Boceprevir

Chemical formula: C₂₇H₄₅N₅O₅  Molecular mass: 519.677 g/mol  PubChem compound: 10324367

Interactions

Boceprevir interacts in the following cases:

Interaction

at least one of
CYP3A4 inducers
CYP3A4 inhibitors

QT prolongation

The data available warrant caution in patients at risk of QT prolongation (long congenital QT, hypokalaemia).

Caution should be exercised with medicines known to prolong QT interval such as amiodarone, quinidine, methadone, pentamidine and some neuroleptics.

Pregnancy

Boceprevir in combination with ribavirin and peginterferon alfa is contraindicated in women who are pregnant.

No effects on foetal development have been observed in rats and rabbits. There are no data on the use of boceprevir in pregnant women.

Due to the combined treatment with peginterferon alfa and ribavirin, extreme care must be taken to avoid pregnancy in female patients or in female partners of male patients. Therefore, female patients of childbearing potential must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded.

Refer to Summary of Product Characteristics for ribavirin and peginterferon alfa for additional information.

Nursing mothers

Boceprevir/metabolites are excreted in rat milk. It is not known whether boceprevir is excreted in human breast milk. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy with boceprevir taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Carcinogenesis, mutagenesis and fertility

Fertility

No human data on the effect of boceprevir on fertility are available. Effects on fertility and Sertoli cells have been observed in rats but not in mice and monkeys. Clinical data (semen analyses and inhibin B levels – [a glycoprotein produced by Sertoli cells – used as a surrogate marker of testicular function]) showed no evidence of altered testicular function. Available pharmacodynamic/toxicological data in rats have shown effects of boceprevir/metabolites on fertility, which in females have been shown to be reversible.

Effects on ability to drive and use machines

Combination therapy of boceprevir, peginterferon alfa and ribavirin may influence some patients' ability to drive and use machines. Patients should be informed that fatigue, dizziness, syncope, blood pressure fluctuations and blurred vision have been reported.

Adverse reactions


Summary of the safety profile

The safety profile represented by approximately 1,500 patients for the combination of boceprevir with peginterferon alfa-2b and ribavirin was based on pooled safety data in two clinical trials: one in patients who were previously untreated, and one in patients who had failed prior therapy.

The most frequently reported adverse reactions were fatigue, anaemia, nausea, headache, and dysgeusia.

The most common reason for dose reduction was anaemia, which occurred more frequently in subjects receiving the combination of boceprevir with peginterferon alfa-2b and ribavirin than in subjects receiving peginterferon alfa-2b and ribavirin alone.

List of adverse reactions

Adverse reactions are listed by System Organ Class. Within each system organ class, adverse reactions are listed under headings of frequency using the categories: 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); not known (cannot be estimated from the available data).

Adverse reactions in combination with boceprevir with peginterferon alfa-2b and ribavirin reported during clinical trials † and ‡:

Infections and infestations

Common: Bronchitis*, cellulitis*, herpes simplex, influenza, oral fungal infection, sinusitis

Uncommon: Gastroenteritis*, pneumonia*, staphylococcal infection*, candidiasis, ear infection, fungal skin infection, nasopharyngitis, onychomycosis, pharyngitis, respiratory tract infection, rhinitis, skin infection, urinary tract infection

Rare: Epiglottitis*, otitis media, sepsis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Rare: Thyroid neoplasm (nodules)

Blood and lymphatic system disorders

Very common: Anaemia*, neutropenia*

Common: Leukopenia*, thrombocytopenia*, pancytopenia, agranulocytosis

Uncommon: Haemorrhagic diathesis, lymphadenopathy, lymphopenia

Rare: Haemolysis

Immune system disorders

Rare: Sarcoidosis*, porphyria non-acute

Endocrine disorders

Common: Goitre, hypothyroidism

Uncommon: Hyperthyroidism

Metabolism and nutrition disorders

Very common: Decreased appetite*

Common: Dehydration*, hyperglycaemia*, hypertriglyceridaemia, hyperuricaemia

Uncommon: Hypokalaemia* ̧ appetite disorder, diabetes mellitus, gout, hypercalcaemia

Psychiatric disorders

Very common: Anxiety*, depression*, insomnia, irritability

__Common: Affect lability, agitation, libido disorder, mood altered, sleep disorder

Uncommon: Aggression*, homicidal ideation*, panic attack*, paranoia*, substance abuse*, suicidal ideation*, abnormal behaviour, anger, apathy, confusional state, mental status changes, restlessness

Rare: Bipolar disorder*, completed suicide*, suicide attempt*, hallucination auditory, hallucination visual, psychiatric decompensation

Nervous system disorders

Very common: Dizziness*, headache*

Common: Hypoaesthesia*, paraesthesia*, syncope*, amnesia, disturbance in attention, memory impairment, migraine, parosmia, tremour, vertigo

Uncommon: Neuropathy peripheral*, cognitive disorder, hyperaesthesia, lethargy, loss of consciousness, mental impairment, neuralgia, presyncope

Rare: Cerebral ischaemia*, encephalopathy

Eye disorders

Common: Dry eye, retinal exudates, vision blurred, visual impairment

Uncommon: Retinal ischaemia*, retinopathy*, abnormal sensation in eye, conjunctival haemorrhage, conjunctivitis, eye pain, eye pruritus, eye swelling, eyelid oedema, lacrimation increased, ocular hyperaemia, photophobia

Rare: Papilloedema

Ear and labyrinth disorders

Common: Tinnitus

Uncommon: Deafness*, ear discomfort, hearing impaired

Cardiac disorders

Common: Palpitations

Uncommon: Tachycardia*, arrhythmia, cardiovascular disorder

Rare: Acute myocardial infarction*, atrial fibrillation*, coronary artery disease*, pericarditis*, pericardial effusion

Vascular disorders

Common: Hypotension*, hypertension

Uncommon: Deep vein thrombosis*, flushing, pallor, peripheral coldness

Rare: Venous thrombosis

Respiratory, thoracic and mediastinal disorders

Very common: Cough*, dyspnoea*

Common: Epistaxis, nasal congestion, oropharyngeal pain, respiratory tract congestion, sinus congestion, wheezing

Uncommon: Pleuritic pain*, pulmonary embolism*, dry throat, dysphonia, increased upper airway secretion, oropharyngeal blistering

Rare: Pleural fibrosis*, orthopnoea, respiratory failure

Gastrointestinal disorders

Very common: Diarrhoea*, nausea*, vomiting* dry mouth, dysgeusia

Common: Abdominal pain*, abdominal pain upper*, constipation*, gastrooesophageal reflux disease*, haemorrhoids*, abdominal discomfort, abdominal distention, anorectal discomfort, aphthous stomatitis, cheilitis, dyspepsia, flatulence, glossodynia, mouth ulceration, oral pain, stomatitis, tooth disorder

Uncommon: Abdominal pain lower*, gastritis*, pancreatitis*, anal pruritus, colitis, dysphagia, faeces discoloured, frequent bowl movements, gingival bleeding, gingival pain, gingivitis, glossitis, lip dry, odynophagia, proctalgia, rectal haemorrhage, salivary hypersecretion, sensitivity of teeth, tongue discolouration, tongue ulceration

Rare: Pancreatic insufficiency

Hepatobiliary disorders

Uncommon: Hyperbilirubinaemia

Rare: Cholecystitis*

Skin and subcutaneous tissue disorders

Very common: Alopecia, dry skin, pruritus, rash

Common: Dermatitis, eczema, erythema, hyperhidrosis, night sweats, oedema peripheral, psoriasis, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, skin lesion

Uncommon: Photosensitivity reaction, skin ulcer, urticaria

Not known: Angioedema, drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-Johnson syndrome

Musculoskeletal and connective tissue disorders

Very common: Arthralgia, myalgia

Common: Back pain*, pain in extremity*, muscle spasms, muscular weakness, neck pain

Uncommon: Musculoskeletal chest pain*, arthritis, bone pain, joint swelling, musculoskeletal pain

Renal and urinary disorders

Common: Pollakiuria

Uncommon: Dysuria, nocturia

Not known: Renal impairment

Reproductive system and breast disorders

Common: Erectile dysfunction

Uncommon: Amenorrhoea, menorrhagia, metrorrhagia

Rare: Aspermia

General disorders and administration site conditions

Very common: Asthenia*, chills, fatigue*, pyrexia*, influenza-like illness

Common: Chest discomfort*, chest pain*, malaise*, feeling of body temperature change, mucosal dryness, pain

Uncommon: Feeling abnormal, impaired healing, non-cardiac chest pain

Investigations

Very common: Weight decreased

Uncommon: Cardiac murmur, heart rate increased

Not known: Glomerular filtration rate decreased

* Includes adverse reactions which may be serious as assessed by the investigator in clinical trial subjects.
Since boceprevir is prescribed with peginterferon alfa and ribavirin, please also refer to the respective Summary of Product Characteristics of peginterferon alfa and ribavirin.
Injection-site reactions have not been included since boceprevir is administered orally.

Description of selected adverse reactions

Anaemia

Anaemia was observed in 49% of subjects treated with the combination of boceprevir with peginterferon alfa-2b and ribavirin compared with 29% of subjects treated with peginterferon alfa-2b and ribavirin alone. Boceprevir was associated with an additional decrease of approximately 1 g/dL in haemoglobin concentration. The mean decreases in haemoglobin values from baseline were larger in previously treated patients compared to patients who had never received prior therapy. Dose modifications due to anaemia/haemolytic anaemia occurred twice as often in patients treated with the combination of boceprevir with peginterferon alfa-2b and ribavirin (26%) compared to peginterferon alfa-2b and ribavirin alone (13%). In clinical trials, the proportion of subjects who received erythropoietin for the management of anaemia was 43% (667/1,548) of subjects in the boceprevir-containing arms compared to 24% (131/547) of subjects receiving peginterferon alfa-2b and ribavirin alone. The majority of the anaemia subjects received erythropoietin when haemoglobin levels were ≤10 g/dL (or 6.2 mmol/L). The proportion of subjects who received a transfusion for the management of anaemia was 3% of subjects in the boceprevir-containing arms compared to <1% of subjects receiving peginterferon alfa-2b and ribavirin alone.

Neutrophils

The proportion of subjects with decreased neutrophils was higher in the boceprevir-containing arms compared to subjects receiving only peginterferon alfa-2b and ribavirin. The percentage of patients with Grades 3-4 neutropenia (neutrophil counts <0.75 × 109/L) was higher in boceprevir-treated patients (29%) than in placebo-treated patients (17%), in combination with peginterferon alfa-2b and ribavirin. Seven percent of subjects receiving the combination of boceprevir with peginterferon alfa-2b and ribavirin had neutrophil counts of <0.5 × 109/L (Grade 4 neutropenia) compared to 4% of subjects receiving only peginterferon alfa-2b and ribavirin.

Platelets

Platelet counts were decreased for subjects in the boceprevir containing-arms (3%) compared to subjects receiving peginterferon alfa-2b and ribavirin alone (1%). In both treatment arms, patients with cirrhosis were at a higher risk to experience Grade 3-4 thrombocytopenia compared with non cirrhotic patients.

Other laboratory findings

The addition of boceprevir to peginterferon alfa–2b and ribavirin was associated to higher incidences of increase in uric acid, triglycerides and cholesterol total compared to peginterferon alfa–2b and ribavirin only.

Patients with HIV co-infection

The safety profile of boceprevir in HCV/HIV-1 co-infected patients (n=64) was overall similar to the safety profile in mono-infected HCV patients.

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