Telaprevir

Telaprevir is a strong inhibitor of CYP3A. Telaprevir is contraindicated when combined with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Telaprevir is contraindicated when combined with drugs that strongly induce CYP3A and thus may lead to lower exposure and loss of efficacy of telaprevir.

Potential pharmacokinetic interaction with drugs that are inducers or inhibitors of P-glycoprotein, with possible alteration in telaprevir concentrations.

Potential pharmacokinetic interaction with alfuzosin (increased alfuzosin concentrations). Concomitant use of telaprevir and alfuzosin is contraindicated because increased alfuzosin concentrations may result in hypotension or cardiac arrhythmia.

Potential pharmacokinetic interaction with antiarrhythmic agents (amiodarone, bepridil (no longer commercially available in US), flecainide, systemic lidocaine, propafenone, quinidine) may result in increased concentrations of the antiarrhythmic agent; potential for serious and/or life-threatening adverse effects. If telaprevir and antiarrhythmic agents are used concomitantly, use caution and clinical monitoring.

For more Interactions (Complete) data for Telaprevir (54 total), please visit the HSDB record page.

In large randomized controlled trials, triple therapy with telaprevir, peginterferon and ribavirin was associated with a high rate of adverse events that often required dose adjustments and led to early discontinuation in 5% to 20% of patients. However, serum ALT elevations and clinically apparent liver injury were not generally mentioned as adverse events of therapy. Telaprevir, however, was associated with a high rate of rash, which was sometimes associated with features of hypersensitivity, including rare instances of DRESS and Stevens Johnson syndrome. These severe cutaneous reactions are often accompanied by laboratory evidence of hepatic injury (ALT and alkaline phosphatase elevations). In reported cases, however, the rash and other features of hypersensitivity typically overshadowed the hepatic injury and none were reported to be associated with jaundice.；Another rare but severe hepatic complications of telaprevir therapy occurs in patients with advanced fibrosis or cirrhosis, among whom de novo, seemingly spontaneous hepatic decompensation occurred in a proportion of treated subjects. Decompensation was particularly common in patients with advanced fibrosis or cirrhosis with a previous history of decompensation. The cause of the decompensation was not clear and the separate role of telaprevir in contrast to peginterferon and ribavirin could not be defined. Nevertheless, in postmarketing studies of triple therapy of chronic hepatitis C with cirrhosis, decompensation was reported in 2% to 8% of patients, and deaths from hepatic failure in 1% to 3%.；Likelihood score for the combination of telaprevir, peginterferon and ribavirin: B (likely cause of liver injury and hepatic decompensation in patients with preexisting cirrhosis or advanced fibrosis).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.0X10+5(SRC), determined from a structure estimation method(2), indicates that telapravir is expected to be immobile in soil(SRC). Volatilization of telapravir from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.8X10-31 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Telapravir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.9X10-26 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation date in soil were not available(SRC, 2013).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.0X10+5(SRC), determined from a structure estimation method(2), indicates that telapravir is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.8X10-31 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 6(SRC), from an estimated log Kow of 1.73(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2013).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), telapravir, which has an estimated vapor pressure of 9.9X10-26 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase telapravir may be removed from the air by wet and dry deposition(SRC). Telapravir contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

It is not known whether telaprevir is excreted in human breast milk. When administered to lactating rats, levels of telaprevir were higher in milk compared to those observed in plasma. Rat offspring exposed to telaprevir in utero showed no effects on body weight at birth. However, when fed via milk from telaprevir-treated dams, body weight gain of pups was lower than pups fed milk from control dams. After weaning, rat pup body weight gain was similar in offspring from telaprevir-treated and control dams. Because of the potential for adverse reactions in nursing infants, nursing must be discontinued prior to initiation of treatment.The following adverse reactions have been identified during post-approval use of INCIVEK. 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. Skin and Subcutaneous Tissue Disorders: Toxic Epidermal Necrolysis (TEN) and Erythema Multiforme (EM).

Antiviral drugs have been recently recognized as one of the emerging contaminants in the environment. These are discharged after therapeutic use through human excretion. Effluent containing high concentration of antiviral drugs discharged from production facilities is also a cause of concern to nearby aquatic bodies. There is an increased interest in their removal because they are highly bioactive. Some antiviral drugs are resistant to conventional methods of degradation, and there is a risk of development of antiviral resistance in humans and animals if exposed repeatedly for long periods. To date, the potential human, animal, and ecological risks associated with the discharge of these antiviral compounds to the environment are not well documented. This study presents a brief summary on occurrence, ecotoxicological risks, and physicochemical properties of antiviral drugs in the environment. The needs regarding removal, disposal, and treatment of antiviral drugs are also addressed(1). /Antiviral drugs/

Using a structure estimation method based on molecular connectivity indices(1), the Koc of telapravir can be estimated to be 1.0X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that telapravir is expected to be immobile.

/SIGNS AND SYMPTOMS/ The highest documented dose administered is 1875 mg every 8 hours for 4 days in healthy subjects with telaprevir alone. In that trial, the following common adverse events were reported more frequently with the 1875 mg q8h regimen compared to the 750 mg q8h regimen: nausea, headache, diarrhea, decreased appetite, dysgeusia, and vomiting.

/SIGNS AND SYMPTOMS/ Fatal and non-fatal serious skin reactions, including Stevens Johnson Syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with INCIVEK combination treatment. Fatal cases have been reported in patients with progressive rash and systemic symptoms who continued to receive INCIVEK combination treatment after a serious skin reaction was identified. For serious skin reactions, including rash with systemic symptoms or a progressive severe rash, INCIVEK, peginterferon alfa, and ribavirin must be discontinued immediately. Discontinuing other medications known to be associated with serious skin reactions should be considered. Patients should be promptly referred for urgent medical care.

/CASE REPORTS/ /Investigators/ report a case of drug rash with eosinophilia and systemic symptoms (DRESS) due to telaprevir (VX-950), a specific inhibitor of the hepatitis C virus (HCV) serine protease. A 57-year-old woman with chronic hepatitis C was included in a phase 2 rollover study of VX-950. She received VX-950 in combination with pegylated interferon alfa-2a and ribavirin. Six weeks later, she developed a generalized pruritic maculopapular exanthema with malaise, fever, dyspnoea and lymph node swelling. She had an eosinophilia (up to 2.7 X 10(+9) cells/L), large activated lymphocytes and increased concentrations of aminotransferases. Histological examination of a cutaneous biopsy was consistent with a drug rash reaction. The HCV treatment was stopped, and she was treated with topical and oral steroids. Cutaneous and systemic symptoms disappeared within 1 month. Telaprevir was considered the culprit drug. The safety data of telaprevir is derived mainly from the PROVE1, PROVE2 and PROVE3 studies. They showed a high frequency of cutaneous side effects reported under the imprecise terms of pruritus and rash, leading to an increased rate of treatment discontinuation. It is important to be aware of the high incidence of cutaneous side effects and better describe them. Our observation suggests that potentially severe hypersensitivity reactions may belong to the spectrum of rashes induced by this drug.

/EPIDEMIOLOGY STUDIES/ Previous studies have reported telaprevir is effective for chronic hepatitis C virus infection, but the safety of a telaprevir-based regimen remains uncertain. A meta-analysis was performed to assess the safety of the addition of telaprevir to a standard regimen of pegylated interferon (peginterferon) plus ribavirin (combination telaprevir with peginterferon plus ribavirin, the TPR group) compared with the standard regimen group (peginterferon plus ribavirin, the PR group). Seven randomized controlled trials involving a total of 2808 patients were included in the meta-analysis. The addition oftelaprevir to the standard regimen was associated with a significantly increased risk of serious adverse events compared with the standard PR group (relative risk [RR]=1.56; 95% confidence interval [CI] 1.21, 2.03; p=0.0007; I2=0%). Telaprevir was also associated with increased risk of treatment discontinuation (RR=2.10; 95% CI 1.56, 2.83; p<?0.0001; I2=42%). In addition, telaprevir was more likely to cause nausea (RR=1.39; p<?0.0001), diarrhoea (RR=1.32; p=?0.004), pruritus (RR=1.56; p=0.0006), rash (RR=1.60; p<?0.0001) and anaemia (RR=1.55; p=0.007). There was no difference in the other kinds of adverse events between the two groups. Sensitivity analysis further validated the credibility of the above outcomes. ...

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Telaprevir

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 6 was calculated in fish for telapravir(SRC), using an estimated log Kow of 1.73(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The Henry's Law constant for telapravir is estimated as 8.8X10-31 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that telapravir is expected to be essentially nonvolatile from water and moist soil surfaces(2). Telapravir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.9X10-26 mm Hg(SRC), determined from a fragment constant method(3).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including telaprevir, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

Antiviral against hepatitis C

INCIVEK (telaprevir) is supplied as purple film-coated capsule-shaped tablets containing 375 mg of telaprevir. Each tablet is debossed with the characters "V 375" on one side and is packaged as follows: 28-day packer contains 4 weekly cartons of 7 blister strips each (6 tablets per blister strip)