Chemical formula: C₃₆H₅₃N₇O₆ Molecular mass: 679.849 g/mol PubChem compound: 3010818
Telaprevir interacts in the following cases:
There are no data from the use of telaprevir in pregnant women. Animal studies are insufficient with respect to human reproductive toxicity. Telaprevir is not recommended during pregnancy and in women of childbearing potential not using contraception.
Telaprevir and its major metabolite are excreted in rat milk. It is not known whether telaprevir is excreted in human breast milk. Because of the potential for adverse reactions in breastfed infants, due to the combined treatment of telaprevir with peginterferon alfa and ribavirin, breast-feeding must be discontinued prior to initiation of therapy. See also the Summary of Product Characteristics for ribavirin.
Because telaprevir must be used in combination with peginterferon alfa and ribavirin, the contraindications and warnings applicable to those medicinal products are applicable to combination therapy.
Due to the combined treatment with peginterferon alfa and ribavirin, female patients of childbearing potential and their male partners as well as male patients and their female partners must use 2 effective contraceptive methods during telaprevir treatment. Following completion of telaprevir therapy contraceptive recommendations should be followed as in the Summary of Product Characteristics for ribavirin, and as described below.
Hormonal contraceptives may be continued but may not be reliable during telaprevir dosing and for up to two months following cessation of telaprevir. During this time, female patients of childbearing potential should use two effective non-hormonal methods of contraception. Two months after completion of telaprevir treatment, hormonal contraceptives are again appropriate as one of the two required effective methods of birth control.
Refer to the Summary of Product Characteristics for ribavirin and peginterferon alpha for additional information.
Telaprevir had no effects on fertility or fecundity when evaluated in rats.
Telaprevir has no or negligible influence on the ability to drive and use machines. No studies on the effects of telaprevir on the ability to drive and use machines have been performed. Syncope and retinopathy have been reported in some patients taking telaprevir and should be considered when assessing a patient’s ability to drive or operate machines. Refer also to the Summary of Product Characteristics for peginterferon alfa and ribavirin for further information.
The overall safety profile of telaprevir is based on Phase 2 and 3 clinical trial data (both controlled and uncontrolled) containing 3,441 patients who received telaprevir combination treatment and on spontaneous postmarketing reports.
Telaprevir must be administered with peginterferon alfa and ribavirin. Refer to their respective Summary of Product Characteristics for their associated adverse reactions.
The incidence of adverse drug reactions (ADRs) of at least moderate intensity (≥Grade 2) was higher in the telaprevir group than in the placebo group.
During the telaprevir/placebo treatment phase, the most frequently reported ADRs of at least Grade 2 in severity in the telaprevir group (incidence ≥5.0%) were anaemia, rash, pruritus, nausea, and diarrhoea.
During the telaprevir/placebo treatment phase, the most frequently reported ADRs of at least Grade 3 in the telaprevir group (incidence ≥1.0%) were anaemia, rash, thrombocytopenia, lymphopenia, pruritus, and nausea.
ADRs to telaprevir are presented below.
ADRs are listed by system organ class (SOC) and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000). Within each frequency grouping, ADRs are presented in order of decreasing seriousness.
Adverse drug reactions to telaprevir (taken in combination with peginterferon alfa and ribavirin) in HCV-infected patients in clinical trialsa and post-marketing:
common: oral candidiasis
very common: anaemia
common: thrombocytopeniab, lymphopeniab
common: hypothyroidism
common: hyperuricaemiab, hypokalaemiab
uncommon: gout
common: dysgeusia, syncope
uncommon: retinopathy
very common: nausea, diarrhoea, vomiting, haemorrhoids, proctalgia
common: anal pruritus, rectal haemorrhage, anal fissure
uncommon: proctitis, pancreatitis
common: hyperbilirubinaemiab
very common: pruritus, rash
common: eczema, swelling face, exfoliative rash
uncommon: drug rash with eosinophilia and systemic symptoms (DRESS), urticaria
rare: SJS, TEN, erythema multiforme
uncommon: blood creatinine increasedb, pre-renal azotemia with or without acute renal failure
common: oedema peripheral, product taste abnormal
a the placebo-controlled Phase 2 and Phase 3 Studies (pooled data) included 1,346 HCV-infected patients
b incidence rates are based on adverse event reporting rates (additionally, see Laboratory abnormalities below)
In the analysis of an additional study, Study C211, the safety profile of combination therapy with telaprevir 1,125 mg twice daily was similar to the safety profile for patients receiving combination therapy with telaprevir 750 mg every 8 hours. No new safety findings were identified.
Selected laboratory abnormalities of at least moderate intensity (≥ Grade 2) that represent a worsening from baseline and are considered ADRs observed in HCV-infected patients treated with telaprevir combination treatment from the pooled data from the placebo-controlled Phase 2 and Phase 3 trials are presented in the table below.
Selected laboratory abnormalities (DAIDS a Grade ≥2) that represent a worsening from baseline and are considered adverse drug reactions in HCV-infected patients treated with telaprevir combination treatment from the pooled data from the placebo-controlled Phase 2 and Phase 3 trials:
| Grade 2 | Grade 3 | Grade 4 | ||
|---|---|---|---|---|
| Increaseb | ||||
| uric acid | 17.9% (10.1-12.0 mg/dl) | 4.6% (12.1-15.0 mg/dl) | 1.1% (>15.0 mg/dl) | |
| bilirubin | 13.6% (1.6-2.5 x ULN) | 3.6% (2.6-5.0 x ULN) | 0.3% (>5.0 x ULN) | |
| total cholestrerol | 15.4% (6.20–7.77 mmol/l 240-300 mg/dl) | 2.0% (>7.77 mmol/l >300 mg/dl) | NA | |
| low-density lipoprotein | 6.9% (4.13–4.90 mmol/l 160–190 mg/dl) | 2.5% (≥4.91 mmol/l ≥191 mg/dl) | NA | |
| creatinine | 0.9% (1.4–1.8 x ULN) | 0.2% (1.9-3.4 x ULN) | 0% (>3.4 x ULN) | |
| Decreaseb | ||||
| haemoglobin | 27.0% (9.0-9.9 g/dl or any decrease 3.5-4.4 g/dl) | 51.1% (7.0-8.9 g/dl or any decrease ≥4.5 g/dl) | 1.1% (<7.0 g/dl) | |
| platelet count | 24.4% (50.000–99.999/mm³) | 2.8% (25.000–49.999/mm³) | 0.2% (<25.000/mm³) | |
| absolute lymphocyte count | 13.1% (500-599/mm³) | 11.8% (350-499/mm³) | 4.8% (<350/mm³) | |
| potassium | 1.6% (2.5–2.9 mEq/l) | 0% (2.0-2.4 mEq/l) | 0% (<2.0 mEq/l) | |
NA = not applicable
a The Division of AIDS Table for Grading the Severity of Adult and Paediatric Adverse Events (DAIDS, version 1.0, December 2004) was used in the pooled laboratory datasets.
b The incidence was calculated by the number of patients for each parameter.
Most laboratory values return to levels observed with peginterferon alfa and ribavirin by week 24, except platelet counts, which remain at levels lower than observed with peginterferon alfa and ribavirin until week 48.
Increases in serum uric acid occur very commonly during treatment with telaprevir in combination with peginterferon alfa and ribavirin. After the end of telaprevir treatment, uric acid values typically decrease over the following 8 weeks and are comparable to those observed in patients receiving peginterferon alfa and ribavirin alone.
Severe, potentially life-threatening and fatal skin reactions have been reported with telaprevir combination treatment, including DRESS, SJS, and TEN. In placebo-controlled Phase 2 and 3 trials, the overall incidence and severity of rash increased when telaprevir was co-administered with peginterferon alfa and ribavirin. During telaprevir treatment, rash events (all grades) were reported in 55% of patients who received telaprevir combination treatment and in 33% of patients who received peginterferon alfa and ribavirin.
More than 90% of rashes were of mild or moderate severity. The rash reported during telaprevir combination treatment was assessed as a typically pruritic, eczematous rash, and involved less than 30% of body surface area. Half the rashes started during the first 4 weeks, but rash can occur at any time during telaprevir combination treatment. Discontinuation of telaprevir combination treatment is not required for mild and moderate rash.
Patients experiencing mild to moderate rash should be monitored for signs of progression; however, progression was infrequent (less than 10%). In clinical trials, the majority of patients were administered antihistamines and topical corticosteroids. Improvement of rash occurs after telaprevir dosing completion or discontinuation; however, rashes may take several weeks to resolve.
In placebo-controlled Phase 2 and 3 trials, anaemia (all grades) was reported in 32.1% of patients who received telaprevir combination treatment and in 14.8% of patients who received peginterferon alfa and ribavirin. Ribavirin dose reductions were used for management of anaemia. 21.6% of patients receiving telaprevir combination treatment required ribavirin dose reduction for anaemia compared to 9.4% of patients receiving peginterferon alfa and ribavirin alone. Erythropoisis-stimulating agents (ESAs) were generally not permitted and used in only 1% of patients in the Phase 2 and 3 clinical trials. In the placebo-controlled Phase 2 and 3 trials, transfusions were reported during the telaprevir/placebo treatment phase in 2.5% of patients receiving telaprevir combination treatment and 0.7% in patients receiving peginterferon alfa and ribavirin alone. Transfusion rates over the whole study period were 4.6% and 1.6%, respectively. In placebo-controlled Phase 2 and 3 trials, 1.9% of patients discontinued telaprevir alone due to anaemia, and 0.9% of patients discontinued telaprevir combination treatment due to anaemia compared to 0.5% receiving peginterferon alfa and ribavirin.
In clinical trials, the majority of these events (e.g., haemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate, very few led to treatment discontinuation and resolved after completion of telaprevir dosing.
The overall safety profile of telaprevir in HCV/HIV-1 co-infected patients (either not on antiretroviral therapy or on antiretroviral therapy) was similar to the safety profile in mono-infected HCV patients, except for patients receiving atazanavir/ritonavir who frequently experienced a transient increase in indirect bilirubin levels (including grades 3 to 4) through week 2, returning to near baseline by week 12.
The overall safety profile of telaprevir in treatment-naïve and treatment-experienced HCV-1 infected patients who were liver transplant recipients on a stable regimen of the immunosuppressants tacrolimus or cyclosporine A was generally similar to the safety profile of telaprevir in patients without a history of liver transplantation, although anaemia was reported more frequently (55.4% versus 32.1% in the Phase 2-3 safety pooling) during the telaprevir treatment phase. To manage anaemia, at initiation of telaprevir treatment a lower starting dose of ribavirin (600 mg/day) was used; during the overall treatment phase the ribavirin dose was further reduced in 36.5% of patients, 41.9% received ESAs and 21.6% received blood transfusions.
The safety and efficacy of telaprevir in children aged <18 years have not yet been established. No data are available.
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