Chemical formula: C₃₈H₄₇N₅O₇S₂ Molecular mass: 749.939 g/mol PubChem compound: 24873435
Simeprevir interacts in the following cases:
There are no adequate and well-controlled studies with simeprevir in pregnant women. Studies in animals have shown reproductive effects. Simeprevir should only be used during pregnancy or in women of childbearing potential if the benefit justifies the risk. Female patients of childbearing potential must use an effective form of contraception.
Because simeprevir must be co-administered with other medicinal products, for the treatment of CHC, the contraindications and warnings applicable to those medicinal products also apply to their use in combination treatment with simeprevir.
Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Female patients of childbearing potential and male patients with female partners of childbearing potential must use an effective form of contraception during treatment with ribavirin and after completion of ribavirin treatment for a duration as specified in the Summary of Product Characteristics for ribavirin.
It is not known whether simeprevir or its metabolites are excreted in human milk. When administered to lactating rats, simeprevir was detected in plasma of suckling rats likely due to excretion of simeprevir via milk. A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from simeprevir therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.
There are no data on the effect of simeprevir on human fertility. No effects on fertility were observed in animal studies.
Simeprevir has no or negligible influence on the ability to drive and use machines. Combination treatment of simeprevir with other medicinal products for the treatment of CHC may affect a patient’s ability to drive and use machines. Refer to the Summary of Product Characteristics for these co-administered medicinal products regarding their potential effect on the ability to drive and use machines.
The overall safety profile of simeprevir is based on data from 580 HCV genotype 1 infected patients who received simeprevir in combination with sofosbuvir with or without ribavirin (pooled data from the clinical phase 2 study HPC2002 and the clinical phase 3 studies HPC3017 and HPC3018) and 1,486 HCV genotype 1 infected patients who received simeprevir (or placebo) in combination with peginterferon alfa and ribavirin (pooled data from the clinical phase 2 studies C205 and C206 and the clinical phase 3 studies C208, C216 and HPC3007).
The safety profile of simeprevir is comparable in patients with HCV genotype 4 infection and HCV genotype 1 infection, when given either in combination with sofosbuvir or in combination with peginterferon alfa and ribavirin.
The safety profile of simeprevir in combination with sofosbuvir in patients with HCV genotype 1 infection with or without cirrhosis is based on pooled data from the phase 2 study HPC2002 and the phase 3 studies HPC3017 and HPC3018 which included 472 patients who received simeprevir with sofosbuvir without ribavirin (155, 286 and 31 patients received 8, 12 or 24 weeks of treatment, respectively) and 108 patients who received simeprevir with sofosbuvir and ribavirin (54 patients each received 12 or 24 weeks of treatment).
The majority of the adverse reactions reported were grade 1 in severity. Grade 2 and 3 adverse reactions were reported in 3.5% (n=10) and 0.3% (n=1) of patients, respectively, receiving 12 weeks simeprevir with sofosbuvir; no grade 4 adverse reactions were reported. In patients receiving 24 weeks simeprevir with sofosbuvir, no grade 2 or 3 adverse reactions were reported; one patient (3.2%) experienced a grade 4 adverse reaction (‘blood bilirubin increased’). No serious adverse reactions were reported.
The most frequently reported adverse reactions (incidence ≥5% following 12 or 24 weeks of treatment) were rash, pruritus, constipation and photosensitivity reaction.
One patient in the 12-week treatment group (0.3%) and none of the patients in the 24-week treatment group discontinued treatment due to adverse reactions.
The safety profile of simeprevir in combination with peginterferon alfa and ribavirin in patients with HCV genotype 1 infection is based on the pooled data from the phase 2 studies and phase 3 studies C205, C206, C208, C216 and HPC3007 which included 924 patients who received simeprevir 150 mg once daily for 12 weeks and 540 patients who received placebo with peginterferon alfa and ribavirin.
In the pooled phase 3 safety data, the majority of the adverse reactions reported during 12 weeks treatment with simeprevir were grade 1 to 2 in severity. Grade 3 or 4 adverse reactions were reported in 3.1% of patients receiving simeprevir with peginterferon alfa and ribavirin versus 0.5% of patients receiving placebo with peginterferon alfa and ribavirin. Serious adverse reactions were reported in 0.3% of simeprevir-treated patients (2 photosensitivity events requiring hospitalisation) and in none of the patients receiving placebo with peginterferon alfa and ribavirin.
During the first 12 weeks of treatment, the most frequently reported adverse reactions (incidence ≥5%) were nausea, rash, pruritus, dyspnoea, blood bilirubin increase and photosensitivity reaction.
Discontinuation of simeprevir due to adverse reactions occurred in 0.9% of patients receiving simeprevir with peginterferon alfa and ribavirin.
Adverse reactions of simeprevir in combination with sofosbuvir or in combination with peginterferon alfa and ribavirin reported in adult patients with HCV genotype 1 infection are listed in table 1. The adverse reactions 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), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).
Table 1. Adverse reactions identified with simeprevir in combination with sofosbuvir or simeprevir in combination with peginterferon alfa and ribavirin1:
| SOC Frequency Category | simeprevir + sofosbuvir | simeprevir + peginterferon alfa + ribavirin N=781 | |
|---|---|---|---|
| 12 weeks N=286 | 24 weeks N=31 | ||
| Respiratory, thoracic and mediastinal disorders | |||
| very common | dyspnoea* | ||
| Gastrointestinal disorders | |||
| very common | nausea | ||
| common | constipation | constipation | constipation |
| Hepatobiliary disorders | |||
| common | blood bilirubin increased* | blood bilirubin increased* | blood bilirubin increased* |
| Skin and subcutaneous tissue disorders | |||
| very common | rash* | rash*, pruritus* | |
| common | rash*, pruritus*, photosensitivity reaction* | pruritus*, photosensitivity reaction* | photosensitivity reaction* |
1 Simeprevir in combination with sofosbuvir: pooled studies HPC2002, HPC3017 and HPC3018 (12 weeks) or study HPC2002 (24 weeks); simeprevir in combination with peginterferon alfa and ribavirin: pooled phase 3 studies C208, C216 and HPC3007 (first 12 weeks of treatments).
* see section below for further details.
Most of the rash and pruritus events in simeprevir-treated patients were of mild or moderate severity (grade 1 or 2).
Simeprevir in combination with sofosbuvir: Rash and pruritus were reported in 8.0% and 8.4%, respectively, of patients receiving 12 weeks of treatment compared to 12.9% and 3.2%, respectively, of patients receiving 24 weeks of treatment (all grades). Grade 3 rash was reported in one patient (0.3%; 12-week treatment group) which led to treatment discontinuation; none of the patients experienced grade 4 rash. None of the patients experienced grade 3 or 4 pruritus; none of the patients discontinued treatment due to pruritus.
In study HPC2002, rash (grouped term) was reported in 10.7% of patients receiving 12 weeks of simeprevir and sofosbuvir without ribavirin versus 20.4% of patients receiving 12 weeks of simeprevir and sofosbuvir with ribavirin.
Simeprevir in combination with peginterferon alfa and ribavirin: During the 12 weeks treatment with simeprevir, rash and pruritus were reported in 21.8% and 21.9% of simeprevir-treated patients, compared to 16.6% and 14.6% in placebo-treated patients, respectively (all grades; pooled phase 3). Grade 3 rash or pruritus occurred in 0.5% and 0.1% of simeprevir-treated patients, respectively. Discontinuation of simeprevir due to rash or pruritus occurred in 0.8% and 0.1% of simeprevir-treated patients, compared to 0.3% and 0% of placebo-treated patients, respectively.
Elevations in direct and indirect bilirubin have been reported in patients treated with simeprevir and were mostly of mild or moderate severity. Bilirubin elevations were generally not associated with elevations in liver transaminases and bilirubin levels normalised after end of treatment.
Simeprevir in combination with sofosbuvir: ‘Blood bilirubin increased’ was reported in 1.0% of patients receiving 12 weeks of treatment compared to 3.2% in patients receiving 24 weeks of treatment (all grades). Grade 2 ‘blood bilirubin increased’ was reported in one patient (0.3%) receiving 12 weeks of treatment. There were no grade 3 events reported. One patient (3.2%) receiving 24 weeks of treatment experienced a grade 4 ‘blood bilirubin increased’ event. None of the patients discontinued treatment due to ‘blood bilirubin increased’.
In study HPC2002, increased bilirubin was reported in 0% of patients receiving 12 weeks of simeprevir and sofosbuvir without ribavirin versus 9.3% of patients receiving 12 weeks of simeprevir and sofosbuvir with ribavirin.
Simeprevir in combination with peginterferon alfa and ribavirin: During the 12 weeks treatment with simeprevir, ‘blood bilirubin increased’ was reported in 7.4% of simeprevir-treated patients, compared to 2.8% in placebo-treated patients (all grades; pooled phase 3). In 2% and 0.3% of the simeprevir-treated patients grade 3 or 4 ‘blood bilirubin increased’ was reported, respectively (pooled phase 3 studies). Discontinuation of simeprevir due to ‘blood bilirubin increased’ was rare (0.1%; n=1).
Simeprevir in combination with sofosbuvir: Photosensitivity reactions were reported in 3.1% of simeprevir-treated patients receiving 12 weeks of treatment compared to 6.5% in patients receiving 24 weeks of treatment (all grades). Most of the photosensitivity reactions were of mild severity (grade 1); grade 2 photosensitivity reactions were reported in two patients (0.7%) receiving 12 weeks of treatment. There were no grade 3 or 4 photosensitivity reactions reported and none of the patients discontinued treatment due to photosensitivity reactions.
In study HPC2002, photosensitivity reactions (grouped term) was reported in 7.1% of patients receiving 12 weeks of simeprevir and sofosbuvir without ribavirin versus 5.6% of patients receiving 12 weeks of simeprevir and sofosbuvir with ribavirin.
Simeprevir in combination with peginterferon alfa and ribavirin: During the 12 weeks treatment with simeprevir, photosensitivity reactions were reported in 4.7% of simeprevir-treated patients compared to 0.8% in placebo-treated patients (all grades; pooled phase 3). Most photosensitivity reactions in simeprevir-treated patients were of mild or moderate severity (grade 1 or 2); 0.3% of the simeprevir-treated patients experienced serious reactions leading to hospitalisation.
Simeprevir in combination with peginterferon alfa and ribavirin: During the first 12 weeks treatment with simeprevir, dyspnoea was reported in 11.8% of simeprevir-treated patients, compared to 7.6% in placebo-treated patients (all grades; pooled phase 3). Only grade 1 and 2 events were reported and there were no events leading to discontinuation of any of the study drugs. In patients aged >45 years, dyspnoea was reported in 16.4% of simeprevir-treated patients compared to 9.1% in placebo-treated patients (all grades; pooled phase 3).
Cases of bradycardia have been observed when simeprevir is used in combination with sofosbuvir and concomitant amiodarone.
Treatment-emergent laboratory abnormalities in amylase and lipase have been observed in patients treated with simeprevir in combination with sofosbuvir (table 2). Elevations in amylase and lipase were transient and mostly of mild or moderate severity. Amylase and lipase elevations were not associated with pancreatitis.
Table 2. Treatment-emergent laboratory abnormalities in amylase and lipase in patients receiving 12 or 24 weeks of simeprevir in combination with sofosbuvir (12 weeks: pooled studies HPC2002, HPC3017 and HPC3018; 24 weeks: study HPC2002):
| Laboratory parameter | WHO toxicity range1 | 12 weeks simeprevir + sofosbuvir N=286 n (%) | 24 weeks simeprevir + sofosbuvir N=31 n (%) |
|---|---|---|---|
| Chemistry | |||
| Amylase | |||
| Grade 1 | ≥1.1 to ≤1.5 x ULN | 34 (11.9%) | 8 (25.8%) |
| Grade 2 | >1.5 to ≤2.0 x ULN | 15 (5.2%) | 2 (6.5%) |
| Grade 3 | >2.0 to ≤5.0 x ULN | 13 (4.5%) | 3 (9.7%) |
| Lipase | |||
| Grade 1 | ≥1.1 to ≤1.5 x ULN | 13 (4.5%) | 1 (3.2%) |
| Grade 2 | >1.5 to ≤3.0 x ULN | 22 (7.7%) | 3 (9.7%) |
| Grade 3 | >3.0 to ≤5.0 x ULN | 1 (0.3%) | 1 (3.2%) |
| Grade 4 | >5.0 x ULN | 1 (0.3%) | 1 (3.2%) |
1 WHO worst toxicity grades 1 to 4.
ULn=Upper Limit of Normal.
There were no differences in haemoglobin, neutrophils or platelets between both treatment groups. Treatment-emergent laboratory abnormalities that were observed at a higher incidence in simeprevir-treated patients than in patients treated with placebo, peginterferon alfa and ribavirin are given in table 3.
Table 3. Treatment-emergent laboratory abnormalities observed at a higher incidence in patients receiving simeprevir in combination with peginterferon alfa and ribavirin (pooled phase 3 studies C208, C216 and HPC3007; first 12 weeks of treatments):
| Laboratory parameter | WHO toxicity range1 | simeprevir + peginterferon alfa + ribavirin N=781 n (%) |
|---|---|---|
| Chemistry | ||
| Alkaline phosphatase | ||
| Grade 1 | ≥1.25 to ≤2.50 x ULN | 26 (3.3%) |
| Grade 2 | >2.50 to ≤5.00 x ULN | 1 (0.1%) |
| Hyperbilirubinemia | ||
| Grade 1 | ≥1.1 to ≤1.5 x ULN | 208 (26.7%) |
| Grade 2 | >1.5 to ≤2.5 x ULN | 143 (18.3%) |
| Grade 3 | >2.5 to ≤5.0 x ULN | 32 (4.1%) |
| Grade 4 | >5.0 x ULN | 3 (0.4%) |
1 WHO worst toxicity grades 1 to 4.
ULn=Upper Limit of Normal.
The safety profile of simeprevir in combination with peginterferon alfa and ribavirin is comparable between HCV genotype 1 infected patients with and without HIV-1 co-infection.
The safety profile of simeprevir 150 mg in combination with peginterferon alfa and ribavirin in a phase 3 study conducted in Asian patients in China and South-Korea is comparable to non-Asian patients from a pooled phase 3 population from global studies, except for higher frequencies for ‘blood bilirubin increased’ events.
Table 4. ‘Blood bilirubin increased’ events observed in Asian patients from the phase 3 study HPC3005 versus the pooled phase 3 studies C208, C216 and HPC3007 receiving simeprevir or placebo in combination with peginterferon alfa and ribavirin (first 12 weeks of treatment):
| Blood bilirubin increased | Phase 3 study in Asian patients | Pooled phase 3 studies | ||
|---|---|---|---|---|
| simeprevir + peginterferon alfa + ribavirin N=152 n (%) | placebo + peginterferon alfa + ribavirin N=152 n (%) | simeprevir + peginterferon alfa + ribavirin N=781 n (%) | placebo + peginterferon alfa + ribavirin N=397 n (%) | |
| All grades | 67 (44.1%) | 28 (18.4%) | 58 (7.4%) | 11 (2.8%) |
| Grade 3 | 10 (6.6%) | 2 (1.3%) | 16 (2.0%) | 2 (0.5%) |
| Grade 4 | 0 (0%) | 0 (0%) | 2 (0,3%) | 0 (0%) |
| Related discontinuations | 1 (0.7%) | 0 (0%) | 1 (0.1%) | 0 (0%) |
During administration of simeprevir with peginterferon alfa and ribavirin, the elevations in direct and indirect bilirubin were generally not associated with elevations in liver transaminases and normalised after end of treatment.
Simeprevir exposure is significantly increased in patients with severe hepatic impairment. A trend for a higher incidence of increased bilirubin levels with increasing simeprevir plasma exposure was observed. These increases in bilirubin levels were not associated with any adverse liver safety finding. However, reports of hepatic decompensation and hepatic failure during simeprevir combination therapy have been received in the post marketing setting. A higher incidence of anaemia in patients with advanced fibrosis receiving simeprevir in combination with peginterferon alfa and ribavirin has been reported.
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