PROLEUKIN

Proleukin should be administered intravenously by continuous infusion or by subcutaneous injection. The following dosage regimen is recommended to treat adult patients with metastatic renal cell carcinoma. Continuous intravenous infusion 18 x 106 IU per m2 per 24-hours is administered as a continuous infusion for 5 days, followed by 2-6 days without Proleukin therapy, an additional 5 days of intravenous Proleukin as a continuous infusion and 3 weeks without Proleukin therapy.

This constitutes one induction cycle. After the 3-weeks without Proleukin therapy period of the first cycle, a second induction cycle should be given.

Maintenance:

Up to four maintenance cycles (18 x 106 IU per m2 as continuous infusion for 5 days) may be given with 4-week intervals to patients who respond or have disease stabilization. ) injection is administered every day for 5 days, followed by 2 days without Proleukin therapy.

c. is administered on days 1 and 2 of each week followed by 9 x 106 IU on days 3-5. On days 6 and 7 no treatment is administered. After 1 week without Proleukin therapy this 4-week cycle should be repeated.

Maintenance:

The same cycle as described above may be given to patients who respond or have disease stabilisation. If a patient does not tolerate the recommended dosage regimen, the dose should be reduced or the administration interrupted until the toxicity has moderated.

It is not known to what extent dose reduction affects response rates and median survival. 4). Elderly patients No formal clinical trials were conducted to compare the pharmacokinetics, efficacy or safety of Proleukin in geriatric patients to those in younger patients.

There were a very small number of patients aged 65 and over in clinical trials of Proleukin. Clinicians should exercise caution in prescribing Proleukin to geriatric patients since decline in renal and hepatic function may occur with increasing age.

2). Paediatric population The safety and efficacy of Proleukin in children and in adolescents have not yet been established.

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 Infections and infestations Common: Respiratory tract infection, sepsis.

Blood and lymphatic system disorders Very common:

Anaemia, thrombocytopenia.

Common:

Leucopenia, coagulopathy including disseminated intravascular coagulation, eosinophilia.

Uncommon:

Neutropenia.

Rare:

Agranulocytosis, aplastic anaemia, haemolytic anaemia, neutropenic fever.

Immune system disorders Uncommon:

Hypersensitivity reactions.

Rare:

Anaphylaxis.

Endocrine disorders Very common:

Hypothyroidism.

Common:

Hyperthyroidism.

Metabolism and nutrition disorders Very common:

Anorexia.

Common:

Acidosis, hyperglycaemia, hypocalcaemia, hypercalcaemia, hyperkalaemia, dehydration.

Uncommon:

Hypoglycaemia.

Rare:

Diabetes mellitus.

Psychiatric disorders Very common:

Anxiety, confusion, depression, insomnia.

Common:

Irritability, agitation, hallucinations.

Nervous system disorders 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).

Eye disorders Common:

Conjunctivitis.

Rare:

Optic nerve disorder including optic neuritis.

Cardiac disorders 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.

Vascular disorders Very common:

Hypotension.

Common:

Phlebitis, hypertension.

Uncommon:

Thrombosis, thrombophlebitis, haemorrhage.

Respiratory, thoracic and mediastinal disorders Very common:

Dyspnoea, cough.

Common:

Pulmonary oedema, pleural effusions, hypoxia, haemoptysis, epistaxis, nasal congestion, rhinitis.

Rare:

Pulmonary embolism, adult respiratory distress syndrome.

Gastrointestinal disorders 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.

Hepatobiliary disorders Common:

Elevation of hepatic transaminases, elevation of alkaline phosphatase, elevation of lactic dehydrogenase, hyperbilirubinaemia, hepatomegaly or hepatosplenomegaly.

Rare:

Cholecystitis, liver failure with fatal outcome.

Skin and subcutaneous tissue disorders Very common:

Erythema and rash, exfoliative dermatitis, pruritus, sweating.

Common:

Alopecia, urticaria.

Uncommon:

Vitiligo, Quincke’s oedema.

Rare:

Vesiculobullous rash, Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders Common:

Myalgia, arthralgia.

Uncommon:

Myopathy, myositis.

Not known:

Rhabdomyolysis.

Renal and urinary disorders Very common:

Oliguria, serum urea increased, serum creatinine increased.

Common:

Haematuria, renal failure, anuria.

General disorders and administration site conditions 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.

Rare:

Injection site necrosis. Notes: * Frequency of injection site reaction, pain and inflammation is less following administration by continuous intravenous infusion. Leukoencephalopathy 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. 4). The frequency and severity of capillary leak syndrome are lower after subcutaneous administration than with continuous intravenous infusion.

Severe manifestations of eosinophilia 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 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 […]

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. 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: - A performance status of ECOG 1 or greater - More than one organ with metastatic disease sites - A period of <24 months between initial diagnosis of primary tumour and the date the patient is evaluated for Proleukin treatment.

Capillary leak syndrome 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. 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. Autoimmune disease 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.

Central nervous system effects 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. 5). Renal or hepatic impairment 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. 5). Close monitoring should be applied to all patients with pre-existing renal or hepatic impairment.

Precautions for use 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. 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. Effusion from serosal surfaces Proleukin may exacerbate effusions from serosal surfaces. g. pericardial effusions). Infections 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 […]

Proleukin therapy is contra-indicated in the following patients: 1. 1. 2. Patients with a performance status of ECOG ≥2*). 3. Patients with a simultaneous presence of a performance status of ECOG 1 or greater*) and more than one organ with metastatic disease sites and a period of <24 months between initial diagnosis of primary tumour and the date the patient is evaluated for Proleukin treatment.

4. Patients with a significant history or current evidence of severe cardiac disease. In questionable cases a stress test should be performed. 5. Patients with evidence of active infection requiring antibiotic therapy. 6. Patients with a PaO2 <60mm Hg during rest.

7. Patients with pre-existing severe major organ dysfunction. 8. Patients with Central Nervous System (CNS) metastases or seizure disorders, with the exception of patients with successfully treated brain metastases (negative computerized tomography (CT); neurologically stable).

In addition, it is recommended to exclude the following patients: 1. 000/mm3; hematocrit (HCT) <30%. 2. Patients with serum bilirubin and creatinine outside normal range. 3. Patients with organ allografts. 4. Patients who are likely to require corticosteroids.

5. Patients with pre-existing auto-immune disease. 1.