Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Dose titration phase
The recommended posology for the titration phase of ropeginterferon alfa-2b (see section 4.2) results in a prolonged time to reach the individual optimal dose compared to hydroxycarbamide. In a clinical study in polycythaemia vera, the end of the mean individual titration phase for ropeginterferon alfa-2b was reached after approximately 3.7 months, for hydroxycarbamide after approximately 2.6 months of treatment. Thus, other products (e.g., hydroxycarbamide) may be preferred in patients for whom an early reduction in elevated blood counts is necessary to prevent thrombosis and bleeding.

During the titration phase the efficacy to reduce the cardiovascular and thromboembolic risk of the underlying disease may not be fully established. Patients should be closely monitored, particularly during the titration phase; complete blood counts including determination of haematocrit level, leukocyte and platelet counts should be performed regularly also after the individual optimal dose has been established. Phlebotomy as rescue treatment to normalise blood hyperviscosity may be necessary.

Endocrine system
Before ropeginterferon alfa-2b therapy, any pre-existing thyroid disease needs to be treated and controlled with conventional therapy (see section 4.3). Patients who develop symptoms indicative of a thyroid dysfunction during ropeginterferon alfa-2b therapy, should evaluate their thyroid stimulating hormone (TSH) levels. If TSH levels can be controlled within the normal range, the therapy can be continued.

Diabetes mellitus have been observed with other interferon alfa medicinal products (see section 4.8).
Patients with this condition who cannot be effectively controlled by medicinal products should not begin ropeginterferon alfa-2b therapy. Patients who develop this condition during treatment and cannot be controlled by medicinal products should discontinue ropeginterferon alfa-2b therapy.


Central nervous system (CNS)
CNS effects, particularly depression, have been observed in some patients treated with ropeginterferon alfa-2b during the clinical development program (see section 4.8). Other CNS effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have been observed with other interferon alfa medicinal products. Patients should be closely monitored for any symptoms of psychiatric disorders and therapeutic management should be considered by the treating physician if such symptoms emerge. If psychiatric symptoms worsen, it is recommended to discontinue ropeginterferon alfa-2b therapy. Ropeginterferon alfa-2b must not be administered in patients with existence of or history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt (see section 4.3).

Cardiovascular system
Cardiac events including cardiomyopathy, myocardial infarction, atrial fibrillation and ischaemic coronary artery disorders have been associated with interferon alfa treatment (see section 4.8). Patients with pre-existing or a history of cardiovascular disorders should be closely monitored during ropeginterferon alfa-2b therapy. This medicinal product is contraindicated in patients with severe pre- existing cardiovascular disease or patients who had recently suffered from a stroke or myocardial infarction (see section 4.3).

Respiratory system
Respiratory disorders such as lung infiltration, pneumonitis, pneumonia, or pulmonary arterial hypertension have been observed rarely in patients treated with interferon alfa (see section 4.8).
Patients who develop respiratory symptoms should be monitored closely and if necessary, ropeginterferon alfa-2b therapy should be discontinued.

Visual system
Severe eye disorders such as retinopathy, retinal haemorrhage, retinal exudates, retinal detachment and retinal artery or vein occlusion which may result in blindness have been observed rarely in patients treated with interferon alfa (see section 4.8). Patients should have eye examinations before and during ropeginterferon alfa-2b therapy, specifically in those patients with retinopathy associated disease such as diabetes mellitus or hypertension. Any patient reporting a decrease or loss of vision or reporting other eye symptoms should have an immediate eye examination. Discontinuation of ropeginterferon alfa-2b should be considered in patients who develop new or worsening eye disorders.

Acute hypersensitivity
Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been rarely observed with other interferon alfa medicinal products. If this occurs, ropeginterferon alfa-2b therapy must be discontinued and appropriate medical therapy instituted immediately. Transient rashes do not necessitate interruption of treatment.

Liver function
Interferon alfa therapy has been associated with hepatotoxicity characterized by potentially significant increases in liver enzymes. Hepatic failure in hepatitis C virus infected patients was reported with other interferon alfa medicinal products (see section 4.8).
Increases in ALT (≥3 times the upper limit of normal), AST (≥3 times the upper limit of normal), GGT (≥3 times the upper limit of normal) and bilirubin (>2 times the upper limit of normal) levels have been observed in patients treated with ropeginterferon alfa-2b. These elevations were mostly transient and occurred during the first treatment year.
Liver disorders have been reported in patients after long-term ropeginterferon alfa-2b therapy (see section 4.8). Liver enzymes and hepatic function should be regularly controlled in patients with long- term ropeginterferon alfa-2b therapy. Treatment with ropeginterferon alfa-2b should be discontinued when, despite dose reduction, the increase in liver enzyme levels is progressive and clinically significant. In patients who develop evidence of hepatic decompensation during treatment, ropeginterferon alfa-2b should be discontinued. Ropeginterferon alfa-2b is contraindicated in patients with decompensated cirrhosis of the liver (see section 4.3).

Renal function
Regardless of the starting dose or degree of renal impairment, patients should be monitored. If renal function decreases during treatment, ropeginterferon alfa-2b therapy should be discontinued.
Ropeginterferon alfa-2b is contraindicated in patients with end stage renal disease (see section 4.3).
Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported with other interferon alfa medicinal products (see section 4.8). In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with ropeginterferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations.

Skin disorders
The use of ropeginterferon alfa-2b is associated with skin disorders (pruritus, alopecia, rash, erythema, psoriasis, xeroderma, dermatitis acneiform, hyperkeratosis, hyperhydrosis). In case of appearance or worsening of this skin disorders, the stop of the treatment must be envisaged.

Excipients
Besremi contains benzyl alcohol.
High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

Besremi contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially ‘sodium-free’.

Effects on Driving

4.7   Effects on ability to drive and use machines
Besremi has minor influence on the ability to drive and use machines. Patients who experience dizziness, somnolence or hallucination (see section 4.8) during Besremi therapy should avoid driving or using machines.