Special Warning : אזהרת שימוש

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 Intron A therapy, 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 disorders, 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 Intron A be discontinued, and the patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions: If treatment with 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. The use of interferon alfa-2b in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated.
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.

Hypersensitivity reactions
Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to interferon alfa-2b have been observed rarely during Intron A therapy.
If such a reaction develops, discontinue the medicine and institute appropriate medical therapy. Transient rashes do not necessitate interruption of treatment.

Adverse experiences including prolongation of coagulation markers and liver abnormalities
Moderate to severe adverse experiences may require modification of the patient's dose regimen, or in some cases, termination of Intron A therapy. Intron A increases the risk of liver decompensation and death in patients with cirrhosis.
Discontinue treatment with Intron A in patients with chronic hepatitis who develop prolongation of coagulation markers which might indicate liver decomposition.
Any patient developing liver function abnormalities during treatment with Intron A must be monitored closely and treatment discontinued if signs and symptoms progress.
Liver enzymes and hepatic function should be closely monitored in cirrhotic patients.

Hypotension
Hypotension may occur during Intron A therapy or up to two days post-therapy and may require supportive treatment.

Need for adequate hydration
Adequate hydration must be maintained in patients undergoing Intron A therapy since hypotension related to fluid depletion has been seen in some patients. Fluid replacement may be necessary.

Pyrexia
While pyrexia may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent pyrexia must be ruled out.

Patients with debilitating medical conditions
Intron A must be used cautiously in patients with debilitating medical conditions, such as those with a history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone to ketoacidosis. Caution must be observed also in patients with coagulation disorders (e.g., thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Pulmonary conditions
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alfa treated patients, including those treated with Intron A. The aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, a Chinese herbal medicine, is administered concomitantly with interferon alfa (see section 4.5). Any patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alfa. While this has been reported more often in patients with chronic hepatitis C treated with interferon alfa, it has also been reported in patients with oncologic diseases treated with interferon alfa. Prompt discontinuation of interferon alfa administration and treatment with corticosteroids appear to be associated with resolution of pulmonary adverse events.

Ocular adverse events
Ocular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, serous retinal detachment, and retinal artery or vein obstruction have been reported in rare instances after treatment with alfa interferons. All patients should have a baseline eye examination. Any patient complaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptoms during treatment with Intron A, must have a prompt and complete eye examination. Periodic visual examinations during Intron A therapy are recommended particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of Intron A should be considered in patients who develop new or worsening ophthalmological disorders.

Obtundation, coma and encephalopathy
More significant obtundation and coma, including cases of encephalopathy, have been observed in some patients, usually elderly, treated at higher doses. While these effects are generally reversible, in a few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high doses of Intron A.

Patients with pre-existing cardiac abnormalities
Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, who require Intron A therapy, must be closely monitored. It is recommended that those patients who have pre-existing cardiac abnormalities and/or are in advanced stages of cancer 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 Intron A therapy. There are no data in children or adolescents with a history of cardiac disease.

Hypertriglyceridemia
Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. Monitoring of lipid levels is, therefore, recommended.

Patients with psoriasis and sarcoidosis
Due to reports of interferon alfa exacerbating pre-existing psoriatic disease and sarcoidosis, use of Intron A in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies the potential risk.

Kidney and liver graft rejection
Preliminary data indicates that interferon alfa therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection has also been reported.


Auto-antibodies and autoimmune disorders
The development of auto-antibodies and autoimmune disorders has been reported during treatment with alfa interferons. Patients predisposed to the development of autoimmune disorders may be at increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also section 4.4 Chronic hepatitis C, Monotherapy (thyroid abnormalities) and section 4.8).
Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be withdrawn and corticosteroid therapy discussed (see section 4.8).

Concomitant chemotherapy
Administration of Intron A in combination with other chemotherapeutic agents (e.g., Ara-C, cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and duration), which may be life-threatening or fatal as a result of the concomitantly administered medicinal product. The most commonly reported potentially life-threatening or fatal adverse events include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of the risk of increased toxicity, careful adjustments of doses are required for Intron A and for the concomitant chemotherapeutic agents (see section 4.5). When Intron A is used with hydroxyurea, the frequency and severity of cutaneous vasculitis may be increased.

Chronic hepatitis C
Combination therapy with ribavirin
Also see ribavirin SPC if Intron A is to be administered in combination with ribavirin in patients with chronic hepatitis C.

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.

Monotherapy
Infrequently, adult patients treated for chronic hepatitis C with Intron A developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using Intron A therapy, 2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled by conventional therapy for thyroid dysfunction. The mechanism by which Intron A may alter thyroid status is unknown. Prior to initiation of Intron A therapy for the treatment of chronic hepatitis C, evaluate serum thyroid- stimulating hormone (TSH) levels. Any thyroid abnormality detected at that time must be treated with conventional therapy. Intron A treatment may be initiated if TSH levels can be maintained in the normal range by medication. Determine TSH levels if, during the course of Intron A therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, Intron A treatment may be continued if TSH levels can be maintained in the normal range by medication. Discontinuation of Intron A therapy has not reversed thyroid dysfunction occurring during treatment.

HCV/HIV Coinfection
Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should be used when adding Intron A and ribavirin to HAART therapy (see ribavirin SPC). Patients 
treated with Intron A and ribavirin combination therapy and zidovudine could be at increased risk of developing anaemia.
Co-infected patients with advanced cirrhosis receiving 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.

HCV/HBV Coinfection
Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients coinfected with hepatitis B and C viruses treated with interferon.
The frequency of such re-activation appears to be low.
All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C; patients co-infected with hepatitis B and C must then be monitored and managed according to current clinical guidelines.

Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving Intron A and ribavirin 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 Intron A and ribavirin.
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 haematological tests and blood chemistries (complete blood count and differential, platelet count, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to be conducted in all patients prior to and periodically during systemic treatment with Intron A.

During treatment for hepatitis B or C the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16, and every other month, thereafter, throughout treatment. If ALT flares during Intron A therapy to greater than or equal to 2 times baseline, Intron A therapy may be continued unless signs and symptoms of liver failure are observed.
During ALT flare, the following liver function tests must be monitored at two-week intervals: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin.

In patients treated for malignant melanoma, liver function and white blood cell (WBC) count and differential must be monitored weekly during the induction phase of therapy and monthly during the maintenance phase of therapy.

Effect on fertility
Interferon may impair fertility (see section 4.6 and section 5.3).

Important information about some of the ingredients of Intron A
This medicinal product contains less than 1 mmol sodium (23 mg) per 1 ml, i.e., essentially "sodium-free".

Effects on Driving

4.7   Effects on ability to drive and use machines

Patients are to be advised that they may develop fatigue, somnolence, or confusion during treatment with Intron A, and therefore it is recommended that they avoid driving or operating machinery.