Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Clinigen Healthcare Ltd., Pitcairn House, Crown Square, First Avenue, Burton-on-Trent, Staffordshire, DE14 2WW, United Kingdom
Proleukin therapy is contra-indicated in the following patients:
In addition, it is recommended to exclude the following patients:
* ECOG: see section 4.1.
See also section 4.3.
Clinical studies have shown that patients with metastatic renal cell carcinoma can be divided into 4 distinct risk groups, predictive for survival and to some extent response, following Proleukin therapy. The 4 risk groups are defined by the number of risk factors, as listed in section 4.1 and 4.3, present at treatment start: the very low risk group has no risk factor, the low risk group one risk factor, the median group any combination of 2 risk factors, and the high risk group has the simultaneous presence of all 3 risk factors. Response rates and median survival decrease with the number of risk factors present. Patients who are positive for all three risk factors should not be treated with Proleukin.
Risk factors associated with decreased response rates and median survival are:
Proleukin administration has been associated with capillary leak syndrome (CLS), which is characterized by a loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. CLS results in hypotension, tachycardia and reduced organ perfusion. Severe CLS resulting in death has been reported. The frequency and severity are lower after subcutaneous administration than with intravenous infusion.
Capillary leak syndrome usually begins within hours after initiation of Proleukin treatment and clinical symptoms (i.e. hypotension, tachycardia, dyspnea, pulmonary oedema) are reported to occur after 2 to 12 hours. Careful monitoring of circulatory and respiratory function is required particularly for patients receiving intravenous Proleukin (see section laboratory and clinical tests).
In some patients hypotension resolves without therapy. In others, treatment is required with cautious use of intravenous fluids. In more refractory cases, low-dose catecholamines are required to maintain blood pressure and organ perfusion. Prolonged use or higher dosages of catecholamines may be associated with cardiac rhythm disturbances.
If intravenous fluids are administered, care must be taken to weigh potential benefits of the expansion of intravascular volume against the risk of pulmonary oedema, ascites, pleural or pericardial effusions secondary to capillary leakage. If these measures are not successful, Proleukin therapy should be interrupted.
Proleukin may exacerbate pre-existing autoimmune disease, resulting in life threatening complications. Activation of quiescent Crohn’s disease has been reported following treatment with Proleukin.
Because not all patients who develop interleukin-2-associated autoimmune phenomena have a pre-existing history of autoimmune disease, awareness and close monitoring for thyroid abnormalities or other potentially autoimmune phenomena is warranted.
Proleukin administration should be discontinued in patients developing severe lethargy or somnolence; continued administration may result in coma.
Proleukin may exacerbate disease symptoms in patients with clinically unrecognized or untreated central nervous system (CNS) metastases. All patients should have adequate evaluation and treatment of CNS metastases prior to receiving Proleukin therapy.
Patients may experience mental status changes including irritability, confusion, or depression while receiving Proleukin. Although generally reversible when administration of medicinal product is discontinued, these mental status changes may persist for several days. Proleukin may alter patient response to psychotropic medicinal products (see section 4.5).
Proleukin administration results in reversible elevation of hepatic transaminases, serum bilirubin, serum urea and serum creatinine. Renal or hepatic metabolism or excretion of concomitantly administered medicinal products may be altered by the administration of Proleukin. Other medicinal products with known nephrotoxic or hepatotoxic potential should be used with caution (see section 4.5). Close monitoring should be applied to all patients with pre-existing renal or hepatic impairment.
Proleukin should only be used under the supervision of a qualified physician, experienced in the use of cancer chemotherapeutic agents. For administration by continuous intravenous infusion it is recommended that patients are admitted to a specialized unit having the facilities of an intensive care unit for monitoring the patient’s relevant clinical and laboratory parameters. Subcutaneous treatment can be administered in an outpatient setting by qualified health care professionals.
Should serious adverse events occur, dosage should be modified according to section 4.2. It is important to note that adverse reactions, although sometimes serious or in rare cases life-threatening, are manageable and usually, although not invariably, resolve within 1 or 2 days of cessation of Proleukin therapy. The decision to resume therapy should be based on the severity and spectrum of the clinical toxicity.
Proleukin may exacerbate effusions from serosal surfaces. Consideration should be given to treating these prior to initiation of Proleukin therapy, particularly when effusions are located in anatomic sites where worsening may lead to impairment of major organ function (e.g. pericardial effusions).
Pre-existing bacterial infections should be treated prior to initiation of Proleukin therapy. Toxicities associated with Proleukin administration may be exacerbated by concurrent bacterial infection.
Administration of Proleukin may be associated with an increased incidence and/or severity of bacterial infection, including septicaemia, bacterial endocarditis, septic thrombophlebitis, peritonitis and pneumonia. This has mainly been reported after intravenous administration. Except for several cases due to Escherichia coli, causative organisms have been Staphylococcus aureus or Staphylococcus epidermidis. During continuous intravenous infusion of Proleukin an increased incidence and/or severity of local catheter site infection has been reported. Patients with central lines in place should be treated prophylactically with antibiotics. In patients on subcutaneous treatment injection site reactions are common, sometimes with necrosis. The effects can be reduced by changing the injection site over the body.
There is a possibility of disturbances in the glucose metabolism during treatment with Proleukin. Blood glucose should be monitored; particular attention should be paid to patients with pre-existing diabetes.
Proleukin administration results in fever and gastrointestinal adverse reactions in most patients treated at the recommended dose. Concomitant therapy with paracetamol can be instituted at the time of Proleukin administration to reduce fever. Pethidine may be added to control the rigours associated with fever. Anti-emetics and antidiarrhoeals may be used as needed to treat other gastrointestinal adverse reactions. Some patients with pruritic rash benefit from concomitant administration of antihistamines.
In addition to those tests normally required for monitoring patients with metastatic renal cell carcinoma, the following tests are recommended for all patients on Proleukin therapy, prior to beginning treatment and then periodically thereafter:
For patients receiving intravenous Proleukin circulatory function should be monitored by regular blood pressure and pulse assessment, and by monitoring other organ function including mental status and urine output. More frequent assessments should be performed for patients experiencing a decrease in blood pressure. Hypovolemia should be assessed by monitoring of central pressure monitoring.
Pulmonary function should be monitored closely in patients who develop rales or increased respiratory rate, or who complain of dyspnoea. Monitoring of pulmonary function during therapy includes pulse oxymetry and arterial blood gas determination.
Proleukin is essentially sodium-free, see section 2.
Fatal Tumour Lysis Syndrome has been reported in combination with treatment with cisplatinum, vinblastine and dacarbazine. Concomitant use of the mentioned active substances is therefore not recommended.
Severe rhabdomyolysis and myocardial injury, including myocardial infarction, myocarditis and ventricular hypokinesia appear to be increased in patients receiving Proleukin (intravenously) and interferon-alpha concurrently.
There has also been exacerbation or the initial presentation of a number of autoimmune and inflammatory disorders observed following concurrent use of interferon-alpha and Proleukin, including crescentic immunoglobulin A (IgA) glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid, and Stevens-Johnson syndrome. It is recommended that patients with pre-existing auto-immune disease should not be treated with Proleukin (see section 4.3).
Concomitantly administered glucocorticoids may decrease the activity of Proleukin and therefore should be avoided. However, patients who develop life-threatening signs or symptoms may be treated with dexamethasone until toxicity resolves to an acceptable level.
Concurrent administration of medicinal products with hepatotoxic, nephrotoxic, myelotoxic, or cardiotoxic effects may increase the toxicity of Proleukin in these systems.
Antihypertensive agents, such as beta-blockers, may potentiate the hypotension seen with Proleukin and therefore blood pressure should be monitored.
Renal or hepatic metabolism or excretion of concomitantly administered medicinal products may be altered by the administration of Proleukin, since Proleukin administration results in reversible elevation of hepatic transaminases, serum bilirubin, serum urea and serum creatinine. Other medicinal products with known nephrotoxic or hepatotoxic potential should be used with caution (see section 4.4).
Proleukin may affect central nervous function. Therefore, interactions could occur following concomitant administration of centrally acting medicinal products. Proleukin may alter patient response to psychotropic medicinal products and therefore patients should be monitored (see section 4.4).
Use of contrast media after Proleukin administration may result in a recall of the toxicity observed during Proleukin administration. Most events were reported to occur within 2 weeks after the last dose of Proleukin, but some occurred months later. Therefore it is recommended not to use contrast media within 2 weeks after treatment with Proleukin.
Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose Proleukin and antineoplastic agents, specifically, dacarbazine, cisplatinum, tamoxifen and interferon-alpha. These reactions consisted of erythema, pruritus, and hypotension and occurred within hours of administration of chemotherapy. These events required medical intervention in some patients.
Both sexually active men and women should use effective methods of contraception during treatment.
There are no adequate data on the use of aldesleukin in pregnant women.
Experimental animal studies are insufficient to assess the safety with respect to reproduction, development of the embryo or foetus, the course of gestation and peri- and postnatal development. Proleukin has been shown to have embryolethal and maternal toxic effects in rats (see also section 5.3).
The potential risk for humans is unknown.
Proleukin should not be used during pregnancy unless the potential benefit to the patient justifies the potential risk to the foetus.
It is not known whether this drug is excreted in human milk.
Because the potential for serious adverse reactions in nursing infants is unknown, mothers should not breast feed their infants during treatment.
Proleukin may affect central nervous system function. Hallucination, somnolence, syncope, convulsions may occur during treatment with Proleukin and may affect the patient’s ability to drive and operate machines.
Patients should not drive or operate machines until they have recovered from the adverse drug reactions.
Frequency and severity of adverse reactions to Proleukin have generally been shown to be dependent on route of administration, dose and schedule.
Most adverse reactions are self-limited and might reverse within 1 to 2 days of discontinuation of therapy. The rate of treatment-related deaths in the 255 metastatic RCC patients who received single-agent Proleukin was 4% (11/255). In patients on subcutaneous treatment less than 1% died of treatment related adverse reactions.
Adverse reactions (Table 1) are ranked under headings of frequency, the most frequent first, 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).
The following adverse drug reactions were reported from clinical studies and from post-marketing experience with Proleukin.
Table 1:
Common: Respiratory tract infection, sepsis.
Very common: Anaemia, thrombocytopenia.
Common: Leucopenia, coagulopathy including disseminated intravascular coagulation, eosinophilia.
Uncommon: Neutropenia.
Rare: Agranulocytosis, aplastic anaemia, haemolytic anaemia, neutropenic fever.
Uncommon: Hypersensitivity reactions.
Rare: Anaphylaxis.
Very common: Hypothyroidism.
Common: Hyperthyroidism.
Very common: Anorexia.
Common: Acidosis, hyperglycaemia, hypocalcaemia, hypercalcaemia, hyperkalaemia, dehydration, hyponatraemia, hypophosphatemia.
Uncommon: Hypoglycaemia.
Rare: Diabetes mellitus.
Very common: Anxiety, confusion, depression, insomnia.
Common: Irritability, agitation, hallucinations.
Very common: Dizziness, headache, paraesthesia, somnolence.
Common: Neuropathy, syncope, speech disorders, taste loss, lethargy.
Uncommon: Coma, convulsions, paralysis, myasthenia.
Not known: Intracranial/cerebral haemorrhage, cerebrovascular accident, leukoencephalopathy (see additional information below the table).
Common: Conjunctivitis.
Rare: Optic nerve disorder including optic neuritis.
Very common: Tachycardia, arrhythmia, chest pain.
Common: Cyanosis, transient ECG changes, myocardial ischaemia, palpitations, cardiovascular disorders including cardiac failure.
Uncommon: Myocarditis, cardiomyopathy, cardiac arrest, pericardial effusion.
Rare: Ventricular hypokinesia.
Not known: Cardiac tamponade.
Very common: Hypotension.
Common: Phlebitis, hypertension.
Uncommon: Thrombosis, thrombophlebitis, haemorrhage.
Very common: Dyspnoea, cough.
Common: Pulmonary oedema, pleural effusions, hypoxia, haemoptysis, epistaxis, nasal congestion, rhinitis.
Rare: Pulmonary embolism, adult respiratory distress syndrome.
Very common: Nausea with or without vomiting, diarrhea, stomatitis.
Common: Dysphagia, dyspepsia, constipation, gastrointestinal bleeding including rectal haemorrhage, haematemesis, ascitis, cheilitis, gastritis.
Uncommon: Pancreatitis, intestinal obstruction, gastrointestinal perforation including necrosis/gangrene.
Rare: Activation of quiescent Crohn’s disease.
Common: Elevation of hepatic transaminases, elevation of alkaline phosphatase, elevation of lactic dehydrogenase, hyperbilirubinaemia, hepatomegaly or hepatosplenomegaly.
Rare: Cholecystitis, liver failure with fatal outcome.
Very common: Erythema and rash, exfoliative dermatitis, pruritus, sweating.
Common: Alopecia, urticaria.
Uncommon: Vitiligo, Quincke’s oedema.
Rare: Vesiculobullous rash, Stevens-Johnson syndrome.
Common: Myalgia, arthralgia.
Uncommon: Myopathy, myositis.
Not known: Rhabdomyolysis.
Very common: Oliguria, serum urea increased, serum creatinine increased.
Common: Haematuria, renal failure, anuria.
Very common: Injection site reaction*, injection site pain*, injection site inflammation*, fever with or without chills, malaise asthenia and fatigue, pain, oedema, weight gain, weight loss.
Common: Mucositis, injection site nodule, hypothermia, influenza like illness.
Rare: Injection site necrosis.
Notes:
* Frequency of injection site reaction, pain and inflammation is less following administration by continuous intravenous infusion.
There have been rare reports of leukoencephalopathy associated with Proleukin in the literature, mostly in patients treated for HIV infection. In some cases there were other risk factors like opportunistic infections, co-administration of interferons as well as multiple courses of chemotherapy that might predispose the treated population to such event.
Cardiac arrhythmias (supraventricular and ventricular), angina pectoris, myocardial infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, renal insufficiency, oedema and mental status changes may be associated with capillary leak syndrome (see section 4.4). The frequency and severity of capillary leak syndrome are lower after subcutaneous administration than with continuous intravenous infusion.
During treatment most patients experience lymphocytopenia and eosinophilia with a rebound lymphocytosis within 24 to 48 hours following treatment. These may be related to the mechanism of antitumour activity of Proleukin. Severe manifestations of eosinophilia have been reported, involving eosinophilic infiltration of cardiac and pulmonary tissues.
Cerebral vasculitis, both isolated and in combination with other manifestations, has been reported. Cutaneous and leukocytoplastic hypersensitivity vasculitis has been reported. Some of these cases are responsive to corticosteroids.
The following undesirable effects have been reported rarely in association with concurrent interferon alpha treatment: crescentic IgA glomerulonephritis, oculo-bulbar myasthenia gravis, inflammatory arthritis, thyroiditis, bullous pemphigoid and Stevens-Johnson syndrome. Severe rhabdomyolysis and myocardial injury, including myocardial infarction, myocarditis and ventricular hypokinesia appear to be increased in patients receiving Proleukin (intravenously) and interferon-alpha concurrently (see section 4.5).
Bacterial infection or exacerbation of bacterial infection, including septicaemia, bacterial endocarditis, septic thrombophlebitis, peritonitis, pneumonia, and local catheter site infection have been reported mainly after intravenous administration (see section 4.4).
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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Reconstitution and dilution procedures other than those recommended may result in incomplete delivery of bioactivity and/or formation of biologically inactive protein.
Use of Bacteriostatic Water for Injection or Sodium Chloride Injection 0.9% should be avoided because of increased aggregation.
Proleukin must not be mixed with other medicinal products except those mentioned in section 6.6.
It is recommended that devices or administration sets containing in-line filters are not used for delivery of Proleukin. Bioassays have shown significant loss of aldesleukin when filters are used.
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