Side Effects of Technivie (ombitasvir, paritaprevir and ritonavir)

Technivie (ombitasvir, paritaprevir and ritonavir) is a fixed-dose combination of antiviral medicines including a hepatitis C virus NS5A inhibitor, a hepatitis C virus NS3/4A protease inhibitor, and a CYP3A inhibitor, used with ribavirin to treat adults with genotype 4 chronic (lasting a long time) hepatitis C virus (HCV) infection without cirrhosis or with a certain type of cirrhosis (compensated). Patients should also read the Medication Guide for ribavirin. 

Common side effects of Technivie include:

• feeling weak,
• tiredness,
• headache,
• changes in mood,
• itching,
• nausea,
• sleep problems,
• trouble breathing,
• muscle or joint pain,
• skin reactions, and
• dizziness.

Serious side effects of Technivie include:

• loss of appetite,
• vomiting,
• yellowing of the skin or eyes (jaundice),
• stool color changes,
• confusion, and
• swelling of the stomach area.

Drug interactions of Technivie include alfuzosin hydrochloride, atorvastatin, carbamazepine, cisapride, colchicine in people who have:

• certain kidney or liver problems,
• dronedarone,
• efavirenz,
• ergot containing medicines,
• ethinyl estradiol-containing medicines (such as combination birth control pills or transdermal systems, hormonal vaginal rings, hormone replacement therapy),
• everolimus,
• lovastatin,
• lurasidone,
• oral midazolam,
• phenytoin,
• phenobarbital,
• pimozide,
• ranolazine,
• rifampin,
• sildenafil citrate when taken for pulmonary artery hypertension (PAH),
• simvastatin,
• sirolimus,
• St. John’s wort,
• tacrolimus, and
• triazolam.

If Technivie is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on use in pregnancy.

It is unknown if Technivie and its metabolites are present in human breast milk, if it affects human milk production, or will have effects on a breastfed infant.  The developmental and heal

WARNING

• Hepatitis B virus reactivation: Before starting treatment with Technivie, your healthcare provider will do blood tests to check for hepatitis B virus infection. If you have ever had hepatitis B virus infection, the hepatitis B virus could become active again during or after treatment for hepatitis C virus with Technivie. Hepatitis B virus that becomes active again (called reactivation) may cause serious liver problems including liver failure and death. Your healthcare provider will monitor you if you are at risk for hepatitis B virus reactivation during treatment and after you stop taking Technivie.
• Severe liver problems, especially in people with certain types of cirrhosis. These severe liver problems can lead to the need for a liver transplant, or can lead to death. If you have cirrhosis, your healthcare provider will check your liver before and during treatment with Technivie.
• Increases in your liver function blood tests, especially if you use ethinyl estradiol-containing medicines (contained in certain birth control products).
• You must stop using ethinyl estradiol-containing medicines before you start treatment with Technivie. See the prescribing information for a list of these medicines.
  • If you use these medicines as a method of birth control, you must use another method of birth control during treatment with Technivie, and for about 2 weeks after you finish treatment with Technivie. Your healthcare provider will tell you when you may begin taking ethinyl estradiolcontaining medicines.
• Your healthcare provider should do blood tests to check your liver function during the first 4 weeks and then as needed, during treatment with Technivie.
• Your healthcare provider may tell you to stop taking Technivie if you develop signs or symptoms of liver problems.

Tell your healthcare provider right away if you develop any of the following symptoms, or if they worsen during treatment with Technivie:

• tiredness
• weakness
• loss of appetite
• nausea and vomiting
• yellowing of your skin or eyes
• color changes in your stools
• confusion
• swelling of the stomach area

Common side effects of Technivie when used with ribavirin include:

• feeling weak
• tiredness
• headache
• change in mood
• itching
• nausea
• sleep problems
• trouble breathing
• muscle or joint pain
• skin reactions
• dizziness

These are not all the possible side effects of Technivie. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Technivie should be administered with ribavirin (RBV). Refer to the prescribing information for ribavirin for a list of ribavirin-associated adverse reactions.

The following adverse reaction is described below and elsewhere in the labeling:

• Risk of Hepatic Decompensation and Hepatic Failure in Patients with Cirrhosis 
• Increased Risk of ALT Elevations 

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of ombitasvir, paritaprevir and ritonavir cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reaction In Subjects Without Cirrhosis

The safety assessment of Technivie is based on data from two clinical studies in subjects with HCV genotype 4 infection. PEARL-I was a study including 135 subjects without cirrhosis, 91 who received ombitasvir 25 mg, paritaprevir 150 mg and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily with ribavirin for 12 weeks and 44 subjects who received ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg (administered as one ombitasvir 25 mg tablet, three paritaprevir 50 mg tablets and one ritonavir 100 mg capsule) once daily without ribavirin for 12 weeks.

Adverse reactions that occurred in subjects without cirrhosis treated with ombitasvir, paritaprevir and ritonavir with or without ribavirin for 12 weeks are listed in Table 2. The majority of adverse reactions in non-cirrhotic subjects were mild in severity, none were serious and none led to discontinuation of treatment.

Table 2. Selected Adverse Reactions (All Grades) with ≥5% Frequency Reported in Subjects with HCV Genotype 4 Infection without Cirrhosis Treated with Ombitasvir, Paritaprevir and Ritonavir with or without Ribavirin for 12 Weeks

Adverse Events In Subjects With Compensated Cirrhosis

AGATE-I was a study including 120 subjects with compensated cirrhosis who received Technivie once daily with ribavirin for a total of 12 weeks (n=60) or 16 weeks (n=60). Adverse events occurring up to and including 12 weeks of treatment (≤ 84 days) from both arms were included in the analysis of adverse events and are listed in Table 3.

Seven of 120 subjects (6%) experienced serious adverse events at or before 12 weeks of treatment. No adverse events led to the discontinuation of Technivie. Thirty-one subjects (26%) underwent ribavirin dose reductions; five discontinued ribavirin, three received transfusion and one received erythropoietin.

Table 3. Selected Adverse Events (All Grades) with ≥5% Frequency Reported in Subjects with HCV Genotype 4 Infection with Compensated Cirrhosis Treated with Technivie and Ribavirin through 12 Weeks

Laboratory Abnormalities

Serum ALT Elevations

None of the 135 subjects without cirrhosis and two (2%) of the 120 subjects with compensated cirrhosis treated with Technivie experienced post-baseline serum ALT levels greater than 5 times the upper limit of normal (ULN) and ≥2 times baseline after starting treatment [see WARNINGS AND PRECAUTIONS].

Serum Bilirubin Elevations in Patients without Cirrhosis

Post-baseline elevations in bilirubin at least 2 times ULN were observed in 5% (7/134) of subjects without cirrhosis, receiving Technivie, all of whom were also receiving RBV. These bilirubin increases were predominately indirect and related to the inhibition of the bilirubin transporters OATP1B1/1B3 by paritaprevir and possibly ribavirin-induced hemolysis. Bilirubin elevations occurred early after initiation of treatment, peaked by study Week 1, and generally resolved with ongoing therapy. Bilirubin elevations were generally not associated with serum ALT elevations.

Serum Bilirubin Elevations/Hepatic Decompensation in Patients with Compensated Cirrhosis

Among the 120 subjects with compensated cirrhosis, mean total bilirubin and mean indirect bilirubin levels increased to approximately 3 fold from baseline on treatment. Mean direct bilirubin levels increased to approximately 2 fold on treatment. Mean bilirubin elevations occurred early, peaked by Week 1, remained elevated on treatment and normalized by post treatment week 4. Bilirubin elevations were generally not associated with serum ALT elevations.

Over 40% (50/120) of subjects across both arms experienced elevated direct bilirubin levels (>ULN) at or before 12 weeks of treatment. Twelve percent (6/50) of these subjects experienced clinical bilirubin or liver related events including jaundice, ocular icterus and portal vein thrombosis.

One subject who did not have direct bilirubin elevations also experienced liver related adverse events of esophageal varices and ascites.

Anemia/Decreased Hemoglobin in Patients without Cirrhosis

The mean change from baseline in hemoglobin levels in subjects without cirrhosis treated with Technivie in combination with ribavirin was -2.1 g/dL and the mean change in subjects treated with Technivie alone was -0.4 g/dL. Decreases in hemoglobin levels occurred early in treatment (Week 1-2) with further reductions through Week 3. Hemoglobin values remained low during the remainder of treatment and returned towards baseline levels by post-treatment Week 4.

One subject treated with Technivie with ribavirin had a single hemoglobin level decrease to less than 8 g/dL during treatment. No subject treated with Technivie alone had hemoglobin levels less than 8 g/dL. Four percent (4/91) of subjects without cirrhosis treated with Technivie with ribavirin underwent ribavirin dose reductions to manage anemia/decreased hemoglobin levels. No subject received erythropoietin.

Anemia/Decreased Hemoglobin in Patients with Compensated Cirrhosis

Across both treatment arms, 4/120 cirrhotic subjects (3%) had anemia (hemoglobin less than LLN) prior to initiation of treatment. However, 88/120 (73%) had anemia (hemoglobin less than LLN) and/or a hemoglobin decrease of ≥ 2g/dl at or before 12 weeks of treatment. One subject (1%) had a single hemoglobin value less than 8.0 g/dL on treatment at or before 12 weeks of treatment. Reductions in hemoglobin are most likely primarily related to ribavirin in this population.

Of 64 subjects with a history of cardiovascular disease or diabetes mellitus, 9 (14%) experienced cardiac adverse events at or before 12 weeks of treatment. These 9 subjects had a mean hemoglobin decrease of 3.9 g/dL (range 1.1 to 5.3 g/dL) from baseline and experienced cardiac events including acute coronary syndrome, angina pectoris, chest pain, atrial fibrillation, palpitations, hypotension and hypertension. Among 56 subjects without a prior history of cardiovascular disease or diabetes, 2 (4%) experienced a cardiac event (mild or moderate hypertension).

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Technivie. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Anaphylactic reactions and other hypersensitivity reactions (including angioedema).

Hepatobiliary Disorders: Hepatic decompensation, hepatic failure.

Skin and Subcutaneous Tissue Disorders: Erythema multiforme (EM).

Potential For Technivie To Affect Other Drugs

Paritaprevir is an inhibitor of OATP1B1 and OATP1B3 and paritaprevir and ritonavir are inhibitors of BCRP and P-gp. Ritonavir is an inhibitor of CYP3A4. Co-administration of Technivie with drugs that are substrates of CYP3A, P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs.

Potential For Other Drugs To Affect One Or More Components Of Technivie

Paritaprevir and ritonavir are primarily metabolized by CYP3A enzymes. Co-administration of Technivie with strong inhibitors of CYP3A may increase paritaprevir and ritonavir concentrations. Ombitasvir is primarily metabolized via amide hydrolysis while CYP enzymes play a minor role in its metabolism. Ombitasvir, paritaprevir and ritonavir are substrates of P-gp. Paritaprevir is a substrate of BCRP, OATP1B1 and OATP1B3. Inhibition of P-gp, BCRP, OATP1B1 or OATP1B3 may increase the plasma concentrations of the various components of Technivie.

Established And Other Potential Drug Interactions

Clearance of HCV infection with direct-acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment.

Frequent monitoring of relevant laboratory parameters (e.g. International Normalized Ratio [INR] in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as CYP P450 substrates with a narrow therapeutic index (e.g. certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.

If dosage adjustments of concomitant medications are made due to treatment with Technivie, dosages should be re-adjusted after administration of Technivie is completed. Dosage adjustment is not required for Technivie.

Table 4 provides the effect of co-administration of Technivie on concentrations of concomitant drugs and the effect of concomitant drugs on the various components of Technivie. Refer to the ritonavir prescribing information for other potentially significant drug interactions with ritonavir.

Table 4. Drug Interactions

Drugs Without Clinically Significant Interactions With Technivie

No dosage adjustments are recommended when Technivie is co-administered with the following medications:

• abacavir,
• dolutegravir,
• duloxetine,
• emtricitabine/tenofovir disoproxil fumarate,
• escitalopram,
• gemfibrozil,
• lamivudine,
• methadone,
• progestin only contraceptives,
• raltegravir,
• sofosbuvir,
• sulfamethoxazole,
• trimethoprim,
• rosuvastatin, and
• zolpidem.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Technivie and any potential adverse effects on the breastfed child from Technivie or from the underlying maternal condition. If Technivie is administered with ribavirin, the nursing information for ribavirin also applies to this combination regimen.