REBETOL

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS REGULATIONS

(PREPARATIONS) 1986

This medicine can be sold under doctor's prescription only

REBETOL

®

200 mg

Capsules

Each capsule contains:

Ribavirin 200 mg

For a list of inactive ingredients see section 6.1 "What Rebetol contains". See also section 2.7 “Important

information about some of the ingredients of Rebetol".

Read all of this leaflet carefully before you start taking this medicine.

This leaflet contains concise information about Rebetol. If you have any further questions, ask your

doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if

their medical condition seems similar to yours.

This medicine is intended for adult patients. This medicine is not intended for children and

adolescents under 18 years of age.

1. WHAT REBETOL IS AND WHAT IT IS USED FOR?

Rebetol capsules contain the active substance ribavirin. This medicine stops the multiplication of

many types of viruses, including hepatitis C virus. Rebetol capsules are intended to treat patients 18 years

of age or older who have chronic hepatitis C.

This medicine must not be used without peginterferon alfa-2b or interferon alfa-2b, i.e. Rebetol must not be

used alone.

Depending on the genotype of the hepatitis C virus that you have, your doctor may choose to treat you

with a combination of this medicine with boceprevir and peginterferon alfa-2b (tritherapy).

Adult patients without genotype 1, can only use peginterferon alfa-2b or interferon alfa-2b and this medicine

(bitherapy).

There may be some further treatment limitations if you have or have not been previously treated for chronic

hepatitis C infection. Your doctor will recommend the best course of therapy.

The combination of this medicine and peginterferon alfa-2b is used to treat previously untreated adult

patients who have chronic hepatitis C (HCV) infection and who are co-infected with clinically stable

HIV.

There is no safety or efficacy information on the use of Rebetol with other forms of interferon (i.e., not

alfa-2b).

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Therapeutic group

guanosine analog.

2. BEFORE YOU USE REBETOL

This medicine is not intended for use in patients under the age of 18 years.

2.1 Do not take Rebetol if you:

Do not take Rebetol

If any of the following apply to you, do not take this medicine, and tell your doctor if you:

are allergic to ribavirin or any of the other ingredients of this medicine (listed in section 6).

are pregnant or planning to become pregnant (see section 2.5 “Pregnancy, breast-feeding and

fertility”).

are breast-feeding.

had a problem with your heart during the past 6 months.

have severe medical conditions that leave you very weak.

have severe kidney disease and/or are on haemodialysis.

have a serious problem with your liver other than chronic hepatitis C.

have any blood disorders, such as anaemia (low blood count), thalassemia, sickle-cell anaemia.

have autoimmune hepatitis or any other problem with your immune system.

are taking medicine that suppresses your immune system (that protects you against infection

and some diseases).

Reminder: Please read the “Do not take” section of the Package Leaflets for boceprevir, peginterferon

alfa-2b or interferon alfa-2b before you begin using them with this medicine.

2.2 Special warnings concerning use of Rebetol

Seek medical help immediately if you develop symptoms of a severe allergic reaction (such as

difficulty in breathing, wheezing or hives) while taking this treatment.

Before starting treatment with Rebetol, tell your doctor if you:

are an adult who has or had a severe nervous or mental disorder, confusion, unconsciousness,

or have had thoughts of suicide or have attempted suicide, or have a history of substance

abuse (e.g., alcohol or drugs).

have ever had depression or develop symptoms associated with depression (e.g. feeling of

sadness, dejection, etc.) while on treatment with this medicine (see section 4 “Side

effects”).

are a woman of childbearing age (see section 2.5 “Pregnancy, breast-feeding and fertility”).

are a male and your female partner is of childbearing age (see section 2.5 “Pregnancy,

breastfeeding and fertility”).

had a previous serious heart condition or have cardiac disease.

are older than 65 years or if you have problems with your kidneys.

have or have had any serious illness.

have thyroid problems.

During treatment with this medicine in combination therapy with an alfa interferon, dental and gum

disorders, which may lead to loss of teeth, have been reported. In addition, dry mouth that could

have a damaging effect on teeth and membranes of the mouth has been reported during long-term

treatment with this medicine in combination therapy with an alfa interferon. You should brush your

teeth thoroughly twice daily and have regular dental examinations. In addition some patients may

experience vomiting. If you have this reaction, be sure to rinse your mouth thoroughly afterwards.

During treatment with Rebetol in combination therapy with an alfa interferon, patients may

experience eye problems, or loss of vision in rare instances. If you receive ribavirin in combination

with an alfa interferon, you should have a baseline eye examination. Any patient complaining of

decrease or loss of vision must have a prompt and complete eye examination. Patients with preexisting

eye disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic eye exams

during combination therapy with ribavirin and an alfa interferon. Combination therapy with ribavirin

and an alfa interferon should be discontinued in patients who develop new or worsening eye

disorders.

Reminder: Please read the “Warnings and precautions” section of the Package Leaflets for boceprevir,

peginterferon alfa-2b or interferon alfa-2b before you begin combination treatment.

2.3 Taking other medicines

If you are taking or have recently taken other medicines, including non-prescription medicines and

nutritional supplements, you should tell the attending doctor or pharmacist.

Especially inform your doctor or pharmacist if you:

- are receiving azathioprine in combination with ribavirin and pegylated alfa interferons and,

therefore may be at an increased risk of developing severe blood disorders.

- are infected with both Human Immunodeficiency Virus (HIV-positive) and Hepatitis C

Virus (HCV) and are being treated with an anti-HIV medicinal product(s) - [nucleoside reverse

transcriptase inhibitor (NRTI), and/or highly active anti-retroviral therapy (HAART)]:

Taking this medicine in combination with an alfa interferon and an anti-HIV medicinal

product(s) may increase the risk of lactic acidosis, liver failure, and blood abnormalities

development (reduction in number of red blood cells which carry oxygen, certain white

blood cells that fight infection, and blood clotting cells called platelets).

With zidovudine or stavudine, it is not certain if this medicine will change the way

these medicines work. Therefore, your blood will be checked regularly to be sure that the

HIV infection is not getting worse. If it gets worse, your doctor will decide whether or

not your Rebetol treatment needs to be changed. Additionally, patients receiving

zidovudine with ribavirin in combination with alfa interferons could be at increased

risk of developing anaemia (low number of red blood cells). Therefore the use of

zidovudine and ribavirin in combination with alfa interferons is not recommended.

Due to the risk of lactic acidosis (a build-up of lactic acid in the body) and pancreatitis,

the use of ribavirin and didanosine is not recommended and the use of ribavirin and

stavudine should be avoided.

Co-infected patients with advanced liver disease receiving HAART may be at increased

risk of worsening liver function. Adding treatment with an alfa interferon alone or in

combination with ribavirin may increase the risk in this patient subset.

Reminder: Please read the “Taking other medicines” section of the Package Leaflet for peginterferon alfa-

2b, interferon alfa-2b, or boceprevir before you begin combination treatment with this medicine.

2.4 Taking Rebetol with food and drink

Rebetol must be taken with food (see section 3 “How to use Rebetol”).

2.5 Pregnancy, breast-feeding and fertility

If you are pregnant, you must not take this medicine. This medicine can be very damaging to your

unborn baby (embryo).

Both female and male patients must take special precautions in their sexual activity if there is any

possibility for pregnancy to occur:

- Woman of childbearing age:

You must have a negative pregnancy test before treatment, each month during treatment, and

for the 4 months after treatment is stopped. This should be discussed with your doctor.

- Men:

Do not have sex with a pregnant woman unless you use a condom. This will lessen the

possibility for ribavirin to be left in the woman’s body.

If your female partner is not pregnant now but is of childbearing age, she must be tested for

pregnancy each month during treatment and for the 7 months after treatment has stopped.

You or your female partner must use an effective contraceptive during the time you are taking

this medicine and for 7 months after stopping treatment. This should be discussed with your

doctor (see section 2.1 “Do not take Rebetol”).

If you are a woman who is breast-feeding, you must not take this medicine. Discontinue breastfeeding

before starting to take this medicine.

2.6 Driving and using machines

This medicine does not affect your ability to drive or use machines; however, boceprevir,

peginterferon alfa-2b or interferon alfa-2b may affect your ability to drive or use machines. Therefore,

do not drive or use machines if you become tired, sleepy, or confused from this treatment.

2.7 Important information about some of the ingredients of Rebetol

Each capsule contains a small amount of lactose.

If you have been told by your doctor that you have an intolerance to some sugars, discuss with your

doctor before taking this medicinal product. See also section 6.1 "What Rebetol contains".

3. HOW TO USE REBETOL?

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist

if you are not sure.

Do not take more than the recommended dosage and take the medicine for as long as prescribed.

Your doctor has determined the correct dose of this medicine based on how much you weighs.

Standard blood tests will be taken to check your blood, kidney and liver function.

Blood tests will be done regularly to help your doctor to know if this treatment is working.

Depending upon the results of these tests, your doctor may change/adjust the number of hard

capsules you take and/or change the length of time to take this treatment.

If you have or develop severe kidney or liver problems, this treatment will be stopped.

The recommended dose of this medicine, according to how much the patient weighs, is shown in the

table below:

1. Look for the line that shows how much the adult weighs.

2. Read across on the same line to see how many hard capsules to take.

Reminder: If your doctor’s instructions are different from the amounts in the below table,

follow your doctor’s instructions.

3. If you have any questions about the dose, ask your doctor.

Rebetol hard capsule for oral use - dose based on body weight

If the adult weighs

(kg)

Usual

daily Rebetol dose

Number of 200 mg capsules

< 65

800 mg

2 capsules in the morning and 2 capsules in the evening

65 – 80

1,000 mg

2 capsules in the morning and 3 capsules in the evening

81 - 105

1,200 mg

3 capsules in the morning and 3 capsules in the evening

> 105

1,400 mg

3 capsules in the morning and 4 capsules in the evening

Take your prescribed dose by mouth with water and during your meal. Do not chew the hard capsules.

Reminder: This medicine is used in combination with peginterferon alfa-2b, interferon alfa-2b or

boceprevir for hepatitis C virus infection. For complete information be sure to read the “How to use” section

of the Package Leaflet for peginterferon alfa-2b, interferon alfa-2b or boceprevir.

Interferon medicine that is used in combination with this medicine may cause unusual tiredness; if you are

injecting this medicine yourself, use it at bedtime.

This medicine is not intended for children under 18 years old.

Examinations and monitoring

Before starting treatment with Rebetol in combination with an alfa interferon, the doctor will refer you to an

eye examination (see section 2.2 "Special warnings concerning use of Rebetol").

During treatment with Rebetol in combination with an alfa interferon, blood tests will be done regularly, you

should have regular dental examinations and you may additionally be referred to periodic eye exams (see

section 2.2 "Special warnings concerning use of Rebetol" and section 3 "How to use Rebetol?").

Woman of childbearing age:

You must have a negative pregnancy test before treatment, each month during treatment, and

for the 4 months after treatment is stopped

Men:

If your female partner is not pregnant now but is of childbearing age, she must be tested for

pregnancy each month during treatment and for the 7 months after treatment has stopped.

(see section 2.5 "Pregnancy, breast-feeding and fertility").

If you take more Rebetol than you should

Tell your doctor or pharmacist as soon as possible.

If you have taken an overdose, or if a child has accidentally swallowed the medicine, proceed immediately

to a hospital emergency room and bring the package of the medicine with you.

If you forget to take Rebetol

If you are self-administering treatment in combination with interferon alfa-2b, peginterferon alfa-2b or

boceprevir, take/administer the missed dose as soon as possible during the same day. If an entire day has

gone by, check with your doctor. Do not take a double dose to make up for a forgotten dose.

Complete the full course of treatment as instructed by the doctor.

Even if there is an improvement in your health, do not discontinue use of this medicine before consulting

your doctor.

How can you contribute to the success of the treatment?

Do not take medicines in the dark! Check the label and the dose each time you take your medicine. Wear

glasses if you need them.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. SIDE EFFECTS

Please read the "Side effects" section of the Package Leaflet for boceprevir, peginterferon alfa-2b or

interferon alfa-2b.

Like all medicines, Rebetol used in combination with an alfa interferon product can cause side effects, in

some of the users.

Do not be alarmed by reading the list of side effects, you may not suffer from any of them. Although not all

of these unwanted effects may occur, they may need medical attention if they do occur.

Psychiatric and Central Nervous System:

Some people get depressed when taking this medicine in combination treatment with an interferon,

and in some cases people had thoughts about threatening the life of others, suicidal thoughts or

aggressive behaviour (sometimes directed against others). Some patients have actually committed

suicide. Be sure to seek emergency care if you notice that you are becoming depressed or have

suicidal thoughts or change in your behaviour. You may want to consider asking a family member or

close friend to help you stay alert to signs of depression or changes in your behaviour.

Contact your doctor immediately if you notice any of the following side effects occurring during

combination treatment with an alpha interferon product:

chest pain or persistent cough; changes in the way your heart beats, fainting,

confusion, feeling depressed; suicidal thoughts or aggressive behaviour, attempt suicide,

thoughts about threatening the life of others,

feelings of numbness or tingling,

trouble sleeping, thinking or concentrating,

severe stomach pain, black or tar-like stools, blood in stool or urine, lower back or side pain,

painful or difficult urination,

severe bleeding from your nose,

fever or chills beginning after a few weeks of treatment,

problems with your eyesight or hearing,

severe skin rash or redness.

Possible side effects listed below are grouped by frequency of occurrence:

Very common (may affect more than 1 in 10 people)

Common (may affect up to 1 in 10 people)

Uncommon (may affect up to 1 in 100 people)

Rare (may affect up to 1 in 1,000 people)

Very rare (may affect up to 1 in 10,000 people)

Not known (frequency cannot be estimated from the available data)

The following side effects have been reported with the combination of this medicine hard capsules

and an alfa interferon product in adults:

Very commonly reported side effects:

decreases in the number of red blood cells (that may cause fatigue, shortness of breath,

dizziness), decrease in neutrophils (that make you more susceptible to different infections),

difficulty concentrating, feeling anxious or nervous, mood swings, feeling depressed or irritable, tired

feeling, trouble falling asleep or staying asleep,

cough, dry mouth, pharyngitis (sore throat),

diarrhoea, dizziness, fever, flu-like symptoms, headache, nausea, shaking chills, virus infection,

vomiting, weakness,

loss of appetite, loss of weight, stomach pain,

dry skin, irritation, pain or redness at the site of injection, hair loss, itching, muscle pain,

muscle aches, pain in joints and muscles, rash.

Commonly reported side effects:

decrease in blood clotting cells called platelets that may result in easy bruising and spontaneous

bleeding, decrease in certain white blood cells called lymphocytes that help fight infection,

decrease in thyroid gland activity (which may make you feel tired, depressed, increase your

sensitivity to cold and other symptoms), excess of sugar or uric acid (as in gout) in the blood, low

calcium level in the blood, severe anaemia,

fungal or bacterial infections, crying, agitation, amnesia, memory impaired, nervousness,

abnormal behaviour, aggressive behaviour, anger, feeling confused, lack of interest, mental

disorder, mood changes, unusual dreams, wanting to harm yourself, feeling sleepy, trouble

sleeping, lack of interest in sex or inability to perform, vertigo (spinning feeling),

blurred or abnormal vision, eye irritation or pain or infection, dry or teary eyes, changes in your

hearing or voice, ringing in ears, ear infection, earache, cold sores (herpes simplex), change in

taste, taste loss, bleeding gums or sores in mouth, burning sensation on tongue, sore tongue,

inflamed gums, tooth problem, migraine, respiratory infections, sinusitis, nose bleed, nonproductive

cough, rapid or difficult breathing, stuffy or runny nose, thirst, tooth disorder,

cardiac murmur (abnormal heart beat sounds), chest pain or discomfort, feeling faint, feeling

unwell, flushing, increased sweating, heat intolerance and excessive sweating, low or high

blood pressure, palpitations (pounding heart beat), rapid heart rate,

bloating, constipation, indigestion, intestinal gas (flatus), increased appetite, irritated colon, irritation

of prostate gland, jaundice (yellow skin), loose stools, pain on the right side around your ribs,

enlarged liver, stomach upset, frequent need to urinate, passing more urine than usual, urinary tract

infection, abnormal urine,

difficult, irregular, or no menstrual period, abnormally heavy and prolonged menstrual periods,

painful menstruation, disorder of ovary or vagina, breast pain, erectile problem,

abnormal hair texture, acne, arthritis, bruising, eczema (inflamed, red, itchy and dryness of the

skin with possible oozing lesions), hives, increased or decreased sensitivity to touch, nail disorder,

muscle spasms, numbness or tingling feeling, limb pain, pain at the site of injection, pain in joints,

shaky hands, psoriasis, puffy or swollen hands and ankles, sensitivity to sunlight, rash with raised

spotted lesions, redness of skin or skin disorder, swollen face, swollen glands (swollen lymph

nodes), tense muscles, tumour (unspecified), unsteady when walking, water impairment.

Uncommonly reported side effects:

hearing or seeing images that are not present (hallucinations),

heart attack, panic attack,

hypersensitivity reaction to the medication,

inflammation of pancreas, pain in bone, diabetes mellitus,

muscle weakness.

Rarely reported side effects:

seizure (convulsions)

pneumonia,

rheumatoid arthritis, kidney problems,

dark or bloody stools, intense abdominal pain

sarcoidosis (a disease characterised by persistent fever, weight loss, joint pain and swelling,

skin lesions and swollen glands),

vasculitis.

Very rarely reported side effects:

suicide,

stroke (cerebrovascular events).

Not known side effects:

thoughts about threatening the life of others,

mania (excessive or unreasonable enthusiasm),

pericarditis (inflammation of the lining of the heart), pericardial effusion [a fluid collection that

develops between the pericardium (the lining of the heart) and the heart itself,

change in colour of the tongue.

The attempt to harm yourself has also been reported in adults, children, and adolescents.

This medicine in combination with an alpha interferon product may also cause:

aplastic anaemia, pure red cell aplasia (a condition where the body stopped or reduced the

production of red blood cells); this causes severe anaemia, symptoms of which would include

unusual tiredness and a lack of energy,

delusions,

upper and lower respiratory tract infection,

inflammation of the pancreas,

severe rashes which may be associated with blisters in the mouth, nose, eyes and other mucosal

membranes (erythema multiforme, Stevens Johnson syndrome), toxic epidermal necrolysis

(blistering and peeling of the top layer of skin).

The following other side effects have also been reported with the combination of this medicine and an

alpha interferon product:

abnormal thoughts, hearing or seeing images that are not present (hallucinations), altered mental

status, disorientation,

angioedema (swelling of the hands, feet, ankles, face, lips, mouth, or throat which may cause

difficulty in swallowing or breathing),

Vogt-Koyanagi-Harada syndrome (an autoimmune inflammatory disorder affecting the eyes, skin

and the membranes of the ears, brain and spinal cord),

bronchoconstriction and anaphylaxis (a severe, whole-body allergic reaction), constant cough,

eye problems including damage to the retina, obstruction of the retinal artery, inflammation of

the optic nerve, swelling of the eye and cotton wool spots (white deposits on the retina),

enlarged abdominal area, heartburn, trouble having bowel movement or painful bowel

movement,

acute hypersensitivity reactions including urticaria (hives), bruises, intense pain in a limb, leg

or thigh pain, loss of range of motion, stiffness, sarcoidosis (a disease characterised by

persistent fever, weight loss, joint pain and swelling, skin lesions and swollen glands).

This medicine in combination with peginterferon alfa-2b or interferon alfa-2b may also cause:

dark, cloudy or abnormally coloured urine,

difficulty breathing, changes in the way your heart beats, chest pain, pain down left arm, jaw

pain,

loss of consciousness,

loss of use, drooping or loss of power of facial muscles, loss of feeling sensation,

loss of vision.

You or your caregiver should call your doctor immediately if you have any of these side effects.

If you are a HCV/HIV co-infected adult patient receiving anti-HIV treatment, the addition of this

medicine and peginterferon alfa-2b may increase your risk of worsening liver function (highly active

anti-retroviral therapy (HAART)) and increase your risk of lactic acidosis, liver failure, and blood

abnormalities development (reduction in number of red blood cells which carry oxygen, certain white

blood cells that fight infection, and blood clotting cells called platelets) (NRTI).

In HCV/HIV co-infected patients receiving HAART, the following other side effects have occurred

with the combination of Rebetol hard capsules and peginterferon alfa-2b (not listed above ):

appetite decreased,

back pain,

CD4 lymphocytes decreased,

defective metabolism of fat,

hepatitis,

limb pain,

oral candidiasis (oral thrush),

various laboratory blood values abnormalities.

If a side effect appears, if any of the side effects gets serious or if you notice any side effect not mentioned

in this leaflet, consult your doctor.

Reminder to patients prescribed combination therapy of this medicine, boceprevir and

peginterferon alpha-2b: Please read also the “side effects” section of the Package Leaflet of

boceprevir for side effects that have been reported with tritherapy.

5. HOW TO STORE REBETOL?

Avoid Poisoning! This medicine, as all other medicines, must be stored in a safe place out of the

reach and sight of children and/or infants, in order to avoid poisoning. Do not induce vomiting unless

explicitly instructed to do so by a doctor!

Do not use Rebetol after the expiry date (exp. date) which is stated on the pack. The expiry date

refers to the last day of the indicated month.

Do not use this medicine without advice of your doctor or pharmacist if you notice any change in the

appearance of the hard capsules.

Storage conditions: Store below 25°C.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how

to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

6.1 What Rebetol contains

The active substance is ribavirin.

Each capsule contains 200 mg of ribavirin.

In addition to the active ingredient the medicine also contains inactive ingredients: microcrystalline

cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate.

The capsule shell contains gelatin, titanium dioxide and sodium lauryl sulfate (used as a manufacturing

aid, at very low levels).

The capsule shell imprint contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol,

propylene glycol, strong ammonia solution and colouring agent (FD&C aluminum lake).

Each capsule contains 40 mg of lactose monohydrate, see also section 2.7 “Important information

about some of the ingredients of Rebetol".

6.2 What Rebetol looks like and contents of the pack

This medicine is a white, opaque, hard capsule imprinted with blue ink.

This medicine is available in different pack sizes containing 70, 84, 140 or 168 capsules of 200 mg

to be swallowed.

Not all pack sizes may be marketed.

Your physician will prescribe the pack size which is best for you.

6.3 Marketing authorization holder

Merck Sharp & Dohme (Israel-1996) Company Ltd., P.O.Box 7121, Petah-Tikva 49170.

6.4 Manufacturer:

Schering-Plough Labo N.V., Heist-op-den-Berg, Belgium.

This Leaflet was checked and approved by the Ministry of Health on January 2015.

Drug registration no. listed in the official registry of the Ministry of Health:

116-93-29850-01

1.

NAME OF THE MEDICINAL PRODUCT

Rebetol

200 mg capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 200 mg of ribavirin.

Excipient with known effect:

Each capsule contains 40 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Capsule

White, opaque and imprinted with blue ink.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Tritherapy:

Rebetol in combination with boceprevir and peginterferon alfa-2b is indicated for the treatment of

chronic hepatitis C (CHC) genotype1 infection in adults patients (18 years of age and older) with

compensated liver disease who are previously untreated or who have failed previous therapy.

Please refer to peginterferon alfa -2b and boceprevir Summary of Product Characteristics (SmPCs)

when using Rebetol in combination with these medicines.

Bitherapy:

Rebetol is indicated for the treatment of chronic hepatitis C virus infection in adults and must only

be used as part of a combination regimen with peginterferon alfa-2b or interferon alfa-2b. Rebetol

monotherapy must not be used.

Please refer to interferon alfa-2b and peginterferon alfa-2b Summary of Product Characteristics

(SmPCs) when using Rebetol in combination with these medicines.

There is no safety or efficacy information on the use of Rebetol with other forms of interferon (i.e., not

alfa-2b).

Previously untreated (naïve) patients

Adult patients

(18 years of age or older): Rebetol is indicated for:

tritherapy- in combination with peginterferon alfa-2b and boceprevir for the treatment of

adult patients with chronic hepatitis C genotype1 infection with compensated liver disease

bitherapy- in combination with interferon alfa-2b or peginterferon alfa-2b, for the treatment

of adult patients with chronic hepatitis C, not previously treated, without liver

decompensation, with elevated alanine aminotransferase (ALT), who are positive for

hepatitis C viral ribonucleic acid (HCV-RNA).

bitherapy- for the treatment of CHC infection in combination with peginterferon alfa-2b for

patients with compensated cirrhosis and/or clinically stable HIV co-infection (see section

4.4).

Previously treated patients

Adult patients: Rebetol is indicated for:

tritherapy- in combination with peginterferon alfa-2b and boceprevir for the treatment of

adult patients having CHC genotype 1 infection with compensated liver disease.

bitherapy- in combination with peginterferon alfa-2b, for the treatment of patients with

chronic hepatitis C who have failed previous treatment with interferon alfa (pegylated or

non-pegylated) alone or in combination with ribavirin (see section5.1).

bitherapy-in combination with interferon alfa-2b, for the treatment of patients with chronic

hepatitis C who have previously responded (with normalisation of ALT at the end of

treatment) to interferon alfa monotherapy but who have subsequently relapsed.

4.2

Posology and method of administration

Treatment should be initiated, and monitored, by a physician experienced in the management of

chronic hepatitis C.

Rebetol must be used in combination with either peginterferon alfa-2b or interferon alfa-2b (bitherapy),

or, in adult patients with chronic hepatitis C genotype 1 infection, in combination with boceprevir and

peginterferon alfa-2b (tritherapy).

Please refer also to the boceprevir, peginterferon alfa-2b or interferon alfa-2b Summary of Product

Characteristics (SmPC) for prescribing information particular to that product.

Dose to be administered

The dose of Rebetol is based on patient body weight. Rebetol capsules are to be administered

orally each day in two divided doses (morning and evening) with food.

Adult patients:

The dose of Rebetol is based on patient body weight (Table 1).

Rebetol must be used in combination with either peginterferon alfa-2b (1.5 micrograms/kg/week) or

interferon alfa-2b (3 million international units [MIU] three times a week). The choice of combination

regimen is based on the characteristics of the patient. The regimen administered should be

selected based on the anticipated efficacy and safety of the combination treatment for an individual

patient (see section 5.1).

Refer to the SmPC for boceprevir for the details of how boceprevir is to

be administered in tritherapy.

Table 1.

Rebetol dose based on body weight for HCV monoinfected or HCV/HIV co-infected

patients and whatever the genotype

Patient weight (kg)

Daily Rebetol dose

Number of 200 mg capsules

< 65

800 mg

65 – 80

1,000 mg

81- 105

1,200 mg

> 105

1,400 mg

a: 2 morning, 2 evening

b: 2 morning, 3 evening

c: 3 morning, 3 evening

d: 3 morning, 4 evening

Rebetol capsules in combination with boceprevir and peginterferon alfa-2b, or with peginterferon

alfa-2b:

Duration of treatment –Naïve patients

Tritherapy:

Refer to the SmPCs for boceprevir and peginterferon alfa-2b.

Bitherapy with peginterferon alfa-2b:

Predictability of sustained virological response: Patients infected with virus genotype 1 who fail to

achieve undetectable HCV-RNA or demonstrate adequate virological response at week 4 or 12 are

highly unlikely to become sustained virological responders and should be evaluated for

discontinuation (see also section 5.1).

Genotype 1:

For patients who have undetectable HCV-RNA at treatment week 12, treatment

should be continued for another nine month period (i.e., a total of 48 weeks).

Patients with detectable but ≥2 log decrease in HCV-RNA level from baseline at

treatment week 12 should be reassessed at treatment week 24 and, if HCV-RNA is

undetectable, they should continue with full course of therapy (i.e., a total of 48

weeks). However, if HCV-RNA is still detectable at treatment week 24, discontinuation

of therapy should be considered.

In the subset of patients with genotype 1 infection and low viral load (< 600,000 IU/ml)

who become HCV-RNA negative at treatment week 4 and remain HCV-RNA negative

at week 24, the treatment could either be stopped after this 24 week treatment course

or pursued for an additional 24 weeks (i.e. overall 48 weeks treatment duration).

However, an overall 24 weeks treatment duration may be associated with a higher

risk of relapse than a 48 weeks treatment duration (see section 5.1).

Genotypes 2 or 3: It is recommended that all patients be treated with bitherapy for 24 weeks,

except for HCV/HIV co-infected patients who should receive 48 weeks of treatment.

Genotype 4: In general, patients infected with genotype 4 are considered harder to treat and

limited study data (n=66) indicate they are compatible with a duration of treatment

with

bitherapy as for genotype 1.

Duration of treatment- naïve HCV/HIV co-infected patients

Bitherapy:

The recommended duration of Rebetol weight-based dosing (see Table 1) for HCV/HIV co-infected

patients is 48 weeks

with bitherapy, regardless of genotype.

Predictability of response and non-response in naïve HCV/HIV Co-infection

Early virological response by week 12, defined as a 2 log viral load decrease or undetectable levels

of HCV-RNA, has been shown to be predictive for sustained response. The negative predictive

value for sustained response in HCV/HIV co-infected patients treated with Rebetol in combination

with peginterferon alfa-2b was 99 % (67/68; Study 1) (see section 5.1). A positive predictive value

of 50% (52/104; Study 1) was observed for HCV/HIV co-infected patients receiving

bitherapy.

Duration of treatment – Retreatment patients

Tritherapy:

Refer to the SmPC for boceprevir and peginterferon alfa-2b.

Bitherapy with peginterferon alfa-2b:

Predictability of sustained virological response: All patients, irrespective of genotype, who have

demonstrated serum HCV-RNA below the limits of detection at week 12 should receive 48 weeks

of bitherapy. Retreated patients who fail to achieve virological response (i.e. HCV-RNA below the

limits of detection) at week 12 are unlikely to become sustained virological responders after

48 weeks of therapy (see also section 5.1).

Retreatment duration greater than 48 weeks in non-responder patients with genotype 1 has not

been studied with pegylated interferon alfa-2b and ribavirin combination therapy.

Rebetol capsules in combination with interferon alfa-2b (bitherapy only):

Duration of treatment

with interferon alfa-2b:

Based on the results of clinical trials, it is recommended that patients be treated

with bitherapy for

at least six months. During those clinical trials in which patients were treated for one year, patients

who failed to show a virological response after six months of treatment (HCV-RNA below lower limit

of detection) were unlikely to become sustained virological responders (HCV-RNA below lower limit

of detection six months after withdrawal of treatment).

Genotype 1: Treatment with bitherapy should be continued for another six month period (i.e., a

total of one year) in patients who exhibit negative HCV-RNA after six months of treatment.

Genotypes Non-1: The decision to extend therapy with bitherapy to one year in patients with

negative HCV-RNA after six months of treatment should be based on other prognostic factors

(e.g., age > 40 years, male gender, bridging fibrosis).

Dose modification for all patients

Combination therapy:

If severe adverse reactions or laboratory abnormalities develop during

combination therapy with

Rebetol and peginterferon alfa-2b or interferon alfa-2b, or with Rebetol and peginterferon alfa-2b and

boceprevir, modify the dosages as indicated in Table 3 if appropriate, until the adverse reactions

abate. Dose reduction of boceprevir is not recommended. Guidelines were developed in clinical trials

for dose modification (see Dosage modification guidelines, Table 3). As adherence might be of

importance for outcome of therapy, the dose should be kept as close as possible to the recommended

standard dose. The potential negative impact of ribavirin dose reduction on efficacy results could

not be ruled out.

Table 3

Dosage modification guidelines for combination therapy based on laboratory

parameters

Laboratory Values

Reduce only Rebetol

daily dose (see note 1) if:

Reduce only

peginterferon alfa-2b

or interferon alfa-2b

dose (see note 2) if:

Discontinue

combination therapy

when the below test

value is reported:**

Haemoglobin

< 10 g/dl

< 8.5 g/dl

Adults:

Haemoglobin in:

patients with

history of stable

cardiac disease

2 g/dl decrease in haemoglobin during any

4 week period during treatment

(permanent dose reduction)

< 12 g/dl after 4 weeks

of dose reduction

Leukocytes

< 1.5 x 10

< 1.0 x 10

Neutrophils

< 0.75 x 10

< 0.5 x 10

Platelets

< 50 x 10

/l (adults)

< 25 x 10

/l (adults)

Bilirubin – Direct

2.5 x ULN*

Bilirubin – Indirect

> 5 mg/dl

> 4 mg/dl (adults)

(for > 4 weeks)

Serum Creatinine

> 2.0 mg/dl

Creatinine

Clearance

Discontinue Rebetol if

CrCl <50 ml/minute

Alanine

aminotransferase

(ALT)

Aspartate

aminotransferase

(AST)

2 x baseline and

> 10 x ULN*

2 x baseline and

> 10 x ULN*

* Upper limit of normal

** Refer to the SmPC for pegylated interferon alfa-2b and interferon alfa-2b for dose modification and

discontinuation.

Note 1: In adult patients, 1

dose reduction of Rebetol is by 200 mg/day (except in patients

receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2

dose

reduction of Rebetol is by an additional 200 mg/day.Patients whose dose of Rebetol is

reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg

capsules in the evening.

Note 2: In adult patients treated with Rebetol plus peginterferon alfa-2b, 1

dose reduction of

peginterferon alfa-2b is to 1 µg/kg/week. If needed, 2

dose reduction of peginterferon alfa-

2b is to 0.5 µg/kg/week. In adult patients treated with Rebetol plus interferon alfa-2b, reduce

the interferon alfa-2b dose by one-half dose.

Special populations

Use in renal impairment: The pharmacokinetics of ribavirin are altered in patients with renal

dysfunction due to reduction of apparent creatinine clearance in these patients (see section 5.2).

Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of

Rebetol. Patients with creatinine clearance < 50 ml/minute must not be treated with Rebetol (see

section 4.3). Patients with impaired renal function should be more carefully monitored with respect

to the development of anaemia. If serum creatinine rises to

2.0 mg/dl (Table 3), Rebetol and

peginterferon alfa-2b/interferon alfa-2b must be discontinued.

Use in hepatic impairment: No pharmacokinetic interaction appears between ribavirin and hepatic

function (see section 5.2). Therefore, no dose adjustment of Rebetol is required in patients with

hepatic impairment.

The use of ribavirin is contraindicated in patients with severe hepatic

impairment or decompensated cirrhosis (see section 4.3).

Use in the elderly (

65 years of age): There does not appear to be a significant age-related effect

on the pharmacokinetics of ribavirin. However, as in younger patients, renal function must be

determined prior to administration of Rebetol (see section 5.2).

Patients co-infected with HCV/HIV: Patients taking nucleoside reverse transcriptase inhibitor

(NRTI) treatment in association with ribavirin and interferon alfa-2b or peginterferon alfa-2b may be

at increased risk of mitochondrial toxicity, lactic acidosis and hepatic decompensation (see section

4.4). Please refer also to the relevant product information for antiretroviral medicinal products.

Method of administration:

Rebetol should be administered orally. No special precautions for disposal or handling are required.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pregnant women (see sections 4.4, 4.6 and 5.3). Rebetol must not be initiated until a report of a

negative pregnancy test has been obtained immediately prior to initiation of therapy.

Lactation

A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac

disease, in the previous six months (see section 4.4).

Patients with severe, debilitating medical conditions.

Patients with chronic renal failure, patients with creatinine clearance < 50 ml/minute and/or on

haemodialysis.

Severe hepatic

impairment (Child-Pugh Classification B or C) or decompensated cirrhosis of

the liver.

Haemoglobinopathies (e.g., thalassemia, sickle-cell anaemia).

Initiation of peginterferon alfa-2b is contraindicated in HCV/HIV patients with cirrhosis and a

Child-Pugh score ≥ 6.

Because of co-administration with peginterferon alfa-2b or interferon alfa-2b:

Autoimmune hepatitis; or history of autoimmune disease.

4.4

Special warnings and precautions for use

Psychiatric and Central Nervous System (CNS):

Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been

observed in some patients during Rebetol combination therapy with peginterferon alfa-2b or

interferon alfa-2b, and even after treatment discontinuation mainly during the 6-month follow-up

period. Other CNS effects including aggressive behaviour (sometimes directed against others such

as homicidal ideation), bipolar disorder, mania, confusion and alterations of mental status have

been observed with alfa interferons. Patients should be closely monitored for any signs or

symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these

undesirable effects must be borne in mind by the prescribing physician and the need for adequate

therapeutic management should be considered. If psychiatric symptoms persist or worsen, or

suicidal or homicidal ideation is identified, it is recommended that treatment with Rebetol and

peginterferon alfa-2b or interferon alfa-2b be discontinued, and the patient followed, with

psychiatric intervention as appropriate.

Patients with existence of or history of severe psychiatric conditions: If treatment with Rebetol in

combination with peginterferon alfa-2b or interferon alfa-2b is judged necessary in adult patients with

existence or history of severe psychiatric conditions, this should only be initiated after having ensured

appropriate individualised diagnostic and therapeutic management of the psychiatric condition.

Patients with substance use/abuse:

HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an

increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric

disorders when treated with alfa interferon. If treatment with alfa interferon is judged necessary in

these patients, the presence of psychiatric co-morbidities and the potential for other substance use

should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-

disciplinary approach including a mental health care provider or addiction specialist should be

considered to evaluate, treat and follow the patient. Patients should be closely monitored during

therapy and even after treatment discontinuation. Early intervention for re-emergence or development

of psychiatric disorders and substance use is recommended.

Based on results of clinical trials, the use of ribavirin as monotherapy is not effective and Rebetol must

not be used alone. The safety and efficacy of combination therapy have been established only using

ribavirin together with peginterferon alfa-2b or interferon alfa-2b solution for injection.

All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain

cases (i.e. patients with genotype 2 and 3), treatment may be possible without histological

confirmation. Current treatment guidelines should be consulted as to whether a liver biopsy is

needed prior to commencing treatment.

Haemolysis: A decrease in haemoglobin levels to < 10 g/dl was observed in up to 14 % of adult

patients treated with Rebetol in combination with peginterferon alfa-2b or interferon alfa-2b in clinical

trials. Although ribavirin has no direct cardiovascular effects, anaemia associated with Rebetol may

result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or

both. Thus, Rebetol must be administered with caution to patients with pre-existing cardiac disease

(see section 4.3). Cardiac status must be assessed before start of therapy and monitored clinically

during therapy; if any deterioration occurs, therapy must be stopped (see section 4.2).

Cardiovascular: Adult patients with a history of congestive heart failure, myocardial infarction and/or

previous or current arrhythmic disorders must be closely monitored. It is recommended that those

patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and

during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to

conventional therapy but may require discontinuation of therapy. There are no data in children or

adolescents with a history of cardiac disease.

Acute hypersensitivity: If an acute hypersensitivity reaction (e.g., urticaria, angioedema,

bronchoconstriction, anaphylaxis) develops, Rebetol must be discontinued immediately and

appropriate medical therapy instituted. Transient rashes do not necessitate interruption of treatment.

Ocular changes: Ribavirin is used in combination therapy with alfa interferons. Retinopathy

including retinal haemorrhages, retinal exudates, papilloedema, optic neuropathy and retinal artery

or vein occlusion which may result in loss of vision have been reported in rare instances with

combination therapy with alfa interferons. All patients should have a baseline eye examination. Any

patient complaining of decrease or loss of vision must have a prompt and complete eye

examination. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive

retinopathy) should receive periodic ophthalmologic exams during combination therapy with alfa

interferons. Combination therapy with alfa interferons should be discontinued in patients who

develop new or worsening ophthalmologic disorders.

Liver function: Any patient developing significant liver function abnormalities during treatment must

be monitored closely. Discontinue treatment in patients who develop prolongation of coagulation

markers which might indicate liver decompensation.

Potential to exacerbate immunosuppression: Pancytopenia and bone marrow suppression have

been reported in the literature to occur within 3 to 7 weeks after the administration of a

peginterferon and ribavirin concomitantly with azathioprine. This myelotoxicity was reversible within

4 to 6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not

recur upon reintroduction of either treatment alone (see section 4.5).

HCV/HIV Co-infection:

Mitochondrial toxicity and lactic acidosis:

Caution should be taken in HIV-positive subjects co-infected with HCV who receive nucleoside

reverse transcriptase inhibitor (NRTI) treatment (especially ddI and d4T) and associated interferon

alfa-2b/ribavirin treatment. In the HIV-positive population receiving an NRTI regimen, physicians

should carefully monitor markers of mitochondrial toxicity and lactic acidosis when ribavirin is

administered. In particular:

co-administration of Rebetol and didanosine is not recommended due to the risk of

mitochondrial toxicity (see section 4.5).

co-administration of Rebetol and stavudine should be avoided to limit the risk of overlapping

mitochondrial toxicity.

Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis:

Co-infected patients with advanced cirrhosis receiving highly active anti-retroviral therapy (HAART)

may be at increased risk of hepatic decompensation and death. Adding treatment with alfa

interferons alone or in combination with ribavirin may increase the risk in this patient subset. Other

baseline factors in co-infected patients that may be associated with a higher risk of hepatic

decompensation include treatment with didanosine and elevated bilirubin serum concentrations.

Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be

closely monitored, assessing their Child-Pugh score during treatment. Patients progressing to

hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and

the ARV treatment reassessed.

Haematological abnormalities in HCV/HIV co-infected patients:

HCV/HIV co-infected patients receiving peginterferon alfa-2b/ribavirin treatment and HAART may

be at increased risk to develop haematological abnormalities (as neutropenia, thrombocytopenia

and anaemia) compared to HCV mono-infected patients. Although, the majority of them could be

managed by dose reduction, close monitoring of haematological parameters should be undertaken

in this population of patients (see section 4.2 and below “Laboratory tests” and section 4.8).

Patients treated with ribavirin and zidovudine are at increased risk of developing anaemia;

therefore, the concomitant use of ribavirin with zidovudine is not recommended (see section 4.5).

Patients with low CD4 counts:

In patients co-infected with HCV/HIV, limited efficacy and safety data (N = 25) are available in

subjects with CD4 counts less than 200 cells/µl. Caution is therefore warranted in the treatment of

patients with low CD4 counts.

Please refer to the respective Summary of Product Characteristics of the antiretroviral medicinal

products that are to be taken concurrently with HCV therapy for awareness and management of

toxicities specific for each product and the potential for overlapping toxicities with Rebetol and

peginterferon alfa-2b.

Dental and periodontal disorders: Dental and periodontal disorders, which may lead to loss of

teeth, have been reported in patients receiving Rebetol and peginterferon alfa-2b or interferon alfa-

2b combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous

membranes of the mouth during long-term treatment with the combination of Rebetol and

peginterferon alfa-2b or interferon alfa-2b. Patients should brush their teeth thoroughly twice daily

and have regular dental examinations. In addition some patients may experience vomiting. If this

reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.

Laboratory tests: Standard haematologic tests and blood chemistries (complete blood count [CBC]

and differential, platelet count, electrolytes, serum creatinine, liver function tests, uric acid) must be

conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered

as a guideline prior to initiation of Rebetol therapy:

Haemoglobin

Adult:

12 g/dl (females);

13 g/dl (males)

Platelets

100,000/mm

Neutrophil Count

1,500/mm

Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as

clinically appropriate.

HCV-RNA should be measured periodically during treatment (see section 4.2).

For females of childbearing potential: Female patients must have a routine pregnancy test performed

monthly during treatment and for four months thereafter. Female partners of male patients must have

a routine pregnancy test performed monthly during treatment and for seven months thereafter (see

section 4.6).

Uric acid may increase with Rebetol due to haemolysis; therefore, the potential for development of

gout must be carefully monitored in pre-disposed patients.

Use in patients with rare hereditary disorders: Each Rebetol capsule contains 40 mg of lactose.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or

glucose-galactose malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction

Results of in vitro studies using both human and rat liver microsome preparations indicated no

cytochrome P450 enzyme mediated metabolism of ribavirin. Ribavirin does not inhibit cytochrome

P450 enzymes. There is no evidence from toxicity studies that ribavirin induces liver enzymes.

Therefore, there is a minimal potential for P450 enzyme-based interactions.

Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere

with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine

monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with

azathioprine. The use of pegylated alfa interferons and ribavirin concomitantly with azathioprine

should be avoided. In individual cases where the benefit of administering ribavirin concomitantly with

azathioprine warrants the potential risk, it is recommended that close hematologic monitoring be done

during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with

these medicines should be stopped (see section 4.4).

No interaction studies have been conducted with Rebetol and other medicinal products, except for

peginterferon alfa-2b, interferon alfa-2b and antacids.

Interferon alfa-2b: No pharmacokinetic interactions were noted between Rebetol and peginterferon

alfa-2b or interferon alfa-2b in a multiple-dose pharmacokinetic study.

Antacid: The bioavailability of ribavirin 600 mg was decreased by co-administration with an antacid

containing magnesium aluminium and simethicone; AUC

decreased 14 %. It is possible that the

decreased bioavailability in this study was due to delayed transit of ribavirin or modified pH. This

interaction is not considered to be clinically relevant.

Nucleoside analogs: Use of nucleoside analogs, alone or in combination with other nucleosides,

has resulted in lactic acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of

purine nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine

nucleoside analogs (e.g. didanosine or abacavir). Co-administration of Rebetol and didanosine is

not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of

which some fatal, have been reported (see section 4.4).

The exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the

regimen used to treat HIV although the exact mechanism remains to be elucidated. The

concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of

anaemia (see section 4.4). Consideration should be given to replacing zidovudine in a combination

anti-retroviral treatment (ART) regimen if this is already established. This would be particularly

important in patients with a known history of zidovudine induced anaemia.

Any potential for interactions may persist for up to two months (five half-lives for ribavirin) after

cessation of Rebetol therapy due to the long half-life (see section 5.2).

There is no evidence that ribavirin interacts with non-nucleoside reverse transcriptase inhibitors or

protease inhibitors.

Conflicting findings are reported in literature on co-administration between abacavir and ribavirin.

Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be

at risk of a lower response rate to pegylated interferon/ribavirin therapy. Caution should be

exercised when both medicines are co-administered.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females

Female patients: Rebetol must not be used by females who are pregnant (see sections 4.3 and 5.3).

Extreme care must be taken to avoid pregnancy in female patients (see section 5.3). Rebetol therapy

must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to

initiation of therapy. Females of childbearing potential must use an effective contraceptive during

treatment and for four months after treatment has been concluded; routine monthly pregnancy tests

must be performed during this time. If pregnancy does occur during treatment or within four months

from stopping treatment, the patient must be advised of the significant teratogenic risk of ribavirin to

the foetus.

Male patients and their female partners: Extreme care must be taken to avoid pregnancy in partners of

male patients taking Rebetol (see sections 4.3 and 5.3). Ribavirin accumulates intracellularly and is

cleared from the body very slowly. It is unknown whether the ribavirin that is contained in sperm will

exert its potential teratogenic or genotoxic effects on the human embryo/foetus. Although data on

approximately 300 prospectively followed pregnancies with paternal exposure to ribavirin have not

shown an increased risk of malformation compared to the general population, nor any specific pattern

of malformation, either male patients or their female partners of childbearing age must be advised to

use an effective contraceptive during treatment with Rebetol and for seven months after treatment.

Men whose partners are pregnant must be instructed to use a condom to minimise delivery of ribavirin

to the partner.

Pregnancy

The use of Rebetol is contraindicated during pregnancy.

Breast-feeding

It is not known whether ribavirin is excreted in human milk. Because of the potential for adverse

reactions in breast-fed infants, breast-feeding must be discontinued prior to initiation of treatment.

Fertility

Preclinical data:

Fertility: In animal studies, ribavirin produced reversible effects on spermatogenesis (see section

5.3).

Teratogenicity: Significant teratogenic and/or embryocidal potential have been demonstrated for

ribavirin in all animal species in which adequate studies have been conducted, occurring at

doses as low as one twentieth of the recommended human dose (see section 5.3).

Genotoxicity: Ribavirin induces genotoxicity (see section 5.3).

4.7

Effects on ability to drive and use machines

Rebetol has no or negligible influence on the ability to drive and use machines; however, peginterferon

alfa-2b or interferon alfa-2b used in combination may have an effect. Thus, patients who develop

fatigue, somnolence, or confusion during treatment must be cautioned to avoid driving or operating

machinery.

4.8

Undesirable effects

Tritherapy

Refer to the SmPC for boceprevir.

Bitherapy

The safety of Rebetol capsules is evaluated from data from four clinical trials in patients with no

previous exposure to interferon (interferon-naïve patients): two trials studied Rebetol in

combination with interferon alfa-2b, two trial studied Rebetol in combination with peginterferon alfa-

Patients who are treated with interferon alfa-2b and ribavirin after previous relapse from interferon

therapy or who are treated for a shorter period are likely to have an improved safety profile than

that described below.

The adverse reactions listed in Table 4 are based on experience from clinical trials in adult

naïve patients treated for 1 year and post-marketing use. A certain number of adverse reactions,

generally attributed to interferon therapy but that have been reported in the context of hepatitis C

therapy (in combination with ribavirin) are also listed for reference in Table 4. Also, refer to

peginterferon alfa-2b and interferon alfa-2b SmPCs for adverse reactions that may be attributable

to interferons monotherapy. Within the organ system classes, adverse reactions are listed under

headings of frequency using the following 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); very rare (<1/10,000); not

known. Within each frequency grouping, undesirable effects are presented in order of decreasing

seriousness.

Table 4

Adverse reactions reported during clinical trials or following the marketing use of

Rebetol with pegylated interferon alfa-2b or interferon alfa-2b

System Organ Class

Adverse Reactions

Infections and infestations

Very common:

Viral infection, pharyngitis

Common:

Bacterial infection (including sepsis), fungal infection,

influenza, respiratory tract infection, bronchitis, herpes

simplex, sinusitis, otitis media, rhinitis, urinary tract

infection

Uncommon

Injection site infection, lower respiratory tract infection

Rare:

Pneumonia*

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

Common:

Neoplasm unspecified

Blood and lymphatic system disorders

Very common:

Anaemia, neutropenia

Common:

Haemolitic anaemia, leukopenia, thrombocytopenia,

lymphadenopathy, lymphopenia

Very rare:

Aplastic anaemia*

Not known:

Pure red cell aplasia, idiopathic thrombocytopenic

purpura, thrombotic thrombocytopenic purpura

Immune system disorders

Uncommon:

Drug hypersensitivity

Rare:

Sarcoidosis*, rheumatoid arthritis (new or aggravated)

Not known:

Vogt-Koyanagi-Harada syndrome, systemic lupus

erythematosus, vasculitis, acute hypersensitivity

reactions including urticaria, angioedema,

bronchoconstriction, anaphylaxis

Endocrine disorders

Common:

Hypothyroidism, hyperthyroidism

Metabolism and nutrition disorders

Very common:

Anorexia

Common:

Hyperglycaemia, hyperuricaemia, hypocalcaemia,

dehydration, increased appetite

Uncommon:

Diabetes mellitus, hypertriglyceridemia*

Psychiatric disorders

Very common:

Depression, anxiety, emotional lability, insomnia

Common:

Suicidal ideation, psychosis, aggressive behaviour,

confusion, agitation, anger, mood altered, abnormal

behaviour, nervousness, sleep disorder, decreased

libido apathy, abnormal dreams, crying

Uncommon:

Suicide attempts, panic attack, hallucination

Rare:

Bipolar disorder*

Very rare:

Suicide*

Not known:

Homicidal ideation*, mania*, mental status change

Table 4

Adverse reactions reported during clinical trials or following the marketing use of

Rebetol with pegylated interferon alfa-2b or interferon alfa-2b

System Organ Class

Adverse Reactions

Nervous system disorders

Very common:

Headache, dizziness, dry mouth, concentration impaired

Common:

Amnesia, memory impairment, syncope, migraine,

ataxia, paraesthaesia, dysphonia, taste loss,

hypoaesthesia, hyperaesthesia, hypertonia, somnolence,

disturbance in attention, tremor, dysgeusia

Uncommon:

Neuropathy, peripheral neuropathy

Rare:

Seizure (convulsion)*

Very rare:

Cerebrovascular haemorrhage*, cerebrovascular

ischaemia*, encephalopathy*, polyneuropathy*

Not known:

Facial palsy, mononeuropathies

Eye disorders

Common:

Visual disturbance, blurred vision, conjunctivitis, eye

irritation, eye pain, abnormal vision, lacrimal gland

disorder, dry eye

Rare:

Retinal haemorrhages*, retinopathies (including macular

oedema)*, retinal artery occlusion*, retinal vein

occlusion*, optic neuritis*, papilloedema*, loss of visual

acuity or visual field*, retinal exudates

Ear and labyrinth disorders

Common:

Vertigo, hearing impaired/loss, tinnitus, ear pain

Cardiac disorders

Common:

Palpitation, tachycardia

Uncommon:

Myocardial infarction

Rare:

Cardiomyopathy, arrhythmia*

Very rare:

Cardiac ischaemia*

Not known:

Pericardial effusion*, pericarditis*

Vascular disorders

Common:

Hypotension, hypertension, flushing

Rare:

Vasculitis

Very rare:

Peripheral ischaemia*

Respiratory, thoracic and mediastinal disorders

Very common:

Dyspnoea, coughing

Common:

Epistaxis, respiratory disorder, respiratory tract

congestion, sinus congestion, nasal congestion,

rhinorrhea, increased upper airway secretion,

pharyngolaryngeal pain, nonproductive cough

Very rare:

Pulmonary infiltrates*, pneumonitis*, interstitial

pneumonitis*

Gastro-intestinal disorders

Very common:

Diarrhoea, vomiting, nausea, abdominal pain

Common:

Ulcerative stomatitis, stomatitis, mouth ulceration, colitis,

upper right quadrant pain, dyspepsia,

gastroesophoageal reflux*, glossitis, cheilitis, abdominal

distension, gingival bleeding, gingivitis, loose stools,

tooth disorder, constipation, flatulence

Uncommon:

Pancreatitis, oral pain

Rare:

Ischaemic colitis

Very rare:

Ulcerative colitis*

Not known:

Periodontal disorder, dental disorder, tongue

pigmentation

Hepatobiliary disorders

Common:

Hepatomegaly, jaundice, hyperbilirubinemia*

Very rare:

Hepatotoxicity (including fatalities)*

Table 4

Adverse reactions reported during clinical trials or following the marketing use of

Rebetol with pegylated interferon alfa-2b or interferon alfa-2b

System Organ Class

Adverse Reactions

Skin and subcutaneous tissue disorders

Very common:

Alopecia, pruritus, skin dry, rash

Common:

Psoriasis, aggravated psoriasis, eczema,

photosensitivity reaction, maculopapular rash,

erythematous rash, night sweats, hyperhidrosis,

dermatitis, acne, furuncule, erythema, urticaria, skin

disorder, bruise, sweating increased, abnormal hair

texture, nail disorder*

Rare:

Cutaneous sarcoidosis

Very rare:

Stevens Johnson syndrome*, toxic epidermal

necrolysis*, erythema multiforme*

Musculoskeletal and connective tissue disorders

Very common:

Arthralgia, myalgia, musculoskeletal pain

Common:

Arthritis, back pain, muscle spasms, pain in extremity

Uncommon:

Bone pain, muscle weakness

Rare:

Rhabdomyolysis*, myositis*

Renal and urinary disorders

Common:

Micturition frequency, polyuria, urine abnormality

Rare:

Renal failure, renal insufficiency*

Very rare:

Nephrotic syndrome*

Reproductive system and breast disorders

Common:

Female: amenorrhea, menorrhagia, menstrual disorder,

dysmenorrhea, breast pain, ovarian disorder, vaginal

disorder. Male: impotence, prostatitis, erectile

dysfunction.

Sexual dysfunction (not specified)*

General disorders and administration site conditions

Very common:

Injection site inflammation, injection site reaction, fatigue,

rigors, pyrexia, influenza like illness, asthenia, irritability

Common:

Chest pain, chest discomfort, peripheral oedema,

malaise, injection site pain, feeling abnormal, thirst

Uncommon:

Face oedema

Rare:

Injection site necrosis

Investigations

Very common:

Weight decrease

Common:

Cardiac murmur

* Since ribavirin is always prescribed with an alpha interferon product, and the listed adverse drug reactions

included reflecting post-marketing experience do not allow precise quantification of frequency, the frequency

reported above is from clinical trials using ribavirin in combination with interferon alfa-2b (pegylated or non-

pegylated).

A reduction in haemoglobin concentrations by > 4 g/dl was observed in 30 % of patients treated

with Rebetol and peginterferon alfa-2b and 37 % of patients treated with Rebetol and interferon

alfa-2b. Haemoglobin levels dropped below 10 g/dl in up to 14 % of adult patients treated with

Rebetol in combination with either peginterferon alfa-2b or interferon alfa-2b.

Most cases of anaemia, neutropaenia, and thrombocytopaenia were mild (WHO grades 1 or 2).

There were some cases of more severe neutropenia in patients treated with Rebetol in combination

with peginterferon alfa-2b (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]);

WHO grade 3 leukopenia was also reported in 7 % of this treatment group.

An increase in uric acid and indirect bilirubin values associated with haemolysis was observed in

some patients treated with Rebetol used in combination with peginterferon alfa-2b or interferon

alfa-2b in clinical trials, but values returned to baseline levels by four weeks after the end of

therapy. Among those patients with elevated uric acid levels, very few patients treated with the

combination developed clinical gout, none of which required treatment modification or

discontinuation from the clinical trials.

HCV/HIV co-infected patients:

For HCV/HIV co-infected patients receiving Rebetol in combination with peginterferon alfa-2b, other

adverse reactions (that were not reported in mono-infected patients) which have been reported in

the studies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %),

CD4 lymphocytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase

increased (9 %), back pain (5 %), blood amylase increased (6 %), blood lactic acid increased

(5 %), cytolytic hepatitis (6 %), lipase increased (6 %) and pain in limb (6 %).

Mitochondrial toxicity:

Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving

NRTI regimen and associated-ribavirin for co-HCV infection (see section 4.4).

Laboratory values for HCV/HIV co-infected patients:

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more

frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification

and rarely required premature discontinuation of treatment (see section 4.4). Haematological

abnormalities were more frequently reported in patients receiving Rebetol in combination with

peginterferon alfa-2b when compared to patients receiving Rebetol in combination with interferon

alfa-2b. In Study 1 (see section 5.1), decrease in absolute neutrophil count levels below

500 cells/mm

was observed in 4 % (8/194) of patients and decrease in platelets below

50,000/mm

was observed in 4 % (8/194) of patients receiving Rebetol in combination with

peginterferon alfa-2b. Anaemia (haemoglobin < 9.4 g/dl) was reported in 12 % (23/194) of patients

treated with Rebetol in combination with peginterferon alfa-2b.

CD4 lymphocytes decrease:

Treatment with Rebetol in combination with peginterferon alfa-2b was associated with decreases in

absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The

decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use

of Rebetol in combination with peginterferon alfa-2b had no observable negative impact on the

control of HIV viraemia during therapy or follow-up. Limited safety data (N = 25) are available in co-

infected patients with CD4+ cell counts < 200/µl (see section 4.4).

Please refer to the respective SmPC of the antiretroviral medicinal products that are to be taken

concurrently with HCV therapy for awareness and management of toxicities specific for each product

and the potential for overlapping toxicities with Rebetol in combination with peginterferon alfa-2b.

Most of the changes in laboratory values in the Rebetol/peginterferon alfa-2b clinical trial were mild or

moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in

bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2).

While changes in laboratory values were observed in some patients treated with Rebetol used in

combination with peginterferon alfa-2b in the clinical trial, values returned to baseline levels within a

few weeks after the end of therapy.

4.9

Overdose

Tritherapy

Refer to the SmPC for boceprevir.

Bitherapy

In clinical trials with Rebetol used in combination with peginterferon alfa-2b or interferon alfa-2b, the

maximum overdose reported was a total dose of 10 g of Rebetol (50 x 200 mg capsules) and 39 MIU

of interferon alfa-2b (13 subcutaneous injections of 3 MIU each) taken in one day by a patient in an

attempt at suicide. The patient was observed for two days in the emergency room, during which time

no adverse reaction from the overdose was noted.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Direct acting antivirals, nucleosides and nucleotides (excl. reverse

transcriptase inhibitors), ATC code: J05A B04.

Mechanism of action

Ribavirin (Rebetol) is a synthetic nucleoside analogue which has shown in vitro activity against some

RNA and DNA viruses. The mechanism by which Rebetol in combination with peginterferon alfa-2b or

interferon alfa-2b exerts its effects against HCV is unknown. Oral formulations of Rebetol

monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials.

Results of these investigations showed that Rebetol monotherapy had no effect on eliminating

hepatitis virus (HCV-RNA) or improving hepatic histology after 6 to 12 months of therapy and

6 months of follow-up.

Clinical trials efficacy and safety in adult subjects

Tritherapy:

Refer to the SmPC for boceprevir.

Bitherapy:

The use of Rebetol in combination treatment with peginterferon alfa-2b or interferon alfa-2b was

evaluated in a number of clinical trials. Eligible patients for these trials had chronic hepatitis C

confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 30 IU/ml), a liver

biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the

chronic hepatitis, and abnormal serum ALT.

Naïve patients

Three trials examined the use of interferon in naïve patients, two with Rebetol + interferon alfa-2b

(C95-132 and I95-143) and one with Rebetol + peginterferon alfa-2b (C/I98-580). In all cases the

treatment was for one year with a follow-up of six months. The sustained response at the end of

follow-up was significantly increased by the addition of Rebetol to interferon alfa-2b (41 % vs 16 %,

p < 0.001).

In clinical trials C95-132 and I95-143, Rebetol + interferon alfa-2b combination therapy proved to

be significantly more effective than interferon alfa-2b monotherapy (a doubling in sustained

response). Combination therapy also decreased the relapse rate. This was true for all HCV

genotypes, particularly Genotype 1, in which the relapse rate was reduced by 30 % compared with

interferon alfa-2b monotherapy.

In clinical trial C/I98-580, 1,530 naïve patients were treated for one year with one of the following

combination regimens:

Rebetol (800 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week) (n = 511).

Rebetol (1,000/1,200 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week for one

month followed by 0.5 microgram/kg/week for 11 months) (n = 514).

Rebetol (1,000/1,200 mg/day) + interferon alfa-2b (3 MIU three times a week) (n = 505).

In this trial, the combination of Rebetol and peginterferon alfa-2b (1.5 micrograms/kg/week) was

significantly more effective than the combination of Rebetol and interferon alfa-2b, particularly in

patients infected with Genotype 1. Sustained response was assessed by the response rate six

months after the cessation of treatment.

HCV genotype and baseline virus load are prognostic factors which are known to affect response

rates. However, response rates in this trial were shown to be dependent also on the dose of

Rebetol administered in combination with peginterferon alfa-2b or interferon alfa-2b. In those

patients that received > 10.6 mg/kg Rebetol (800 mg dose in typical 75 kg patient), regardless of

genotype or viral load, response rates were significantly higher than in those patients that received

10.6 mg/kg Rebetol (Table 5), while response rates in patients that received > 13.2 mg/kg

Rebetol were even higher.

Table 5

Sustained response rates with Rebetol + peginterferon alfa-2b

(by Rebetol dose [mg/kg], genotype and viral load)

HCV Genotype

Rebetol dose

(mg/kg)

P 1.5/R

P 0.5/R

All Genotypes

All

54 %

47 %

47 %

10.6

50 %

41 %

27 %

> 10.6

61 %

48 %

47 %

Genotype 1

All

42 %

34 %

33 %

10.6

38 %

25 %

20 %

> 10.6

48 %

34 %

34 %

Genotype 1

600,000 IU/ml

73 %

51 %

45 %

10.6

74 %

25 %

33 %

> 10.6

71 %

52 %

45 %

Genotype 1

> 600,000 IU/ml

30 %

27 %

29 %

10.6

27 %

25 %

17 %

> 10.6

37 %

27 %

29 %

Genotype 2/3

All

82 %

80 %

79 %

10.6

79 %

73 %

50 %

> 10.6

88 %

80 %

80 %

P1.5/R

Rebetol (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg)

P0.5/R

Rebetol (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg)

Rebetol (1,000/1,200 mg) + interferon alfa-2b (3 MIU)

In a separate trial, 224 patients with genotype 2 or 3 received peginterferon alfa-2b,

1.5 microgram/kg subcutaneously, once weekly, in combination with ribavirin 800 mg –1,400 mg

p.o. for 6 months (based on body weight, only three patients weighing > 105 kg, received the 1,400

mg dose) (Table 6). Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4).

Table 6 Virologic Response at End of Treatment, Sustained Virologic Response and

Relapse by HCV Genotype and Viral Load*

Rebetol 800-1,400 mg/day plus peginterferon alfa-2b 1.5

g/kg once

weekly

End of Treatment

Response

Sustained Virologic

Response

Relapse

All Subjects

94 % (211/224)

81 % (182/224)

12 % (27/224)

HCV 2

100 % (42/42)

93 % (39/42)

7 % (3/42)

600,000

IU/ml

100 % (20/20)

95 % (19/20)

5 % (1/20)

> 600,000

IU/mL

100 % (22/22)

91 % (20/22)

9 % (2/22)

HCV 3

93 % (169/182)

79 % (143/182)

14 % (24/166)

600,000

IU/ml

93 % (92/99)

86 % (85/99)

8 % (7/91)

> 600,000

IU/ml

93 % (77/83)

70 % (58/83)

23 % (17/75)

* Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at

the follow-up week 24 visit was considered a sustained responder. Any subject with missing data in

and after the follow-up week 12 window was considered to be a non-responder at week 24 of follow-

up.

The 6 month treatment duration in this trial was better tolerated than one year of treatment in the

pivotal combination trial; for discontinuation 5 % vs. 14 %, for dose modification 18 % vs. 49 %.

In a non-comparative trial, 235 patients with genotype 1 and low viral load (< 600,000 IU/ml)

received peginterferon alfa-2b, 1.5 microgram/kg subcutaneously, once weekly, in combination with

weight adjusted Rebetol. The overall sustained response rate after a 24-week treatment duration

was 50 %. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at

week 4 and week 24 of therapy. In this subgroup, there was a 92 % (89/97) sustained virological

response rate. The high sustained response rate in this subgroup of patients was identified in an

interim analysis (n=49) and prospectively confirmed (n=48).

Limited historical data indicate that treatment for 48 weeks might be associated with a higher

sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96

following 24 weeks of treatment).

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two

peginterferon alfa-2b/Rebetol regimens [peginterferon alfa-2b 1.5 μg/kg and 1 μg/kg

subcutaneously once weekly both in combination with Rebetol 800 to 1,400 mg p.o. daily (in two

divided doses)] and peginterferon alfa-2a 180 μg subcutaneously once weekly with ribavirin 1,000

to 1,200 mg p.o. daily (in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis

C genotype 1. Response to the treatment was measured by Sustained Virologic Response (SVR)

which is defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table 7).

Table 7 Virologic response at treatment week 12, end of treatment response, relapse rate*

and Sustained Virologic Response (SVR)

Treatment group

% (number) of patients

peginterferon alfa-2b

1.5 µg/kg

+ Rebetol

peginterferon alfa-2b

1 µg/kg

+ Rebetol

peginterferon alfa-2a

180 µg

+ ribavirin

Undetectable HCV-RNA

at treatment week 12

40 (407/1,019)

36 (366/1,016)

45 (466/1,035)

End of treatment

response*

53 (542/1,019)

49 (500/1,016)

64 (667/1,035)

Relapse*

24 (123/523)

20 (95/475)

32 (193/612)

SVR*

40 (406/1,019)

38 (386/1,016)

41 (423/1,035)

SVR in patients with

undetectable HCV-RNA

at treatment week 12

81 (328/407)

83 (303/366)

74 (344/466)

*HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/ml

Lack of early virologic response by treatment week 12 (detectable HCV-RNA with a < 2 log

reduction from

baseline) was a criterion for discontinuation of treatment.

In all three treatment groups, sustained virologic response rates were similar. In patients of African

American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with

peginterferon alfa-2b (1.5 μg/kg)/Rebetol combination therapy resulted in a higher sustained

virologic response rate compared to peginterferon alfa-2b 1 μg/kg dose. At the peginterferon alfa-

2b 1.5 μg/kg plus Rebetol dose, sustained virologic response rates were lower in patients with

cirrhosis, in patients with normal ALT levels, in patients with a baseline viral load > 600,000 IU/ml

and in patients > 40 years old. Caucasian patients had a higher sustained virologic response rate

compared to the African Americans. Among patients with undetectable HCV-RNA at the end of

treatment, the relapse rate was 24 %.

Predictability of sustained virological response in naïve patients

Virological response by week 12, defined as at least 2-log viral load decrease or undetectable

levels of HCV RNA. Virological response by week 4 is defined as at least 1-log viral load decrease

or undetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12)

have been shown to be predictive for sustained response (Table 8).

Table 8

Predictive Value of In-Treatment Virologic Response while on peginterferon alfa-2b 1.5

µg/kg/Rebetol 800-1,400 mg Combination Therapy

Negative

Positive

response

Treatment

Week

sustained

Response

Predictive

Value

Response

Treatment

Week

Sustained

Response

Predictive

Value

Genotype 1*

By Week 4***

(n= 950)

HCV-RNA negative

65%

(539/834)

92%

(107/116)

HCV-RNA negative

≥ 1 log decrease in

viral load

95%

(210/220)

54%

(392/730)

By Week 12***

(n= 915)

HCV-RNA negative

85%

(433/508)

81%

(328/407)

HCV-RNA negative

≥ 2 log decrease in

viral load

N/A

†

57%

(402/709)

Genotype 2, 3**

By Week 12

(n=215)

HCV-RNA negative

≥ 2 log decrease in

viral load

50%

(1/2)

83%

(177/213)

*Genotype 1 receive 48 weeks treatment

**Genotype 2, 3 receive 24 weeks treatment

***The presented results are from a single point of time. A patient may be missing or have had a different

result for week 4 or week 12.

These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2 log

decrease from

baseline, patients to stop therapy. If week 12 HCV-RNA is positive and decreased ≥ 2 log

from baseline,

then retest HCV-RNA at week 24 and if positive, patients to stop therapy.

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. The response to

treatment in both of these trials is presented in Table 9. Study 1 (RIBAVIC; P01017) was a

randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic

hepatitis C who were co-infected with HIV. Patients were randomized to receive either Rebetol

(800 mg/day) plus peginterferon alfa-2b (1.5 µg/kg/week) or Rebetol (800 mg/day) plus interferon

alfa-2b (3 MIU TIW) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a

randomized, single centre study that enrolled 95 previously untreated adult patients with chronic

hepatitis C who were co-infected with HIV. Patients were randomized to receive either Rebetol

(800-1,200 mg/day based on weight) plus peginterferon alfa-2b (100 or 150 µg/week based on

weight) or Rebetol (800-1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW). The

duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected

with genotypes 2 or 3 and viral load < 800,000 IU/ml (Amplicor) who were treated for 24 weeks with

a 6 month follow-up period.

Table 9 Sustained virological response based on genotype after Rebetol in combination with

peginterferon alfa-2b in HCV/HIV co-infected patients

Study 1

Study 2

Rebetol

(800 mg/day)

peginterferon

Rebetol

(800 mg/day)

Interferon

value

Rebetol (800-

1,200 mg/day)

peginterferon

Rebetol (800-

1,200 mg/day)

Interferon alfa-

value

alfa-2b

(1.5 µg /kg/

week)

alfa-2b (3 MIU

TIW)

alfa-2b (100 or

µg/week)

(3 MIU TIW)

27 %

(56/205)

20 % (41/205)

0.047

44 % (23/52)

21 % (9/43)

0.017

Genotype

1, 4

17 %

(21/125)

6 % (8/129)

0.006

38 % (12/32)

7 % (2/27)

0.007

Genotype

2, 3

44 % (35/80)

43 % (33/76)

0.88

53 % (10/19)

47 % (7/15)

0.730

MIU = million international units; TIW = three times a week.

a: p value based on Cochran-Mantel Haenszel Chi square test.

b: p value based on chi-square test.

c: subjects < 75 kg received 100 µg/week peginterferon alfa-2b and subjects ≥ 75 kg received

150 µg/week peginterferon alfa-2b .

d: Rebetol dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for

patients > 75 kg.

Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.

Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.

Histological response

Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of

the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects

treated with Rebetol in combination with peginterferon alfa-2b. This decline was significant among

responders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak)

among non-responders. In terms of activity, about one-third of sustained responders showed

improvement and none showed worsening. There was no improvement in terms of fibrosis

observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype

Previously treated patients

- Retreatment of prior treatment failures (relapse and nonresponder patients) with peginterferon

alfa-2b in combination with Rebetol:

In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous

treatment with combination alfa interferon/ribavirin were retreated with peginterferon alfa 2b,

1.5 microgram/kg subcutaneously, once weekly, in combination with weight adjusted Rebetol.

Failure to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a

minimum of 12 weeks of treatment).

Patients who were HCV-RNA negative at Treatment week 12 continued treatment for 48 weeks

and were followed for 24 weeks post-treatment. Responseweek 12 was defined as undetectable

HCV-RNA

after 12 weeks of treatment. Sustained Virologic Response (SVR) is defined as

undetectable HCV-RNA at 24 weeks post-treatment (Table 10).

Table 10

Rates of Response to retreatment in prior treatment failures

Patients with undetectable HCV–RNA

at treatment week 12 and SVR upon retreatement

interferon alpha/ribavirin

peginterferon alpha/ribavirin

Overall

Population*

Response

week 12 %

(n/N)

SVR % (n/N)

99% CI

Response

week 12 %

(n/N)

SVR % (n/N)

99% CI

SVR % (n/N)

99 % CI

Overall

38.6

(549/1,423)

59.4

(326/549)

54.0,64.8

31.5

(272/863)

50.4

(137/272)

42.6, 58.2

21.7

(497/2,293)

19.5, 23.9

Prior Response

Relapse

67.7 (203/300)

59.6

(121/203)

50.7, 68.5

58.1

(200/344)

52.5

(105/200)

43.4, 61.6

37.7 (243/645)

32.8, 42.6

Table 10

Rates of Response to retreatment in prior treatment failures

Patients with undetectable HCV–RNA

at treatment week 12 and SVR upon retreatement

interferon alpha/ribavirin

peginterferon alpha/ribavirin

Overall

Population*

Response

week 12 %

(n/N)

SVR % (n/N)

99% CI

Response

week 12 %

(n/N)

SVR % (n/N)

99% CI

SVR % (n/N)

99 % CI

Genotype

59.7 (129/216)

51.2 (66/129)

39.8, 62.5

48.6

(122/251)

44.3 (54/122)

32.7, 55.8

28.6 (134/468)

23.3, 34.0

Genotype

88.9 (72/81)

73.6 (53/72)

(60.2, 87.0)

83.7 (77/92)

64.9 (50/77)

50.9, 78.9

61.3 (106/173)

51.7, 70.8

28.6 (258/903)

57.0

(147/258)

49.0, 64.9

12.4

(59/476)

44.1 (26/59)

27.4, 60.7

13.6

(188/1,385)

11.2, 15.9

Genotype

23.0 (182/790)

51.6 (94/182)

42.1, 61.2

9.9 (44/446)

38.6 (17/44)

19.7, 57.5

(123/1,242)

7.7, 12.1

Genotype

67.9 (74/109)

70.3 (52/74)

56.6, 84.0

53.6 (15/28)

60.0 (9/15)

27.4, 92.6

46.0 (63/137)

35.0, 57.0

Genotype

30.2

(343/1,135)

51.3

(176/343)

44.4, 58.3

23.0

(162/704)

42.6 (69/162)

32.6, 52.6

14.6

(270/1,846)

12.5, 16.7

77.1 (185/240)

73.0

(135/185)

64.6, 81.4

75.6

(96/127)

63.5 (61/96)

50.9, 76.2

55.3 (203/367)

48.6, 62.0

42.5 (17/40)

70.6 (12/17)

42.1, 99.1

44.4 (12/27)

50.0 (6/12)

12.8, 87.2

28.4 (19/67)

14.2, 42.5

METAVIR

Fibrosis score

46.0 (193/420)

66.8

(129/193)

58.1, 75.6

33.6

(78/232)

57.7 (45/78)

43.3, 72.1

29.2 (191/653)

24.7, 33.8

38.0 (163/429)

62.6

(102/163)

52.8, 72.3

32.4

(78/241)

51.3 (40/78)

36.7, 65.9

21.9 (147/672)

17.8, 26.0

33.6 (192/572)

49.5 (95/192)

40.2, 58.8

29.7

(116/390)

44.8 (52/116)

32.9, 56.7

16.5 (159/966)

13.4, 19.5

Baseline Viral

Load

HVL (>600,000

IU/ml)

32.4 (280/864)

56.1

(157/280)

48.4, 63.7

26.5

(152/573)

41.4 (63/152)

31.2, 51.7

16.6

(239/1,441)

14.1, 19.1

LVL (≤600,000

IU/ml)

48.3 (269/557)

62.8

(169/269)

55.2, 70.4

41.0

(118/288)

61.0 (72/118)

49.5, 72.6

30.2 (256/848)

26.1, 34.2

NR: Non-responder defined as serum/plasma HCV-RNA positive at the end of a minimum of 12 weeks of

treatment.

Plasma HCV-RNA is measured with a research-based quantitative polymerase chain reaction assay by a

central laboratory

*Intent to treat population includes 7 patients for whom at least 12 weeks of prior therapy could not be

confirmed.

Overall, approximately 36 % (821/2,286) of patients had undetectable plasma HCV-RNA levels at

week 12 of therapy measured using a research-based test (limit of detection 125 IU/ml). In this

subgroup, there was a 56 % (463/823) sustained virological response rate. For patients with prior

failure on therapy with non-pegylated interferon or pegylated interferon and negative at week 12,

the sustained response rates were 59 % and 50 %, respectively. Among 480 patients with > 2 log

viral reduction but detectable virus at week 12, altogether 188 patients continued therapy. In those

patients the SVR was 12%.

Non-responders to prior therapy with pegylated interferon alfa/ribavirin were less likely

to achieve a

week 12 response to retreatment than non-responders to non-pegylated interferon alfa/ribavirin

(12.4% vs. 28.6%). However, if a week 12 response was achieved, there was little difference in

SVR regardless of prior treatment or prior response.

- Retreatment of relapse patients with Rebetol and interferon alfa-2b combination treatment:

Two trials examined the use of Rebetol and interferon alfa-2b combination treatment in relapse

patients (C95-144 and I95-145); 345 chronic hepatitis patients who had relapsed after previous

interferon treatment were treated for six months with a six month follow-up. Combination therapy

with Rebetol and interferon alfa-2b resulted in a sustained virological response that was ten-fold

higher than that with interferon alfa-2b alone (49 % vs 5 %, p < 0.0001). This benefit was

maintained irrespective of standard predictors of response to interferon alfa-2b such as virus level,

HCV genotype and histological staging.

Long-term efficacy data- Adults

Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment in

prior studies with non-pegylated interferon alfa-2b (with or without Rebetol) and pegylated

interferon alfa-2b (with or without Rebetol), respectively. The purpose of the studies was to

evaluate the durability of sustained virologic response (SVR) and assess the impact of continued

viral negativity on clinical outcomes. At least 5 years of long-term follow-up was completed after

treatment in 462 patients and 327 patients, respectively. 12 out of 492 sustained responders and

only 3 out of 366 sustained responders relapsed, respectively, in the studies.

The Kaplan-Meier estimate for continued sustained response over 5 years is 97 % (95 % CI: 95-

99 %) for patients receiving non-pegylated interferon alfa-2b (with or without Rebetol), and is 99 %

(95 % CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without Rebetol).

SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and non-pegylated, with or

without Rebetol) results in long-term clearance of the virus providing resolution of the hepatic

infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of

hepatic events in patients with cirrhosis (including hepatocarcinoma).

5.2

Pharmacokinetic properties

Absorption

Ribavirin is absorbed rapidly following oral administration of a single dose (mean T

= 1.5 hours),

followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption,

distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with

approximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability is

approximately 45 %-65 %, which appears to be due to first pass metabolism. There is a linear

relationship between dose and AUC

following single doses of 200-1,200 mg ribavirin. Volume of

distribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins.

Distribution

Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and

has been identified to be primarily via an e

-type equilibrative nucleoside transporter. This type of

transporter is present on virtually all cell types and may account for the high volume of distribution of

ribavirin. The ratio of whole blood:plasma ribavirin concentrations is approximately 60:1; the excess of

ribavirin in whole blood exists as ribavirin nucleotides sequestered in erythrocytes.

Biotransformation

Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative

pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. Both

ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted renally.

Ribavirin has been shown to produce high inter- and intra-subject pharmacokinetic variability following

single oral doses (intrasubject variability of approximately 30 % for both AUC and C

), which may be

due to extensive first pass metabolism and transfer within and beyond the blood compartment.

Elimination

Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose

to single-dose AUC

12hr

. Following oral dosing with 600 mg BID, steady-state was reached by

approximately four weeks, with mean steady state plasma concentrations approximately 2,200 ng/ml.

Upon discontinuation of dosing the half-life was approximately 298 hours, which probably reflects slow

elimination from non-plasma compartments.

Transfer into seminal fluid: Seminal transfer of ribavirin has been studied. Ribavirin concentration in

seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic

exposure of a female partner after sexual intercourse with a treated patient has been estimated and

remains extremely limited compared to therapeutic plasma concentration of ribavirin.

Food effect: The bioavailability of a single oral dose of ribavirin was increased by co-administration of

a high fat meal (AUC

and C

both increased by 70 %). It is possible that the increased bioavailability

in this study was due to delayed transit of ribavirin or modified pH. The clinical relevance of results

from this single dose study is unknown. In the pivotal clinical efficacy trial, patients were instructed to

take ribavirin with food to achieve the maximal plasma concentration of ribavirin.

Renal function: Single-dose ribavirin pharmacokinetics were altered (increased AUC

and C

) in

patients with renal dysfunction compared with control subjects (creatinine clearance > 90 ml/minute).

This appears to be due to reduction of apparent clearance in these patients. Ribavirin concentrations

are essentially unchanged by haemodialysis.

Hepatic function: Single-dose pharmacokinetics of ribavirin in patients with mild, moderate or severe

hepatic dysfunction (Child-Pugh Classification A, B or C) are similar to those of normal controls.

Elderly patients (

65 years of age): Specific pharmacokinetic evaluations for elderly subjects have not

been performed. However, in a population pharmacokinetic study, age was not a key factor in the

kinetics of ribavirin; renal function is the determining factor.

Population pharmacokinetic analysis was performed using sparsely sampled serum concentration

values from four controlled clinical trials. The clearance model developed showed that body weight,

gender, age, and serum creatinine were the main covariates. For males, clearance was approximately

20 % higher than for females. Clearance increased as a function of body weight and was reduced at

ages greater than 40 years. Effects of these covariates on ribavirin clearance appear to be of limited

clinical significance due to the substantial residual variability not accounted for by the model.

5.3

Preclinical safety data

Ribavirin: Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended

human dose in all animal species in which studies have been conducted. Malformations of the skull,

palate, eye, jaw, limbs, skeleton and gastrointestinal tract were noted. The incidence and severity of

teratogenic effects increased with escalation of the dose. Survival of foetuses and offspring was

reduced.

In a juvenile rat toxicity study, pups dosed from postnatal day 7 to 63 with 10, 25 and 50 mg/kg of

ribavirin demonstrated a dose-related decrease in overall growth, which was subsequently

manifested as slight decreases in body weight, crown-rump length and bone length. At the end of

the recovery period, tibial and femoral changes were minimal although generally statistically

significant compared to controls in males at all dose levels and in females dosed with the two

highest doses compared to controls. No histopathological effects on bone were observed. No

ribavirin effects were observed regarding neurobehavioural or reproductive development. Plasma

concentrations achieved in rat pups were below human plasma concentrations at the therapeutic

dose.

Erythrocytes are a primary target of toxicity for ribavirin in animal studies. Anaemia occurs shortly after

initiation of dosing, but is rapidly reversible upon cessation of treatment.

In 3- and 6-month studies in mice to investigate ribavirin-induced testicular and sperm effects,

abnormalities in sperm, occurred at doses of 15 mg/kg and above. These doses in animals produce

systemic exposures well below those achieved in humans at therapeutic doses. Upon cessation of

treatment, essentially total recovery from ribavirin-induced testicular toxicity occurred within one or two

spermatogenic cycles (see section 4.6).

Genotoxicity studies have demonstrated that ribavirin does exert some genotoxic activity. Ribavirin

was active in the Balb/3T3 in vitro Transformation Assay. Genotoxic activity was observed in the

mouse lymphoma assay, and at doses of 20-200 mg/kg in a mouse micronucleus assay. A dominant

lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted

through male gametes.

Conventional carcinogenicity rodent studies with low exposures compared to human exposure

under therapeutic conditions (factor 0.1 in rats and 1 in mice) did not reveal tumorigenicity of

ribavirin. In addition, in a 26 week carcinogenicity study using the heterozygous p53(+/-) mouse

model, ribavirin did not produce tumours at the maximally tolerated dose of 300 mg/kg (plasma

exposure factor approximately 2.5 compared to human exposure). These studies suggest that a

carcinogenic potential of ribavirin in humans is unlikely.

Ribavirin plus interferon : When used in combination with peginterferon alfa-2b or interferon alfa-2b,

ribavirin did not cause any effects not previously seen with either active substance alone. The

major treatment-related change was a reversible mild to moderate anaemia, the severity of which

was greater than that produced by either active substance alone.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Capsule contents:

Microcrystalline cellulose,

Lactose monohydrate,

Croscarmellose sodium,

Magnesium stearate.

Capsule shell:

Gelatine,

Titanium dioxide,

Sodium lauryl sulfate (used as a manufacturing aid, at very low levels).

Capsule imprint:

Shellac,

Dehydrated Alcohol,

Isopropyl Alcohol,

Butyl Alcohol,

Propylene glycol,

Strong Ammonia Solution,

Colouring agent ( FD&C Blue # 2 Aluminum Lake).

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

24 months

6.4

Special precautions for storage

Store below 25°C.

6.5

Nature and contents of container

Ribavirin capsules are packaged in blisters consisting of polyvinyl chloride (PVC)/polyethylene

(PE)/polyvinylidene chloride (PVdC).

Packs of 70, 84, 140, 168 capsules.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

7.

MANUFACTURER

Schering-Plough Labo N.V., Heist- op-den-Berg, Belgium.

8. LICENSE HOLDER

Merck Sharp & Dohme (Israel – 1996) Company Ltd., P.O.Box 7121, Petah-Tikva 49170.

9. LICENSE No.

116-93-29850-01

The format of this leaflet was determined by the Ministry of Health and its content was checked and

approved in January 2015.