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Drug Details
IMMUKIN
- Drug Class Description
Interferons. - Generic Name
Interferon gamma-1b - Presentation
Solution for injection A clear, colourless solution - Description
Each vial (0.5 ml) contains 2 x 106 IU (0.1 mg) recombinant human interferon gamma-1b. Interferon gamma-1b is produced in an E. coli expression system. - Indications
Immukin is indicated for the reduction of the frequency of serious infections in patients with chronic granulomatous disease (CGD) . Immukin is indicated for the reduction in frequency of serious infections in patients with severe, malignant osteopetrosi. - Adult Dosage
Immukin is for subcutaneous use. The recommended dosage of Immukin for the treatment of patients with CGD or severe, malignant osteopetrosis is 50 mcg / m2 for patients whose body surface area is greater than 0.5 m2 and 1.5 mcg / kg / dose for patients whose body surface area is equal to or less than 0.5 m2. The actually drawn volume has to be controlled before injection. Injections should be administered subcutaneously preferably in the evening three times weekly (for example, Monday, Wednesday, Friday). The optimum sites of injection are the right and the left deltoid and anterior thigh. Immukin can be administered by a physician, nurse, family member or patient when trained in the administration of subcutaneous injections.
Although the most beneficial dose of Immukin is not known yet higher doses are not recommended. Safety and efficacy has not been established for Immukin given in doses greater or less than the recommended dose of 50 mcg / m2. If severe reactions occur, the dosage should be modified (50 % reduction) or therapy should be discontinued until the adverse reaction abates.
The experience in children is limited.
- Child Dosage
Under 6 months, not recommmended. - Contra Indications
Hypersensitivity to the active substance (interferon gamma-1b) or known hypersensitivity to closely related interferons or to any of the excipients.
- Special Precautions
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.
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.
In addition to tests normally required for monitoring patients with CGD or severe, malignant osteopetrosis, patients should have performed the following tests before beginning Immukintherapy 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.
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.
- Interactions
Interaction studies have only been performed in adults. 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.
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.
- Adverse Drug Reactions
a) General Description
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.
b) Table of Adverse Reactions
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.
System Organ Class MedDRA Term Frequency Blood and lymphatic disorders: Neutropenia; Thrombocytopenia Not known2 < Psychiatric disorders Depression Common Confusion < Rare1 Nervous system disorders: Headache Very common Gastrointestinal disorders: Nausea; vomiting; abdominal pain; diarrhea Common Skin and subcutaneous tissue disorders: Rash Very common Musculoskeletal and connective tissue disorders Myalgia; arthralgia; back pain Common Systemic lupus erythematosus Rare1 Renal and urinary disorders: Proteinuria Not known2 General disorders and administration site conditions: Fever; chills; injection site pain Very common Fatigue Common Investigations: Autoantibody response Rare1 AST increase, ALT increase Not known2 1It has been assumed that these events have a reporting frequency of less than 1/1,000 and, therefore, they have been systematically classified “rare”.
2Because of the limitations of the applicable datasets available, no frequencies could be assigned.
In addition to the above mentioned undesirable effects reported in the registered indications CGD and osteopetrosis there were a number of undesirable effects seen in clinical trials of conditions other than in these indications. In these trials interferon gamma-1b was usually administered at higher doses than recommended for the registered indications.
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.
System Organ Class:
MedDRA Term1
Metabolism and Nutritional disorders:
Hyponatremia, hyperglycemia and hypertriglyceridemia;
Nervous System disorders:
Confusional state, disorientation, gait disturbance, Parkinsonian gait and tremor, convulsion, hallucinations;
Cardiac disorders:
Tachyarrhythmia, atrioventricular block, cardiac failure, myocardial infarction;
Vascular disorders:
Hypotension, syncope, transient ischemic attack, deep venous thrombosis, pulmonary embolism;
Respiratory, Thoracic and Mediastinal disorders:
Tachypnea, bronchospasm, interstitial lung disease;
Gastrointestinal disorders:
Gastrointestinal haemorrhage, pancreatitis, including pancreatitis with fatal outcome;
Hepatobiliary disorders:
Hepatic failure;
Skin and Subcutaneous disorders:
Exacerbation of dermatomyositis;
Musculosketal and Connective Tissue disorders:
Systemic lupus erythematosus;
Renal and urinary disorders:
Reversible renal failure;
General disorders and Administration site conditions:
Chest discomfort;
Investigations:
Autoantibody positive.
c) Information Characterising Individual Serious and/or Frequently Occurring Adverse Reactions
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.