Ombitasvir, Paritaprevir and Ritonavir

Paritaprevir, ombitasvir and dasabuvir are inhibitors of UGT1A1. Co-administration of ombitasvir/paritaprevir/ritonavir with or without dasabuvir with medicinal products that are primarily metabolized by UGT1A1 result in increased plasma concentrations of such medicinal products.

Routine clinical monitoring is recommended for narrow therapeutic index medicinal products (i.e. levothyroxine).

Clinical monitoring and dose reduction is recommended for angiotensin receptor blockers when coadministered with ombitasvir/paritaprevir/ritonavir with or without dasabuvir.

When ombitasvir/paritaprevir/ritonavir combination is co-administered with dasabuvir, decrease amlodipine dose by 50% and monitor patients for clinical effects.

Similar effect is expected when ombitasvir/paritaprevir/ritonavir is administered without dasabuvir.

Concomitant use is contraindicated.

Atazanavir can be used in combination with ombitasvir/paritaprevir/ritonavir and dasabuvir, if administered at the same time. To be noted, atazanavir should be taken without ritonavir, since ritonavir 100 mg once daily is provided as part of ombitasvir/paritaprevir/ritonavir. The combination carries an increased risk for hyperbilirubinemia (including ocular icterus), in particular when ribavirin is part of the hepatitis C regimen.

The recommended dose of atazanavir is 300 mg, without ritonavir, in combination with ombitasvir/paritaprevir/ritonavir with dasabuvir. Atazanavir must be administered at the same time as ombitasvir/paritaprevir/ritonavir with dasabuvir. Ritonavir dose in ombitasvir/paritaprevir/ritonavir will provide atazanavir pharmacokinetic enhancement).

Treatment with atazanavir + ombitasvir/paritaprevir/ritonavir without dasabuvir is not recommended.

Effect on ciclosporin is due to CYP3A4 inhibition by ritonavir and increase in paritaprevir exposures may be due to OATP/BCRP/P-gp inhibition by ciclosporin.

When starting coadministration with ombitasvir/paritaprevir/ritonavir, give one fifth of the total daily dose of ciclosporin once daily with ombitasvir/paritaprevir/ritonavir. Monitor ciclosporin levels and adjust dose and/or dosing frequency as needed.

No dose adjustment needed for ombitasvir/paritaprevir/ritonavir with or without dasabuvir.

A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function if treatment with ombitasvir/paritaprevir/ritonavir with or without dasabuvir is required.

Ombitasvir/paritaprevir/ritonavir without dasabuvir may increase the plasma concentrations of dabigatran etexilate. Use with caution.

Darunavir, dosed 800 mg once daily, if administered at the same time as ombitasvir/paritaprevir/ritonavir and dasabuvir, can be used in the absence of extensive PI resistance (darunavir exposure lowered). To be noted, darunavir should be taken without ritonavir, since ritonavir 100 mg once daily is provided as part of ombitasvir/paritaprevir/ritonavir.

Treatment with darunavir + ombitasvir/paritaprevir/ritonavir without dasabuvir is not recommended.

While paritaprevir, ritonavir and dasabuvir are in vitro inhibitors of P-gp, no significant change was observed in the exposure of the P-gp substrate digoxin when administered with ombitasvir/paritaprevir/ritonavir and dasabuvir. While no dose adjustment is necessary for digoxin, appropriate monitoring of serum digoxin levels is recommended.

Co-administration of digoxin with ombitasvir/paritaprevir/ritonavir without dasabuvir may result in increased plasma concentrations. Decrease digoxin dose by 30-50%. Appropriate monitoring of serum digoxin levels is recommended.

Caution is advised due to the expected increase in paritaprevir exposures.

Dose decrease and clinical monitoring of calcium channel blockers is recommended when coadministered with ombitasvir/paritaprevir/ritonavir with and without dasabuvir.

Administration of ombitasvir/paritaprevir/ritonavir with or without dasabuvir with erythromycin may result in increased concentrations of erythromycin and paritaprevir. Caution is advised.

Caution should be used when ombitasvir/paritaprevir/ritonavir with or without dasabuvir is coadministered with fexofenadine.

Patients should be monitored for clinical effects; a decrease in furosemide dose of up to 50% may be required.

No dose adjustment needed for ombitasvir/paritaprevir/ritonavir with or without dasabuvir.

A reduction of hydrocodone dose by 50% and/or clinical monitoring should be considered when administered with ombitasvir/paritaprevir/ritonavir with or without dasabuvir.

Clinical monitoring and lower doses of imatinib are recommended.

Dose decrease and clinical monitoring of calcium channel blockers is recommended when co-administered with ombitasvir/paritaprevir/ritonavir with and without dasabuvir.

Reduce pravastatin dose by 50%.

No dose adjustment needed for ombitasvir/paritaprevir/ritonavir with or without dasabuvir.

Caution should be used and dose decrease maybe needed for repaglinide when administered with ombitasvir/paritaprevir/ritonavir with or without dasabuvir.

Rilpivirine exposure is substantially increased (3-fold) when rilpivirine is given in combination with ombitasvir/paritaprevir/ritonavir and dasabuvir, with a consequent potential for QT-prolongation. If an HIV protease inhibitor is added (atazanavir, darunavir), rilpivirine exposure may increase even further and is, therefore, not recommended. Rilpivirine should be used cautiously, in the setting of repeated ECG monitoring.

Ombitasvir/paritaprevir/ritonavir with dasabuvir is expected to increase the exposure to rosuvastatin more than 3-fold. If rosuvastatin treatment is required during the treatment period, the maximum daily dose of rosuvastatin should be 5 mg. The increase in rosuvastatin when combined with ombitasvir/paritaprevir/ritonavir without dasabuvir is less pronounced. In this combination, the maximum daily dose of rosuvastatin should be 10 mg.

Caution should be used when sulfasalazine is coadministered with ombitasvir/paritaprevir/ritonavir with or without dasabuvir.

Co-administration of ombitasvir/paritaprevir/ritonavir and dasabuvir with systemic tacrolimus, sirolimus or everolimus increases the concentrations of the immunosuppressant due to CYP3A inhibition by ritonavir. Serious and/or life threatening events have been observed with co-administration of ombitasvir/paritaprevir/ritonavir and dasabuvir with systemic tacrolimus, and a similar risk can be expected with sirolimus and everolimus.

Avoid concomitant use of tacrolimus or sirolimus with ombitasvir/paritaprevir/ritonavir and dasabuvir unless the benefits outweigh the risks. If tacrolimus or sirolimus are used together with ombitasvir/paritaprevir/ritonavir and dasabuvir, caution is advised. Everolimus cannot be used due to lack of suitable dose strengths for dose adjustments.

Tacrolimus or sirolimus whole blood concentrations should be monitored upon initiation and throughout co-administration with ombitasvir/paritaprevir/ritonavir and dasabuvir and the dose and/or dosing frequency should be adjusted as needed. Patients should be monitored frequently for any changes in renal function or tacrolimus or sirolimus associated adverse reactions. Refer to the tacrolimus or sirolimus Summary of Product Characteristics for additional dosing and monitoring instructions.

While no change to the pharmacokinetics of warfarin is expected, close monitoring of INR is recommended with all vitamin K antagonists. This is due to liver function changes during treatment with ombitasvir/paritaprevir/ritonavir ± dasabuvir.

Caution should be used in patients with a pre-existing history of depression or psychiatric illness.

Hepatic decompensation and hepatic failure, including liver transplantation or fatal outcomes, have been reported postmarketing in patients treated with ombitasvir/paritaprevir/ritonavir with and without dasabuvir and with and without ribavirin. Most patients with these severe outcomes had evidence of advanced or decompensated cirrhosis prior to initiating therapy. Although causality is difficult to establish due to background advanced liver disease, a potential risk cannot be excluded.

For patients with cirrhosis:

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

Cases of hepatitis B virus (HBV) reactivation, some of them fatal, have been reported during or after treatment with direct-acting antiviral medicinal products. HBV screening should be performed in all patients before initiation of treatment. HBV/HCV co-infected patients are at risk of HBV reactivation, and should, therefore, be monitored and managed according to current clinical guidelines.

Diabetics may experience improved glucose control, potentially resulting in symptomatic hypoglycaemia, after initiating HCV direct acting antiviral treatment. Glucose levels of diabetic patients initiating direct acting antiviral therapy should be closely monitored, particularly within the first 3 months, and their diabetic medicinal products modified when necessary. The physician in charge of the diabetic care of the patient should be informed when direct acting antiviral therapy is initiated.

There are very limited data from the use of ombitasvir/paritaprevir/ritonavir in pregnant women. Studies with ombitasvir and paritaprevir/ritonavir in animals have shown malformations. The potential risk for humans is unknown. Ombitasvir/paritaprevir/ritonavir combination should not be used during pregnancy or in women of childbearing potential not using effective contraception.

If ribavirin is co-administered with ombitasvir/paritaprevir/ritonavir, the contraindications regarding use of ribavirin during pregnancy apply (see also the Summary of Product Characteristics of ribavirin).

It is not known whether paritaprevir/ritonavir or ombitasvir and their metabolites are excreted in human breast milk. Available pharmacokinetic data in animals have shown excretion of active substance and metabolite in milk. Because of the potential for adverse reactions from the medicinal product in breastfed infants, a decision must be made whether to discontinue breast-feeding or discontinue treatment with ombitasvir/paritaprevir/ritonavir, taking into account the importance of the therapy to the mother. For patients coadministered ribavirin refer to the Summary of Product Characteristics of ribavirin.

Women of childbearing potential/contraception in males and females

Extreme caution must be taken to avoid pregnancy in female patients and female partners of male patients when ombitasvir/paritaprevir/ritonavir is taken in combination 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 the male partners of women who are pregnant. Refer to the Summary of Product Characteristics for ribavirin for additional information.

Female patients

Women of childbearing potential should not receive ribavirin unless they are using an effective form of contraception during treatment with ribavirin and for 4 months after treatment. Ethinyloestradiol is contraindicated in combination with ombitasvir/paritaprevir/ritonavir.

Male patients and their female partners

Either male patients or their female partners of childbearing potential must use a form of effective contraception during treatment with ribavirin and for 7 months after treatment.

Fertility

No human data on the effect of ombitasvir/paritaprevir/ritonavir on fertility are available. Animal studies do not indicate harmful effects on fertility.

Ombitasvir/paritaprevir/ritonavir combination has no or negligible influence on the ability to drive and use machines. Patients should be informed that fatigue has been reported during treatment with ombitasvir/paritaprevir/ritonavir in combination with dasabuvir and ribavirin.

Summary of the safety profile

In subjects receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin, the most commonly reported adverse reactions (greater than 20% of subjects) were fatigue and nausea. The proportion of subjects who permanently discontinued treatment due to adverse reactions was 0.2% (5/2,044) and 4.8% (99/2,044) of subjects had ribavirin dose reductions due to adverse reactions.

Tabulated list of adverse reactions

The safety summary is based on pooled data from phase 2 and 3 clinical trials in subjects who received ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin. The majority of adverse reactions presented in Table 3 were of grade 1 severity in ombitasvir/paritaprevir/ritonavir and dasabuvir-containing regimens.

The adverse reactions are listed below by system organ class and frequency. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) or very rare (<1/10,000).

Table 3. Adverse drug reactions identified with ombitasvir/paritaprevir/ritonavir in combination with dasabuvir with and without ribavirin:

^* Data set includes all genotype 1-infected subjects in Phase 2 and 3 trials including subjects with cirrhosis.
Note: For laboratory abnormalities, refer to Table 4

Description of selected adverse reactions

Compared to subjects without cirrhosis, in subjects with compensated cirrhosis there was an increased rate of indirect hyperbilirubinemia when ribavirin was part of the regimen.

Laboratory abnormalities

Changes in selected laboratory parameters are described in Table 4. A side-by-side tabulation is shown to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

Table 4. Selected treatment emergent laboratory abnormalities:

^* ULN: Upper limit of normal according to testing laboratory.

Serum ALT elevations

In a pooled analysis of clinical trials with ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin, 1% of subjects experienced serum ALT levels greater than 5 times the upper limit of normal (ULN) after starting treatment. As the incidence of such elevations was 26% among women taking a concomitant ethinyloestradiol-containing medicinal product, such medicinal products are contraindicated with ombitasvir/paritaprevir/ritonavir with or without dasabuvir. No increase in incidence of ALT elevations was observed with other types of estrogens commonly used for hormone replacement therapy (e.g. oestradiol and conjugated estrogens). ALT elevations were typically asymptomatic, generally occurred during the first 4 weeks of treatment (mean time 20 days, range 8-57 days) and most resolved with ongoing therapy. Two patients discontinued ombitasvir/paritaprevir/ritonavir and dasabuvir due to elevated ALT, including one on ethinyloestradiol. Three interrupted ombitasvir/paritaprevir/ritonavir and dasabuvir for one to seven days, including one on ethinyloestradiol. The majority of these ALT elevations were transient and assessed as drug-related. Elevations in ALT were generally not associated with bilirubin elevations. Cirrhosis was not a risk factor for elevated ALT.

Serum bilirubin elevations

Transient elevations in serum bilirubin (predominantly indirect) were observed in subjects receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin, related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and ribavirin-induced haemolysis. 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.

Liver transplant recipients

The overall safety profile in HCV-infected transplant recipients who were administered ombitasvir/paritaprevir/ritonavir and dasabuvir and ribavirin (in addition to their immunosuppressant medications) was similar to subjects treated with ombitasvir/paritaprevir/ritonavir and dasabuvir and ribavirin in phase 3 clinical trials, although some adverse reactions were increased in frequency. 10 subjects (29.4%) had at least one post baseline haemoglobin value of less than 10 g/dL. 10 of 34 subjects (29.4%) dose modified ribavirin due to decrease in haemoglobin and 2.9% (1/34) had an interruption of ribavirin. Ribavirin dose modification did not impact SVR rates. 5 subjects required erythropoietin, all of whom initiated ribavirin at the starting dose of 1000 to 1200 mg daily. No subject received a blood transfusion.

HIV/HCV co-infected patients

The overall safety profile in HCV/HIV-1 co-infected subjects was similar to that observed in HCV monoinfected subjects. Transient elevations in total bilirubin >3 x ULN (mostly indirect) occurred in 17 (27.0%) subjects; 15 of these subjects were receiving atazanavir. None of the subjects with hyperbilirubinemia had concomitant elevations of aminotransferases.

GT1-infected subjects with or without cirrhosis with severe renal impairment or end-stage renal disease (ESRD)

Ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin were assessed in 68 subjects with genotype 1 infection with or without cirrhosis who have severe renal impairment or ESRD. The overall safety profile in subjects with severe renal impairment was similar to that seen in prior Phase 3 studies in subjects without severe renal impairment, except that a greater proportion of subjects required intervention due to ribavirin-associated decreases in serum haemoglobin. The mean baseline haemoglobin level was 12.1 g/dL and the mean decline in haemoglobin at the end of treatment for subjects taking RBV was 1.2 g/dL. Thirty-nine of the 50 subjects who received ribavirin required interruption of ribavirin, and 11 of these subjects were also treated with erythropoietin. Four subjects experienced a haemoglobin level <8 g/dL. Two subjects received a blood transfusion. Adverse events of anaemia were not seen in the 18 GT1b-infected subjects who did not receive ribavirin. Ombitasvir/paritaprevir/ritonavir with or without dasabuvir was also evaluated without ribavirin in 18 GT1a- and GT4-infected patients; no adverse events of anaemia were seen in these subjects.

Paediatric population

The safety of ombitasvir/paritaprevir/ritonavir in children and adolescents aged <18 years has not yet been established. No data are available.