Victrelis 200 mg hard capsules

1. Name Of The Medicinal Product

Victrelis® 200 mg hard capsules

2. Qualitative And Quantitative Composition

Each hard capsule contains 200 mg of boceprevir.

Excipient: each capsule contains 56 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Hard capsule.

Each capsule has a yellowish-brown, opaque cap with an "MSD" logo imprinted in red ink and off-white, opaque body with the code "314" imprinted in red ink.

4. Clinical Particulars

4.1 Therapeutic Indications

Victrelis is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection, in combination with peginterferon alfa and ribavirin, in adult patients with compensated liver disease who are previously untreated or who have failed previous therapy.

See sections 4.4 and 5.1.

4.2 Posology And Method Of Administration

Treatment with Victrelis should be initiated and monitored by a physician experienced in the management of chronic hepatitis C.

Posology

Victrelis must be administered in combination with peginterferon alfa and ribavirin. The Summary of Product Characteristics of peginterferon alfa and ribavirin (PR) must be consulted prior to initiation of therapy with Victrelis.

The recommended dose of Victrelis is 800 mg administered orally three times daily (TID) with food (a meal or light snack). Maximum daily dose of Victrelis is 2,400 mg. Administration without food could be associated with a net loss of efficacy due to sub-optimal exposure.

Patients without cirrhosis who are previously untreated or who have failed previous therapy

The following dosing recommendations differ for some subgroups from the dosing studied in the Phase 3 trials (see section 5.1).

Table 1

Duration of therapy using Response-Guided Therapy (RGT) guidelines in patients without cirrhosis who are previously untreated or who have failed previous therapy to interferon and ribavirin therapy

Previously Untreated Patients	ASSESSMENT* (HCV-RNA Results†)	ACTION
At Treatment Week 8	At Treatment Week 24
Undetectable	Undetectable	Treatment duration = 28 weeks 1. Administer peginterferon alfa and ribavirin for 4 weeks, and then 2. Continue with all three medicines (peginterferon alfa and ribavirin [PR] + Victrelis) and finish through Treatment Week 28 (TW 28).
Detectable	Undetectable	Treatment duration = 48 weeks‡ 1. Administer peginterferon alfa and ribavirin for 4 weeks, and then 2. Continue with all three medicines (PR + Victrelis) and finish through TW 36; and then 3. Administer peginterferon alfa and ribavirin and finish through TW 48.
Patients Who have Failed Previous Therapy	Undetectable	Undetectable	Treatment duration = 48 weeks 1. Administer peginterferon alfa and ribavirin for 4 weeks, and then 2. Continue with all three medicines (PR + Victrelis) and finish through TW 36, and then 3. Administer peginterferon alfa and ribavirin and finish through TW 48.
Detectable	Undetectable
*Stopping rule If the patient has hepatitis C virus ribonucleic acid (HCV-RNA) results greater than or equal to 100 IU/ml at TW 12; then discontinue three-medicine regimen. If the patient has confirmed, detectable HCV-RNA at TW 24; then discontinue three-medicine regimen. † In clinical trials, HCV-RNA in plasma was measured with the Roche COBAS Taqman 2.0 assay with a limit of detection of 9.3 IU/ml and a limit of quantification of 25 IU/ml. ‡ This regimen has only been tested in subjects who have failed previous therapy who were late responders (see section 5.1).

All cirrhotic patients and null responders:

- Recommended treatment duration is 48 weeks: 4 weeks of bitherapy with peginterferon alfa+ ribavirin + 44 weeks of tritherapy with peginterferon alfa + ribavirin + Victrelis. (Refer to the stopping rule in Table 1 for all patients.)
	• The duration of the tritherapy after the first 4 weeks of bitherapy should not be less than 32 weeks. Given the incremental risk of adverse events with Victrelis (anaemia notably); in case the patient cannot tolerate the treatment, consideration could be given to pursue with 12 weeks of bitherapy for the final 12 weeks of treatment instead of tritherapy (see sections 4.8 and 5.1).

Missed doses

If a patient misses a dose and it is less than 2 hours before the next dose is due, the missed dose should be skipped.

If a patient misses a dose and it is 2 or more hours before the next dose is due, the patient should take the missed dose with food and resume the normal dosing schedule.

Dose reduction

Dose reduction of Victrelis is not recommended.

If a patient has a serious adverse reaction potentially related to peginterferon alfa and/or ribavirin, the peginterferon alfa and/or ribavirin dose should be reduced. Refer to the Summary of Product Characteristics for peginterferon alfa and ribavirin for additional information about how to reduce and/or discontinue the peginterferon alfa and/or ribavirin dose. Victrelis must not be administered in the absence of peginterferon alfa and ribavirin.

Special populations

Renal impairment

No dose adjustment of Victrelis is required in patients with any degree of renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment of Victrelis is required for patients with mild, moderate or severe hepatic impairment. Victrelis has not been studied in patients with decompensated cirrhosis (see section 5.2).

Paediatric population

The safety and efficacy of Victrelis in children aged below 18 years have not yet been established. No data are available.

Elderly

Clinical studies of Victrelis did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between the elderly and younger patients (see section 5.2).

Method of administration

To obtain the hard capsules the foil of the blister should be peeled off. Victrelis is to be taken orally with food (a meal or light snack).

4.3 Contraindications

Victrelis, in combination with peginterferon alfa and ribavirin, is contraindicated in:

• Patients with hypersensitivity to the active substance or any of its excipients.

• Patients with autoimmune hepatitis.

• Co-administration with medicines that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events such as orally administered midazolam and triazolam, bepridil, pimozide, lumefantrine, halofantrine, tyrosine kinase inhibitors, and ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine) (see section 4.5).

• Pregnancy (see section 4.6).

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

4.4 Special Warnings And Precautions For Use

Anaemia

The onset of anaemia has been reported with peginterferon alfa and ribavirin therapy by Treatment Week 4. The addition of Victrelis to peginterferon alfa and ribavirin is associated with an additional decrease in haemoglobin concentrations of approximately 1 g/dl by Treatment Week 8 compared to standard of care (see section 4.8). Complete blood counts should be obtained pretreatment, Treatment Week 4, Treatment Week 8, and thereafter, as clinically appropriate. If haemoglobin is < 10 g/dl (or < 6.2 mmol/l) management of anaemia may be warranted (see section 4.8).

Please refer to the Summary of Product Characteristics for ribavirin for statements regarding dose reduction and/or interruption or discontinuation of ribavirin.

Neutropenia

The addition of Victrelis to peginterferon alfa-2b and ribavirin resulted in higher incidences of neutropenia and Grade 3-4 neutropenia compared with peginterferon alfa-2b and ribavirin alone (see section 4.8).

The frequency of severe or life threatening infections tends to be higher in Victrelis-containing arms than the control arm. Neutrophils counts should therefore be evaluated before treatment initiation and regularly thereafter. Prompt evaluation and treatment of infections is recommended.

Combined use with peginterferon alfa-2a as compared to alfa-2b:

As compared to the combination of Victrelis with peginterferon alfa-2b and ribavirin, the combination of Victrelis with peginterferon alfa-2a and ribavirin was associated with a higher rate of neutropenia (including grade 4 neutropenia) and a higher rate of infections.

Please refer to the Summary of Product Characteristics for peginterferon alfa.

Drospirenone-containing medicines

Caution should be exercised in patients taking drospirenone-containing medicines with conditions that predispose them to hyperkalaemia or patients taking potassium-sparing diuretics. Alternative contraceptives should be considered (see section 4.5).

Use in prior null responders

Based on a retrospective analysis performed with requalifying on the basis of their on treatment virologic response at treatment week 4 (using the peginterferon alfa/ribavirin lead in period) as compared to baseline, null responders might gain some benefit in adding Victrelis to the bitherapy. However, this cannot be reliably quantified from the retrospective analysis. Moreover, the optimal management of null responders remains to be established and might in the future require antiviral combination.

HCV protease monotherapy

Based on results of clinical studies, Victrelis must not be used alone due to the high probability of increased resistance without combination anti-HCV therapies (see section 5.1).

It is unknown what effect therapy with Victrelis will have on the activity of subsequently administered HCV protease inhibitors, including re-treatment with Victrelis.

Use in patients with HIV co-infection

The safety and efficacy of Victrelis alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic hepatitis C genotype 1 infection have not been established in patients co-infected with Human Immunodeficiency Virus (HIV) and HCV. A clinical study is ongoing.

Use in patients with HBV co-infection

The safety and efficacy of Victrelis alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic hepatitis C genotype 1 infection in patients co-infected with hepatitis B Virus (HBV) and HCV have not been studied.

Use in patients with an organ transplant

The safety and efficacy of Victrelis alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic hepatitis C genotype 1 infection in liver or other organ transplant recipients have not been studied.

Use in patients having HCV genotypes other than genotype 1

The safety and efficacy of Victrelis alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic hepatitis C genotypes other than genotype 1 have not been established.

Use in patient who have previously failed treatment with an HCV protease inhibitor

The safety and efficacy of Victrelis alone or in combination with peginterferon alfa and ribavirin for the treatment of chronic hepatitis C genotype 1 infection has not been studied in patients who have failed previous therapy with Victrelis or other HCV protease inhibitors.

Potent CYP3A4 inducers

The concomitant use of Victrelis with potent CYP3A4 inducers (rifampicin, carbamazepine, phenobarbital, phenytoin) is not recommended (see section 4.5).

Use in patients with rare hereditary disorders

Victrelis contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Proarrhythmic effects:

The data available (see section 5.3) warrant caution in patients at risk of QT prolongation (long congenital QT, hypokalaemia).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Victrelis is a strong inhibitor of CYP3A4/5. Medicines metabolized primarily by CYP3A4/5 may have increased exposure when administered with Victrelis, which could increase or prolong their therapeutic and adverse reactions (see Table 2). Victrelis does not inhibit or induce the other enzymes of the CYP450.

Boceprevir has been shown to be a P-gp and breast cancer resistant protein (BCRP) substrate in vitro. There is potential for inhibitors of these transporters to increase concentrations of boceprevir; the clinical implications of these interactions are not known.

Victrelis is partly metabolized by CYP3A4/5. Co-administration of Victrelis with medicines that induce or inhibit CYP3A4/5 could increase or decrease exposure to Victrelis (see section 4.4).

Victrelis, in combination with peginterferon alfa and ribavirin, is contraindicated when co-administered with medicines that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events such as orally administered midazolam and triazolam, bepridil, pimozide, lumefantrine, halofantrine, and tyrosine kinase inhibitors, and ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine) (see section 4.3).

Boceprevir is primarily metabolized by aldoketo reductase (AKR). In medicine interaction trials conducted with AKR inhibitors diflunisal and ibuprofen, boceprevir exposure did not increase to a clinically significant extent. Victrelis may be co-administered with AKR inhibitors.

The concomitant use of Victrelis with rifampicin or anticonvulsants (such as phenytoin, phenobarbital or carbamazepine) may significantly reduce the plasma exposure of Victrelis. No data are available, therefore, the combination of boceprevir with these medicines is not-recommended (see section 4.4).

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

Table 2

Pharmacokinetic interactions data

Medicinal products by therapeutic areas	Interaction* (postulated mechanism of action, if known)	Recommendations concerning co-administration
ANTI-INFECTIVES
Antifungals
Ketoconazole (ketoconazole 400 mg two times daily + Victrelis 400 mg single dose) Itraconazole, Posaconazole, Voriconazole	boceprevir AUC  ↑ 131% boceprevir Cmax ↑ 41% boceprevir Cmin N/A Not studied	Caution should be exercised when boceprevir is combined with ketoconazole or azole antifungals (itraconazole, posaconazole, voriconazole).
Antiretroviral
Nucleoside Reverse Transcriptase Inhibitor (NRTI)
Tenofovir (tenofovir 300 mg daily + Victrelis 800 mg three times daily)	boceprevir AUC ↔ 8%** boceprevir Cmax ↔ 5% boceprevir Cmin ↔  8% tenofovir AUC  ↔  5% tenofovir Cmax ↑  32%	No dose adjustment required for Victrelis or tenofovir.
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Efavirenz (efavirenz 600 mg daily + Victrelis 800 mg three times daily)	boceprevir AUC  ↔ 19%** boceprevir Cmax ↔  8% boceprevir Cmin  efavirenz AUC  ↔  20% efavirenz Cmax ↔  11%	Plasma trough concentrations of Victrelis were decreased when administered with efavirenz. The clinical outcome of this observed reduction of Victrelis trough concentrations has not been directly assessed.
HIV Protease Inhibitor (PI)
Ritonavir (ritonavir 100 mg daily + Victrelis 400 mg three times daily)	boceprevir AUC  ↔  19% boceprevir Cmax  boceprevir Cmin ↔  4%	No data are currently available with ritonavir as a booster in combination with protease inhibitors. Theoretically, the combination of boceprevir with PIs/ritonavir is not expected to result in clinically significant interactions. However, while waiting for additional data, particular attention is warranted if boceprevir is co administered with HIV protease inhibitors/ritonavir.
Integrase inhibitor
Raltegravir	Not studied	Based on theoretical data, the combination of boceprevir and raltegravir is not expected to result in clinically significant interactions. However, while waiting for additional data, particular attention is warranted using the combination.
ORAL CONTRACEPTIVES
Drospirenone/Ethinyl estradiol: (drospirenone 3 mg daily + ethinyl estradiol 0.02 mg daily + Victrelis 800 mg three times daily)	drospirenone AUC  ↑  99% drospirenone Cmax ↑ 57% ethinyl estradiol AUC   ethinyl estradiol Cmax ↔  (drospirenone - CYP3A4/5 inhibition)	Caution should be exercised in patients with conditions that predispose them to hyperkalaemia or patients taking potassium-sparing diuretics (see section 4.4). Alternative contraceptives should be considered for these patients.
SEDATIVES
Midazolam (oral administration) (4 mg single oral dose + Victrelis 800 mg three times daily)   Triazolam (oral administration)	midazolam AUC  ↑  430% midazolam Cmax ↑  177% (CYP3A4/5 inhibition) Interaction not studied (CYP3A4/5 inhibition)	Co-administration of oral midazolam and oral triazolam with Victrelis is contraindicated (see section 4.3).
Alprazolam, midazolam, triazolam (intravenous administration)	Interaction not studied (CYP3A4/5 inhibition)	Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during co-administration of Victrelis with intravenous benzodiazepines (alprazolam, midazolam, triazolam). Dose adjustment of the benzodiazepine should be considered.
Immunosuppressants	Not studied	Therapeutic medicine monitoring is recommended when administering Victrelis with CYP3A4/5 substrates that have a narrow therapeutic window (e.g., tacrolimus, cyclosporine). Individual patients may require additional titration of their immunosuppressant dosage when Victrelis is started or stopped to ensure clinically effective blood levels.
Statins (e.g., simvastatin and atorvastatin.)	Not studied	Therapeutic monitoring is recommended when administering Victrelis with simvastatin or atorvastatin, CYP3A4/5 substrates that have a narrow therapeutic window. Individual patients may require additional titration of their statin dosage when Victrelis is started or stopped to ensure clinically effective blood levels.
Methadone	Not studied	Therapeutic monitoring is recommended when administering Victrelis with CYP3A4/5 substrates that have a narrow therapeutic window. Individual patients may require additional titration of their methadone dosage when Victrelis is started or stopped to ensure clinically effective blood levels.
* Interaction of Victrelis with other medicinal products (change in mean ratio estimate of Victrelis in combination with co-administered medicine/Victrelis alone): ** 0-8 hours

4.6 Pregnancy And Lactation

Pregnancy

Victrelis in combination with ribavirin and peginterferon alfa is contraindicated in women who are pregnant (see section 4.3).

No effects on foetal development have been observed in rats and rabbits (see section 5.3). There are no data on the use of Victrelis in pregnant women.

Treated patients and their partners must use two effective forms of contraceptive methods when boceprevir is used in combination with peginterferon alfa and ribavirin. Refer to Summary of Product Characteristics for ribavirin and peginterferon alfa for additional information.

Breastfeeding

Boceprevir/metabolites are excreted in rat milk (see section 5.3). 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 breastfeeding or to discontinue/abstain from therapy with Victrelis taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

No human data on the effect of Victrelis 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 (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

Combination therapy of Victrelis, 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 (see section 4.8).

4.8 Undesirable Effects

The safety profile represented by approximately 1,500 patients for the combination of Victrelis with peginterferon alfa-2b and ribavirin was based on pooled safety data in two clinical trials in patients who were previously untreated and one clinical trial in patients who had failed prior therapy (see section 5.1).

The most frequently reported adverse reactions were fatigue, anaemia (see section 4.4), nausea, headache, and dysgeusia.

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

Adverse reactions are listed by System Organ Class (see Table 3). Within each system organ class, adverse reactions are listed under headings of frequency using the categories: very common (

Table 3

Adverse reactions in combination with Victrelis with peginterferon alfa-2b and ribavirin reported during clinical trials^{† and‡}

System Organ Class	Adverse Reactions
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*
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: