Ribavirin Mylan (Previously Ribavirin Three Rivers)

Adult patients:

The safety of Ribavirin is evaluated from data from four clinical trials in patients with no previous exposure to interferon (interferon-naïve patients): two trials studied ribavirin capsules in combination with interferon alfa-2b, two trials studied ribavirin capsules in combination with peginterferon alfa- 2b.

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 SPCs for adverse reactions that may be attributable to interferon 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 (cannot be estimated from the available data).

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 Ribavirin 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,Medicinal product no longer authorised 14 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 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* Gastrointestinal 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, flatulenceMedicinal product no longer authorised 15 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)* 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, […]

Psychiatric and Central Nervous System (CNS):

Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during Ribavirin combination therapy with peginterferon alfa-2b or interferon alfa-2b, and even after treatment discontinuation mainly during the 6-month follow-up period.

4% versus 1%) during treatment and during the 6-month follow-up after treatment. , depression, emotional lability, and somnolence). 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 alpha 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 ideation is identified, it is recommended that treatment with Ribavirin and peginterferon alfa-2b or interferon alfa-2b be discontinued, and the patient followed, with psychiatric intervention as appropriate.

3).

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 alpha interferon.

If treatment with alpha 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.

Paediatric population:

Growth and development: During the course of interferon (standard and pegylated)/ribavirin therapy lasting up to 48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common. Long-term data available in children treated with the combination therapy of pegylated interferon/ribavirin are indicative of substantial growth retardation.

1). The longer term data available in children treated with the combination therapy with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile decrease in height percentile as compared to baseline) in 21 % (n=20) of children despite being off treatment for more than 5 years.

Final adult height was available for 14 of those children and show that 12 continued to have height deficits > 15 percentiles, 10 to 12 years after the end of treatment. 1). − It is important to consider that the combination therapy induced a growth inhibition that resulted in reduced height in some patients.

− This risk should be weighed against the disease characteristics of the child, such as evidence of disease progression (notably fibrosis), co-morbidities that may negatively influence the disease progression (such as HIV-co-infection), as well as prognostic factors of response (HCV genotype and viral load).

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the risk of growth inhibition. Although data are limited, no evidence of long-term effects on sexual maturation was noted in the 5 year observational follow-up study.

Based on results of clinical trials, the use of ribavirin as monotherapy is not effective and Ribavirin must not be used alone. The safety and efficacy of this combination have been established only using ribavirin capsules together with peginterferon alfa-2b or interferon alfa-2b solution for injection.

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 and 7% of children and adolescents treated with Ribavirin in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials.

Although ribavirin has no direct cardiovascular […]

1. 3). Ribavirin Mylan must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. - Lactation. 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. , thalassemia, sickle-cell anaemia). Initiation of peginterferon alfa-2b is contraindicated in HCV/HIV patients with cirrhosis and a Child- Pugh score ≥ 6.

Children and adolescents: - Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal ideation, or suicide attempt. Because of co-administration with interferon alfa-2b: - Autoimmune hepatitis; or history of autoimmune disease.