Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Clinigen Healthcare Limited, Pitcairn House, Crown Square, First Avenue, Burton-on-Trent, Staffordshire, DE14 2WW, United Kingdom
Hypersensitivity to the active substance (interferon gamma-1b) or known hypersensitivity to closely related interferons or to any of the excipients listed in section 6.1.
The use of IMMUKIN does not exclude the need for any additional antimicrobial coverage that might be required for the management of CGD. In the pivotal clinical efficacy study the overwhelming majority of the patients were receiving prophylactic antimicrobial therapy (see section 5.1).
Patients with pre-existing cardiac disease may experience an acute, self-limiting exacerbation of their cardiac condition at doses of 250 mcg/m²/day or higher, as observed in early clinical trials, although no direct cardiotoxic effect has been demonstrated.
Caution should be exercised when treating patients with known seizure disorders and/or compromised central nervous system function.
Patients with serious hepatic insufficiency and patients with severe renal insufficiency should be treated with caution since the possibility of interferon gamma-1b accumulation exists in those patients.
Elevations of AST and/or ALT (up to 25-fold) have been observed during IMMUKIN therapy. The incidence appeared to be higher in patients less than 1 year of age compared to older children with 6 out of 10 developing elevated enzyme levels. In one case this occurred as early as 7 days after starting therapy. Treatment with IMMUKIN was interrupted in all 6 of these patients and restarted at a reduced dosage in 4. Liver transaminase values returned to baseline in all patients and did not recur with rechallenge except in one patient. Caution should be especially observed in patients with hepatic insufficiency.
Reversible neutropenia and thrombocytopenia that can be severe and may be dose related have been observed during IMMUKIN therapy. Caution should be exercised when administering IMMUKIN to patients with myelosuppression.
Simultaneous administration of interferon gamma-1b with other heterologous serum protein preparations or immunological preparations (e.g. vaccines) should be avoided because of the risk for unexpected amplified immune response (see section 4.5).
In addition to tests normally required for monitoring patients with CGD or severe, malignant osteopetrosis, patients should have performed the following tests before beginning IMMUKIN therapy and at appropriate periods during treatment: haematologic tests, including complete blood counts, differential and platelet counts; blood chemistries, including renal and liver function tests; urinalysis.
Interferon gamma-1b is an exogenous protein, which may lead to the occurrence of antibodies during the course of treatment. Up to now IMMUKIN administered to CGD or severe, malignant osteopetrosis patients in the recommended dose does not seem to be associated with significant risk for the induction of neutralising antibodies to interferon gamma-1b.
The stopper of the glass vial with IMMUKIN contains natural rubber (a derivative of latex) which may cause allergic reactions.
Based on the information available it cannot be excluded that the presence of higher levels of interferon gamma-1b may impair male and female fertility (see section 4.6).
IMMUKIN does not reduce the efficacy of antibiotics or glucocorticoids in CGD or severe, malignant osteopetrosis patients.
Drug interactions seen with IMMUKIN are similar to those seen with other interferons in animal experiments.
It is theoretically possible that hepatotoxic and/or nephrotoxic drugs might have effects on the clearance of IMMUKIN. Also the effects of anti-inflammatory drugs, NSAIDs, theophylline, immunosuppressive and cytostatic drugs on the acute cellular effects of IMMUKIN and its therapeutic effects in CGD or severe, malignant osteopetrosis patients when such drugs are used concomitantly in chronic conditions are not known. The concomitant administration of heterologous serum protein preparations or immunological preparations (e.g. vaccines) may increase the immunogenicity of IMMUKIN (see section 4.4).
IMMUKIN potentially can prolong the half-lives of simultaneously administered drugs, which are metabolised by the cytochrome P-450 system.
Concurrent use of drugs having neurotoxic (including effects on the central nervous system), haemotoxic, myelosuppressive or cardiotoxic effects may increase the toxicity of interferons in these systems.
Interaction studies have only been performed in adults.
There are no adequate data from the use of interferon gamma-1b in pregnant women. Higher levels of endogenous interferon gamma were found in women with recurrent first trimester miscarriage compared to women with normal pregnancy. There is no evidence of any clinical relevance for IMMUKIN.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IMMUKIN should not be used during pregnancy unless vitally indicated.
It is not known whether interferon gamma-1b is excreted in human milk. Because of the lack of data on neonatal effects, breastfeeding is not recommended.
Based on the information available it cannot be excluded that the presence of higher levels of interferon gamma-1b may impair male and female fertility. Studies in animals have shown an impact on male fertility at dose levels which are considered not relevant for human use (see section 5.3). In younger patients the long-term effect on fertility is also not known.
No studies on the effect on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as fatigue, convulsion, confusional state, disorientation or hallucination during treatment. Therefore, caution should be recommended when driving a car or operating machinery.
If patients experience any of these events, they should avoid potentially hazardous tasks such as driving or operating machinery.
The clinical and laboratory toxicity associated with multiple-dose IMMUKIN therapy is dose- and schedule-dependent.
The most common adverse events are flu-like symptoms characterised by fever, headache, chills, myalgia or fatigue.
Adverse reactions have been ranked under headings of frequency using the following convention:
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.
Not Known: Neutropenia#, thrombocytopenia#
Not known: Hyponatraemia*, hypoglycaemia*, hypertriglyceridaemia*
Common: Depression
Not known: Confusional state*, disorientation*, hallucination*
Not known: Convulsion*, Parkinsonian gait*, Parkinsonian rest tremor*, gait disturbance*
Not known: Cardiac failure*, myocardial infarction*, tachyarrhythmia*, atrioventricular block*
Not known: Transient ischemic attack*, deep vein thrombosis*, pulmonary embolism*, hypotension*, syncope*
Not known: Interstitial lung disease*, bronchospasm*, tachypnoea*
Very common: Nausea, vomiting, diarrhea
Common: Abdominal pain
Not known: Pancreatitis (including fatal outcome), gastrointestinal haemorrhage
Very common: Hepatic enzymes increased+
Not known: Hepatic failure*
Very common: Rash
Not known: (exacerbation of) Dermatomyositis*
Common: Myalgia, athralgia, back pain
Not known: Systemic lupus erythematosus*
Not known: (reversible) Renal failure*, proteinuria#
Very common: Fever, headache, chills fatigue, injection site pain
Not known: Chest discomfort*
Not known: Autoantibody positive*
# Cannot be estimated from the available data
+ Frequency higher in placebo group than in verum group
* Undesirable effects seen in clinical trials of conditions other than the registered indications CGD and osteopetrosis. In these trials interferon gamma-1b was usually administered at higher doses than recommended for the registered indications (see also section 4.9). Since these events have not been seen in clinical trials involving CGD or osteopetrosis but are reported in trials of patients with very diverse indications and health statuses, it is not possible to provide meaningful frequencies.
The flu-like symptoms may decrease in severity as treatment continues. Some of these symptoms can be minimised by bedtime administration. Acetaminophen (paracetamol) may also be used to ameliorate these effects. Vomiting, nausea, arthralgia and injection site tenderness have been reported in some patients.
Transient cutaneous rashes, e.g. dermatitis, maculopapular rash, pustular and vesicular eruptions, and erythema at injection site have occurred in some patients following injection but have rarely necessitated treatment interruption.
The inclusion of autoantibody production and systemic lupus erythematosus is the result of case reports in the literature. The adverse reaction “confusion” is also in the literature as a case report.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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