYLTRANSFERASE (ACAT) INHBITORS
avasimibe* CONTRAINDICATED since ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of HOLKIRA PAK.
ALPHA1-ADRENORECEPTOR ANTAGONISTS
alfuzosin HCL CONTRAINDICATED due to potential for increased alfuzosin concentrations which can result in hypotension.
ANTIBACTERIAL
nafcillin* CONTRAINDICATED since ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of HOLKIRA PAK.
ANTIBIOTICS
fusidic acid (oral formulation)* CONTRAINDICATED due to potential for increased fusidic acid concentrations with risk of adverse events such as hepatotoxicity.
ANTICONVULSANTS
carbamazepine, phenytoin,
phenobarbital
CONTRAINDICATED since ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of HOLKIRA PAK.
ANTIHISTAMINES
astemizole, terfenadine CONTRAINDICATED due to potential for cardiac arrhythmias.
ANTIHYPERLIPIDEMICS
gemfibrozil CONTRAINDICATED with dasabuvir due to an increase in dasabuvir exposures by 10-fold which may increase the risk of QT prolongation.
ANTIMYCOBACTERIALS
rifampin CONTRAINDICATED since ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of HOLKIRA PAK.
ANTIVIRALS
efavirenz-containing regimens,
such as Atripla, etravirine
CONTRAINDICATED since co-administration of efavirenz-based regimen with paritaprevir, ritonavir plus dasabuvir was poorly tolerated and resulted in liver enzyme elevations; and during co-administration with etravirine, ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease, leading to a potential loss of therapeutic activity of HOLKIRA PAK.
BENZODIAZEPINES
oral midazolam, triazolam CONTRAINDICATED 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 HOLKIRA PAK may cause large increases in the concentration of these benzodiazepines.
ENDOTHELIN RECEPTOR ANTAGONIST
bosentan CONTRAINDICATED since ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of HOLKIRA PAK.
ERGOT DERIVATIVES
ergotamine, dihydroergotamine,
ergonovine*, methylergonovine*
CONTRAINDICATED 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* CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
HERBAL PRODUCTS
St. John’s Wort (Hypericum
perforatum)
CONTRAINDICATED since ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of HOLKIRA PAK.
HORMONAL PRODUCTS
ethinyl estradiol-containing drugs
(combined oral contraceptives,
contraceptive vaginal rings,
contraceptive patch)
CONTRAINDICATED due to potential for ALT elevations.
HMG CoA REDUCTASE INHIBITORS
lovastatin, simvastatin CONTRAINDICATED due to potential for serious reactions such as myopathy including rhabdomyolysis.
LONG-ACTING BETA-ADRENOCEPTOR AGONISTS
salmeterol CONTRAINDICATED as concomitant use of salmeterol and HOLKIRA PAK may result in increased cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
NEUROLEPTICS
pimozide CONTRAINDICATED due to potential for cardiac arrhythmias.
PDE5 ENZYME INHIBITORS
sildenafil only at the doses used
daily for the treatment of
pulmonary arterial hypertension
CONTRAINDICATED due to increased potential for sildenafil-associated adverse events such as visual disturbances, hypotension, priapism, and syncope.
OTHERS
modafinil CONTRAINDICATED since ombitasvir, paritaprevir, ritonavir and dasabuvir exposures may decrease leading to a potential loss of therapeutic activity of HOLKIRA PAK.

* Drugs not sold in Canada

Drugs that Should not be Co-administered with HOLKIRA PAK

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

Table 6. Drugs that Should not be Co-administered with HOLKIRA PAK
Drug Class: Specific Drugs Clinical Comment
ANTIARRHYTHMICS
amiodarone, disopyramide,
flecainide, lidocaine (systemic),
propafenone, quinidine
Should not be co-administered since these drugs are CYP3A substrates and their exposures may increase during co-administration with HOLKIRA PAK.
ANTIPSYCHOTICS
quetiapine Should not be co-administered since this drug is a CYP3A substrate and its exposure may increase during co-administration with HOLKIRA PAK.
ANTIVIRALS
rilpivirine Should not be co-administered since rilpivirine exposures increased by up to 243% during co-administration with HOLKIRA PAK, which may lead to potential for QT interval prolongation.
ritonavir and ritonavir-containing
regimens, including
atazanavir/ritonavir,
lopinavir/ritonavir
Should not be co-administered with HOLKIRA PAK due to the potential for an increase in paritaprevir exposures. For administration of HOLKIRA PAK 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 HOLKIRA PAK.
OPIOID ANALGESICS
alfentanil, fentanyl Should not be co-administered since these drugs are CYP3A substrates and their exposures may increase during co-administration with HOLKIRA PAK.

Established and Other Potential Drug Interactions

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

Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug
Name
Effect on
Concentration of
Concomitant Drug
Clinical comments
ANTIARRHYTHMICS
digoxin ↑ digoxin Co-administration with HOLKIRA PAK increased digoxin AUC by 16%. While no dose adjustment is necessary for digoxin, appropriate monitoring of serum digoxin levels is recommended. Monitor P-gp substrate concentration for NTI drugs.
ANTICOAGULANTS
warfarin ↓ warfarin Co-administration with HOLKIRA PAK decreased S-warfarin and R-warfarin AUC by 12%. 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 HOLKIRA PAK increased ketoconazole exposure by 117%, and paritaprevir exposure increased by nearly 2-fold. The effect of multiple doses of HOLKIRA PAK on ketoconazole exposure could be of much greater magnitude. Caution is warranted, and patients should be monitored for adverse reactions to ketoconazole and HOLKIRA PAK. Similar drug interactions with other CYP3A inhibitors are expected; monitor patients for adverse reactions and reduce the dose of the co-administered drug as appropriate or discontinue HOLKIRA PAK. Doses of ketoconazole should be reduced as appropriate.
CALCIUM CHANNEL BLOCKERS
amlodipine ↑ amlodipine Co-administration with HOLKIRA PAK increased amlodipine exposure (AUC) by 157%. When co-administering amlodipine with HOLKIRA PAK, caution is warranted and a 50% reduction in the dose of amlodipine should be considered.
DIURETICS
furosemide ↑ furosemide (Cmax) Co-administration with HOLKIRA PAK increased furosemide Cmax by 42%. Caution is warranted when co-administering furosemide with HOLKIRA PAK, and furosemide dose may be decreased up to 50% based on clinical response.
HIV-ANTIVIRAL AGENTS
atazanavir atazanavir
administered in the
morning ↔ atazanavir
↑ paritaprevir
Atazanavir should be taken without ritonavir with HOLKIRA PAK since ritonavir is included in HOLKIRA PAK.
Atazanavir plus ritonavir is not recommended with HOLKIRA PAK.
darunavir ↓ darunavir (Ctrough) Darunavir dose should be taken without ritonavir when co-administered with HOLKIRA PAK. Because of decreased darunavir trough concentrations, patients should be monitored for HIV-1viral breakthrough.
raltegravir ↑ raltegravir Co-administration with HOLKIRA PAK increased raltegravir exposures by 130% to 135%. However, no dose adjustment is necessary for raltegravir.
HMG CoA REDUCTASE INHIBITORS
rosuvastatin ↑ rosuvastatin Following multiple doses with HOLKIRA PAK, rosuvastatin Cmax and AUC from a 5 mg dose were 7.1-fold and 2.6-fold compared to rosuvastatin administered alone. Co-administration of rosuvastatin with HOLKIRA PAK should be avoided. If used together, caution should be exercised and patients should be monitored for rosuvastatin side effects such as myopathy/rhabdomyolysis. Rosuvastatin dose should not exceed 5 mg per day.
pravastatin ↑ pravastatin Pravastatin 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 6-fold. When starting co-administration with HOLKIRA PAK, give one fifth of the total daily dose of cyclosporine once daily with HOLKIRA PAK. Monitor cyclosporine levels and adjust dose and/or dosing frequency as needed.
tacrolimus ↑ tacrolimus Tacrolimus exposure increased by > 57-fold. Tacrolimus t½ increased from 32 to 232 hours in the presence of HOLKIRA PAK. When starting co-administration with HOLKIRA PAK, 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
Co-administration with HOLKIRA PAK increased buprenorphine and norbuprenorphine exposures by 41% and 42%, respectively. However, no dose adjustment of buprenorphine/naloxone is required upon co-administration with HOLKIRA PAK.
PROTON PUMP INHIBITORS
omeprazole ↓ omeprazole Omeprazole AUC decreased by 38%. Use higher doses of omeprazole if clinically indicated.
SEDATIVES/HYPNOTICS
alprazolam ↑ alprazolam Alprazolam 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.

For the co-administered drug, the direction of the arrow indicates the direction of the change in exposures (Cmax and AUC)

Drugs with No Observed Interactions with HOLKIRA PAK

Drug interaction studies in subjects reveal no clinically significant interaction between HOLKIRA PAK and the following commonly co-prescribed medications. No dose adjustments are required when co-administering these drugs with HOLKIRA PAK:

  • methadone, naloxone
  • duloxetine, escitalopram
  • norethindrone
  • tenofovir, emtricitabine
  • zolpidem

Drug-Food Interactions

Food increased the exposure (AUC) of paritaprevir, ombitasvir, ritonavir, and dasabuvir by up to 211%, 82%, 49%, and 30% 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, HOLKIRA™ PAK 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, a potent hepatic and intestinal CYP3A4 and/or P-gp inducer, may decrease HOLKIRA PAK plasma concentrations, which may result in loss of therapeutic effect.

St. John’s wort is contraindicated with HOLKIRA PAK (see CONTRAINDICATIONS).

Drug-Laboratory Interactions

Interactions of HOLKIRA PAK with laboratory tests have not been established.

Dosage and Administration

Dosing Considerations

  • HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir) is ombitasvir/paritaprevir/ritonavir fixed dose combination tablets copackaged with dasabuvir tablets. Ombitasvir/paritaprevir/ritonavir tablets must be administered with dasabuvir tablets.
  • HOLKIRA PAK is used in combination with ribavirin in patients with genotype 1a infection and all patients with cirrhosis. HOLKIRA PAK can be used without ribavirin in patients with genotype 1b infection without cirrhosis (see Table 8).

Recommended Dose and Dosage adjustment

The recommended oral dose of HOLKIRA PAK is two ombitasvir/paritaprevir/ritonavir 12.5/75/50 mg tablets once daily (in the morning) and one dasabuvir 250 mg tablet twice daily (morning and evening). HOLKIRA PAK is used in combination with ribavirin in certain patient populations (see Table 8).

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

HOLKIRA PAK tablets should be swallowed whole, with water if required, and not chewed, broken, or crushed. To maximize absorption, HOLKIRA PAK should be taken with food without regard to fat or calorie content (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption, Effects of Food on Oral Absorption).

Table 8 shows the recommended treatment regimen and duration based on patient population.

Table 8. Treatment Regimen and Duration by Patient Population
Patient Population Treatment Duration
Genotype 1b, without cirrhosis HOLKIRA PAK 12 weeks
Genotype 1a, without cirrhosis HOLKIRA PAK + ribavirin 12 weeks
Genotypes 1a and 1b, with cirrhosis HOLKIRA PAK + ribavirin 12 weeks†

† 24 weeks of HOLKIRA PAK + ribavirin is recommended for patients with genotype 1a-infection with cirrhosis who have had a previous null response to pegylated interferon (pegIFN) and ribavirin (see CLINICAL TRIALS).

Note: HOLKIRA PAK with ribavirin is recommended in patients with an unknown genotype 1 subtype or with mixed genotype 1 infection.

For specific dosage instructions for ribavirin, including dose modification, refer to the ribavirin Product Monograph.

HOLKIRA PAK should be taken as directed for the prescribed duration, without interruption or dose modification. If HOLKIRA PAK is used in combination with ribavirin, ribavirin should be administered for the same duration as HOLKIRA PAK.

Hepatic Impairment

No dose adjustment of HOLKIRA PAK is required in patients with mild hepatic impairment (Child-Pugh A). The safety and efficacy of HOLKIRA PAK have not been established in HCV-infected patients with moderate hepatic impairment (Child-Pugh B). HOLKIRA PAK should not be used in patients with moderate (Child-Pugh B). HOLKIRA PAK 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).

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 of the scheduled time for the dose that was missed.

In case a dose of dasabuvir is missed, the prescribed dose can be taken within 6 hours of the scheduled time for the dose that was missed.

If more than 12 hours has passed since ombitasvir/paritaprevir/ritonavir is usually taken or more than 6 hours has passed since dasabuvir is usually taken, 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 volunteers was 350 mg for ombitasvir, 400 mg for paritaprevir (with 100 mg ritonavir), 200 mg for ritonavir (with 100 mg paritaprevir), and 2000 mg for dasabuvir. In case of overdosage, 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

HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir) combines three 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. Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. 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 pharmacokinetic enhancer that increases peak and trough plasma drug concentrations of paritaprevir and overall drug exposure (i.e., area under the curve).

Pharmacodynamics

Effects on Electrocardiogram

In a double blind, placebo and active-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT study in 60 healthy subjects, a single dose of paritaprevir/ritonavir/ombitasvir 200/150/25 mg co-administered with dasabuvir 250 mg resulted in statistically significant QTcF prolongation from 3 to 8 hours post-dosing, with a maximum mean difference from placebo of 3.6 msec (90% CI 1.8, 5.4) at 5 hours. A single dose of paritaprevir/ritonavir/ombitasvir 350/150/50 mg co-administered with dasabuvir 500 mg resulted in statistically significant QTcF prolongation from 3 to 8 hours post-dosing, with a maximum mean difference from placebo of 5.9 msec (90% CI 4.1, 7.7) at 5hours. These combination treatments had no noteworthy effect on the QRS duration, the PR interval, or heart rate.

Pharmacokinetics

The pharmacokinetic properties of the combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir have been evaluated in healthy adult subjects and in subjects with chronic hepatitis C. Table 9 shows mean Cmax and AUC of ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily with dasabuvir 250 mg twice daily following multiple doses with food in healthy volunteers.

Table 9. Geometric Mean Cmax, AUC of Multiple Doses of Ombitasvir/Paritaprevir/Ritonavir 25/150/100 mg Once Daily with Dasabuvir 250 mg Twice Daily with Food in Healthy Volunteers
Cmax (ng/mL) AUC(ng*hr/mL)
Ombitasvir 127 1420
Paritaprevir 1470 6990
Dasabuvir 1030 6840
Ritonavir 1600 9470

Absorption

Ombitasvir/paritaprevir/ritonavir and dasabuvir were absorbed after oral administration with mean Tmax of approximately 4 to 5 hours. While ombitasvir and dasabuvir 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 dasabuvir and approximately 1.5- to 2-fold for ritonavir and paritaprevir. Pharmacokinetic steady state for the combination is achieved after approximately 12 days of dosing.

Effects of Food on Oral Absorption

Food increased the exposure (AUC) of ombitasvir, paritaprevir, ritonavir, and dasabuvir by up to 82, 211, 49, and 30% 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).

Distribution

Ombitasvir, paritaprevir, ritonavir and dasabuvir 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, paritaprevir, and dasabuvir were preferentially distributed in the plasma compartment of whole blood. Ombitasvir was approximately 99.9% bound to human plasma proteins over a concentration range of 0.09 to 9 mcg per mL. Paritaprevir was approximately 97 to 98.6% bound to human plasma proteins over a concentration range of 0.08 to 8 mcg per mL. Ritonavir was greater than 99% bound to human plasma proteins over a concentration range of 0.007 to 22 mcg per mL. Dasabuvir was greater than 99.9% bound to human plasma proteins over a concentration range of 0.05 to 5 mcg per mL.

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

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.

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.

Dasabuvir

Dasabuvir is predominantly metabolized by CYP2C8 and to a lesser extent by CYP3A. Following a 400 mg 14C-dasabuvir dose in humans, unchanged dasabuvir was the major component (approximately 60%) of drug related radioactivity in plasma; seven metabolites were identified in plasma. The most abundant plasma metabolite was M1, which represented 21% of drug-related radioactivity (AUC) in circulation and has similar activity as the parent drug against genotype 1 in vitro.

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

Ombitasvir

Following dosing of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, mean plasma half-life of ombitasvir was approximately 21 to 25 hours. Following a 25 mg 14C-ombitasvir dose, approximately 90.2% of the radioactivity was recovered in feces with limited radioactivity (1.91%) in urine.

Paritaprevir

Following dosing of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, mean plasma half-life of paritaprevir was approximately 5.5 hours. 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.

Dasabuvir

Following dosing of dasabuvir with ombitasvir/paritaprevir/ritonavir, mean plasma half-life of dasabuvir was approximately 5.5 to 6 hours. Following a 400 mg 14C-dasabuvir dose, approximately 94.4% of the radioactivity was recovered in feces with limited radioactivity (approximately 2%) in urine.

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.

Special Populations and Conditions

Pediatrics

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

Geriatrics (> 65 years of age)

Population pharmacokinetic analysis of data from Phase 3 clinical studies with HOLKIRA PAK showed that a 10 year increase or decrease in age from 54 years (median age in the Phase 3 studies) would result in approximately 10% change in ombitasvir exposures, ≤ 20% change in paritaprevir exposures and < 10% change in dasabuvir exposures. Age was not a significant predictor for ritonavir exposures. There is no pharmacokinetic information in patients > 75 years. Phase 3 studies of HOLKIRA PAK included 174 patients aged 65 and over. The response rates observed for patients ≥ 65 years of age (97%) were similar to those of patients < 65 years of age (96%), across treatment groups (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics (> 65 years of age)).

Gender

Population pharmacokinetic analysis of data from Phase 3 clinical studies with HOLKIRA PAK showed that female subjects would have approximately 55% higher ombitasvir exposures, 100% higher paritaprevir exposures, 15% higher ritonavir exposures and 14 to 30% higher dasabuvir exposures than male subjects. The relationship between gender and HOLKIRA PAK exposures was not considered clinically relevant as high response rates (SVR > 90%) were achieved in male and female patients across the Phase 3 studies.

Race

Based on population pharmacokinetic analyses, exposures of ombitasvir, paritaprevir, dasabuvir and ritonavir were not significantly different in subjects of Black race compared to subjects of other races. Population pharmacokinetic analysis of data from Phase 3 clinical studies with HOLKIRA PAK showed that Asian subjects had 18 to 21% higher ombitasvir exposures, 37 to 39% higher paritaprevir exposures and 29 to 39% higher dasabuvir exposures than non-Asian subjects. The ritonavir exposures were comparable between Asians and non-Asians. These differences in exposures were not clinically significant.

Hepatic Insufficiency

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 (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment.

In subjects with mild hepatic impairment, ombitasvir, paritaprevir and ritonavir mean AUC values decreased by 8, 29 and 34%, respectively, and dasabuvir mean AUC values were 17% higher compared to subjects with normal hepatic function. No dose adjustment for HOLKIRA PAK is recommended for HCV-infected subjects with mild hepatic impairment.

In subjects with moderate hepatic impairment, ombitasvir and ritonavir mean AUC values decreased by 30%, paritaprevir mean AUC value increased by 62% and dasabuvir mean AUC values were 16% lower compared to subjects with normal hepatic function. The safety and efficacy of HOLKIRA PAK 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 HOLKIRA PAK at steady state has not been assessed in subjects with moderate hepatic impairment, hence no dosing recommendation can be made. HOLKIRA PAK should not be used in subjects with moderate hepatic impairment.

In subjects with severe hepatic impairment, paritaprevir and dasabuvir mean AUC values increased by 945% and 325%, respectively, ritonavir mean AUC value was 13% higher, and ombitasvir mean AUC value decreased by 54% compared to subjects with normal hepatic function. HOLKIRA PAK is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see CONTRAINDICATIONS).

Renal Insufficiency

Pharmacokinetics of the combination of paritaprevir 150 mg, ombitasvir 25 mg, and ritonavir 100 mg, with or without dasabuvir 400 mg were evaluated in subjects 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.

In subjects with mild renal impairment, the mean AUC values of ombitasvir, paritaprevir, ritonavir and dasabuvir were < 1, 19, 42, and 21% higher, respectively, compared to subjects with normal renal function.

In subjects with moderate renal impairment, the mean AUC values of ombitasvir, paritaprevir, ritonavir and dasabuvir were < 1, 33, 80, and 37% higher, respectively, compared to subjects with normal renal function.

In subjects with severe renal impairment, the mean AUC values of ombitasvir, paritaprevir, ritonavir and dasabuvir were < 1, 45, 114, and 50% higher, respectively, compared to subjects with normal renal function.

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

HOLKIRA PAK (ombitasvir/paritaprevir/ritonavir and dasabuvir) is ombitasvir/paritaprevir/ritonavir fixed dose combination tablets co-packaged with dasabuvir tablets.

  • Ombitasvir/paritaprevir/ritonavir 12.5/75/50 mg tablets are pink-colored, film-coated, oblong biconvex shaped, debossed with “AV1” on one side.
  • Dasabuvir 250 mg tablets are beige-colored, film-coated, oval-shaped, debossed with “AV2” on one side.

HOLKIRA PAK 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 four tablets: two 12.5/75/50 mg ombitasvir/paritaprevir/ritonavir tablets and two 250 mg dasabuvir tablets, and indicates which tablets need to be taken in the morning and evening.

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.

Each dasabuvir immediate release tablet contains 250 mg dasabuvir (as dasabuvir sodium monohydrate) with the following non-medicinal ingredients: colloidal silicon dioxide/anhydrous colloidal silica, copovidone, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose. The film-coating ingredients include: iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol/macrogol, polyvinyl alcohol, purified water, talc, and titanium dioxide. The tablets do not contain gluten.