Exviera 250 mg film-coated tablets

https://www.ema.europa.eu/en/documents/product-information/exviera-epar-product-information_en.pdf

During clinical trials with dasabuvir and ombitasvir/paritaprevir/ritonavir with or without ribavirin, transient elevations of ALT to greater than 5 times the upper limit of normal occurred in approximately 1% of subjects (35 of 3,039). ALT elevations were asymptomatic and generally occurred during the first 4 weeks of treatment, without concomitant elevations of bilirubin, and declined within approximately two weeks of onset with continued dosing of dasabuvir and ombitasvir/paritaprevir/ritonavir with or without ribavirin.

These ALT elevations were significantly more frequent in the subgroup of subjects who were using ethinyloestradiol -containing medicinal products such as combined oral contraceptives or contraceptive vaginal rings (6 of 25 subjects); (see section 4.3). In contrast, the rate of ALT elevations in subjects using other types of oestrogens as typically used in hormonal replacement therapy (i.e., oral and topical oestradiol and conjugated oestrogens) was similar to the rate observed in subjects who were not using oestrogen-containing products (approximately 1% in each group).

While dasabuvir is an in vitro inhibitor of P-gp, no significant change was observed in the exposure of the P-gp substrate, digoxin, when administered with dasabuvir with ombitasvir/paritaprevir/ritonavir. It may not be excluded that the systemic exposure of dabigatran etexilate is increased by dasabuvir due to inhibition of P-gp in the intestine.

What is Exviera and what does it do?

https://easternliver.files.wordpress.com/2018/03/dasabuvir-exviera.pdf

Exviera (also known as dasabuvir) is used to treat hepatitis C and is used together with Viekirax® and ribavirin. It stops replication of the hepatitis C viruses by directly affecting the mechanisms used by the virus to make copies of itself. It is therefore known as a direct acting antiviral (DAA).

Exviera® should only ever be taken with other medication for hepatitis C, such as Viekirax®. Exviera® comes as a tablet containing 250mg of dasabuvir and should be taken twice a day, ideally every 12 hours. The duration of treatment will depend on your hepatitis C genotype and the extent of your liver disease. Usually treatment is taken for between 12 and 24 weeks. If you forget to take your dose but remember within 6 hours, take your normal dose, but if it is after this then you skip that day’s dose

It is common for patients taking Exviera® to experience itching whilst taking this medication. Rarely, it can cause facial swelling (angioedema). Other possible symptoms include nausea, difficulty sleeping, tiredness and physical weakness. These are more common when ribavirin is taken alongside Exviera. If you experience any adverse effects you should contact your nurse specialist or prescriber. Some patients may require a dose adjustment.

Summary of the risk management plan (RMP) for Exviera dasabuvir)

https://fimea.fi/documents/147152901/159459773/28729_Exviera_RMP_summary-EN.pdf/fa4722e6-3a65-46a5-9299-a1537375c2fe/28729_Exviera_RMP_summary-EN.pdf?t=1689770538147

This is a summary of the risk management plan (RMP) for Exviera, which details the measures to be taken in order to ensure that Exviera is used as safely as possible.

Exviera in combination with Viekirax is used to treat hepatitis C, an infectious disease of the liver that is caused by the hepatitis C virus (HCV). Every year, 3 to 4 million people worldwide are infected with HCV. Chronic (long-term) HCV infection may cause complications such as cirrhosis (scarring of the liver), liver failure and liver cancer, and may lead to death. Several HCV genotypes and subtypes exist, with genotype 1 being the most common in Europe. Young adults and men are more frequently infected. HCV is usually transmitted through contact with the blood of an infected person. The main risk factors for infection include use of illegal drugs, unsafe injections and blood transfusions.

In 6 main studies involving around 2,300 patients infected with hepatitis C virus genotypes 1a or 1b, Exviera in combination with Viekirax was effective in clearing the virus from the blood. Between 96% and 100% of patients without liver scarring had their blood cleared of the virus after 12 weeks of treatment (with or without ribavirin). In patients with liver scarring, Exviera treatment in combination with Viekirax and ribavirin resulted in a clearance rate of between 93% and 100% after 24 weeks of treatment. In these studies, the addition of ribavirin to Exviera and Viekirax helped increase the clearance rates in patients with liver scarring. The clearance rates were particularly high in patients infected with genotype 1b, reaching almost 100%.

Discovery and preclinical development of dasabuvir for the treatment of hepatitis C infection

https://web.archive.org/web/20190223214951id_/http://pdfs.semanticscholar.org/4dc9/f230e6a6132a9435a897f3cace2ce4556aaf.pdf

Hepatitis C virus (HCV) is a global pathogen and a leading cause of morbidity and mortality. In the last 15 years, the seroprevalence of HCV infection has increased to 2.8%, which accounts for 185 million infections worldwide. Chronic HCV infection is associated with the development of many complications like liver cirrhosis, liver cell failure, hepatocellular cancer, and death. In the past, administration of pegylated interferon and ribavirin, administered for 24–48 weeks, was long considered as the standard treatment therapy for HCV. However, this treatment mode was found to be associated with several side effects. Despite comparable treatment outcomes between low-middle income countries and well-resourced countries, the financial burden has been a considerable barrier for healthcare systems in the former’s case. Consequently, there was a worldwide agreement to make a remarkable and dramatic shift in the treatment of HCV infection in the present decade. Unfortunately, the first generation of new direct-acting antivirals (DAAs) that was administered with interferon and ribavirin showed several side effects despite having increased efficacy. The second generation of DAA therapies showed higher cure rates and minimal side effects in Phase II or III trials. This has led to the development of multiple DAA therapies. When given in combination, they rendered the need for interferon treatment unnecessary, leading to the emergence of the term ‘interferon-free regimens’

Combinations of DAAs that target different steps of viral replication have significantly improved the efficacy of HCV treatment by increasing its safety and tolerability. The duration of therapy has also been shortened along with simplified treatment algorithms. In addition, these therapies have significantly reduced the public health burden of this disease. DAAs include inhibitors of HCV NS3/4A protease (telaprevir, boceprevir, and simeprevir), HCV NS5A protein (ledipasvir, daclatasvir), and the nucleotide analog NS5B polymerase inhibitors (sofosbuvir). One of the newly developed NS5B polymerase inhibitors is dasabuvir. It was formerly known as ABT-333, and its chemical name is sodium 3-(3-tert-butyl-4-methoxy-5-{6- [(methylsulfonyl) amino] naphthalene-2-yl}phenyl)-2,6-dioxo3,6-dihydro-2H-pyrimidin-1-ide hydrate [1:1:1]). While there is much information available on the use of DAA combinations in clinical practice, there is limited available data on the discovery and development of each agent in these combinations. Thus, we conducted this review with the aim of collating the available data on the discovery and preclinical development of dasabuvir.