PROLEUKIN 18 x 106 IUPowder for solution for injection or in
白细胞介素2（阿地流律，白介-2）
英文名称：
Interleukin 2(T-Cell Growth,Factor,IL-2,Aldesleukin,Proleukin)
性状：
IL-2靠与IL-2受体特异结合而产生作用。IL-2的作用广泛，它是T淋巴细胞增殖分化所需的调控因子。IL-2对B细胞、NK细胞、抗体依赖性杀伤细胞和淋巴因子激活的杀伤细胞（LAK细胞）等具有促进分化增殖的作用，也为体外维持激活的T细胞克隆的增殖所必需。IL-2可刺激许多细胞因子的产生，在体内和体外均能增加肿瘤坏死因子、干扰素和白细胞介素的生成。目前，过继细胞治疗中所用的来自肿瘤的淋巴细胞-肿瘤浸润淋巴细胞（TIL细胞），需要IL-2才能在体外扩增。

作用与作用机制：
本品静脉给药，Cmaz与给药量呈正相关。静注后，肾脏分布最多，其次为血清、甲状腺、骨髓、脾脏、下颌下腺、肺、肝等。体内消除快，主要靠肾排泄。IL-2的消除呈二相，α相给t1/2为0.12-0.21,β相的t1/2为0.88-1.21h。大多数临床用药方案为连续输注或多次间断给药，还有用脂质体包裹IL-2和用IL-2与聚乙烯乙二醇的连接物，以延长IL-2的t1/2,增强肿瘤内免疫细胞的传递。腹腔内或皮下注射可使血中IL-2水平维持较久，达2-6h。

药动学：
IL-2的毒性反应多与血管通透性，即血管渗漏综合征（VLS）有关，并随IL-2剂量的增大而加剧，导致体液渗出而器管功能障碍，其中肾功能损害最为严重，主要表现为寒战、发热、皮肤瘙痒，消化道症状有恶心、呕吐、腹泻、高胆红素血症，谷丙转氨酶和血肌酐升高、水肿、少尿、低血压，其次为定向力障碍、贫血、血小板减少症，气通和肺功能异常，严重者出现支气管痉挛、肺水肿、呼吸困难和心率失常。对本品过敏或有对疫苗等生物制剂过敏史者禁用。过敏体质、心脏病患者、严重肝肾损害者慎用。

临床应用：
由于本品的应用尚处研究阶段，且不同药厂制剂的药量的表示法不一，故下面仅为参考剂量：每日静脉注射或静滴（6.7-11）×105U/m2，连续28d。

用法计量：
注射用冻干粉针剂。
美国产，每瓶含22百万单位（MU），供一次静注使用。

英国产，每毫克含18MU。

Proleukin category:
Human
Antineoplastic Agents
Active ingredients:
Aldesleukin
Proleukin forms, composition and dosages:
Injectable; IV (Infusion); Aldesleukin 18 MIU
Injectable; IV (Infusion); Aldesleukin 22 MIU
Indications, usages and classification codes:
L03AC01 - Aldesleukin

PROLEUKIN 18 x 106 IUPowder for solution for injection or in
1. NAME OF THE MEDICINAL PRODUCT
PROLEUKIN 18 x 106 IU
Powder for solution for injection or infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
After reconstitution with 1.2 ml water for injections, according to the instructions (see section 6.6), each 1 ml solution contains 18 x 106 IU (1.1 mg) aldesleukin.
Each vial of Proleukin powder for solution for injection or infusion contains 22 x 106 IU aldesleukin. Aldesleukin is produced by recombinant DNA technology using an Escherichia coli strain which contains a genetically engineered modification of the human Interleukin-2 (IL-2) gene.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder for solution for injection or infusion.
The powder is sterile, white and lyophilized.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of metastatic renal cell carcinoma.
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 eva luated for Proleukin treatment.
*) ECOG (Eastern Cooperative Oncology Group) 0 = normal activity, 1 = symptoms but ambulatory; 2 = in bed less than 50% of time; 3 = in bed more than 50% of time.
Response rates and median survival decrease with the number of risk factors present. Patients positive for all three risk factors should not be treated with Proleukin.
4.2 Posology and method of administration
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 as a continuous infusion for 5 days, followed by 2-6 days without active substance, an additional 5 days of intravenous Proleukin as a continuous infusion and 3 weeks without active substance. This constitutes one induction cycle. After the 3-week rest 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.
Subcutaneous injection
18 x 106 IU as subcutaneous (s.c.) injection every day for 5 days, followed by 2 days rest. For the following 3 weeks 18 x 106 IU s.c. 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 rest this 4-week cycle should be repeated.
Maintenance: Maintenance cycles as described above may be given to patients who respond or have disease stabilisation.
If a patient cannot 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.
Elderly:
Elderly patients may be more susceptible to the side effects of Proleukin and caution is recommended in the treatment of such patients.
Children:
Safety and efficacy of Proleukin in children have not yet been established.
4.3 Contraindications
Proleukin therapy is contra-indicated in the following patients:
1. Patients with hypersensitivity to the active substance or to any of the excipients.
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 eva luated 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 < 60 mm 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. Patients with White Blood Count (WBC) < 4.000/mm3; platelets < 100.000/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.
*) ECOG: see section 4.1.
4.4 Special warnings and precautions for use
Patient screening
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 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 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 eva luated for Proleukin treatment.
Warnings
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 and reduced organ perfusion. Severe CLS resulting in death has been reported. Capillary leak syndrome usually begins within hours after initiation of Proleukin treatment. The frequency and severity are lower after subcutaneous administration than with continuous intravenous infusion. In some patients hypotension resolves without therapy. In others, treatment is required with cautious use of intravenous fluids, albumin or, in more refractory cases, low-dose dopamine. If these measures are not successful, the Proleukin therapy should be interrupted.
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 secondary to capillary leakage.
Proleukin may exacerbate pre-existing autoimmune disease, resulting in life threatening complications. 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. A few patients with quiescent Crohn's disease had activation of their disease following treatment with Proleukin, requiring surgical intervention.
Proleukin administration should be discontinued in patients developing severe lethargy or somnolence; continued administration may result in coma.
Pulmonary function should be monitored closely in patients who develop rales or increased respiratory rate, or who complain of dyspnoea. Some patients may require intubation for management of transient respiratory failure. Intubation has only been reported for patients treated with intravenous Proleukin.
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).
Since Proleukin administration results in reversible elevation of hepatic transaminases, serum bilirubin, serum urea and serum creatinine, patients with pre-existing renal or hepatic dysfunction should be closely monitored. 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).
There is a possibility of disturbances in the glucose metabolism in diabetes patients when Proleukin is administered subcutaneously.
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.
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 disease symptoms in patients with clinically unrecognized or untreated CNS metastases. All patients should have adequate eva luation and treatment of CNS metastases prior to receiving Proleukin therapy.
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).
Baseline electrocardiogram (ECG) (+ stress test if indicated), performance status, vital signs, objective eva luation for coronary vascular disease and, in patients with a history of smoking or respiratory disease, pulmonary function tests with arterial blood gases are recommended as adjuncts to history and physical examination in the pre-treatment eva luation of patients.
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.
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.
Laboratory and clinical tests: 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:
- Standard haematologic tests– including WBC (with differential and platelet counts). Proleukin administration may cause anaemia and thrombocytopenia.

- Blood chemistry– including fluid and electrolyte balance, renal and hepatic function tests. Proleukin may cause renal dysfunction with oliguria, and reversible elevation of hepatic transaminases, serum bilirubin, serum urea and serum creatinine.
- Chest x-rays.
4.5 Interaction with other medicinal products and other forms of interaction
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. 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.
4.6 Pregnancy and lactation
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.
4.7 Effects on ability to drive and use machines
Proleukin causes adverse events that affect the ability to drive and operate machines.
Patients should not drive or operate machines until they have recovered from the undesirable effects.
4.8 Undesirable effects
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. A small number of patients receiving continuous intravenous infusion (3%) died of treatment related adverse reactions. 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.
Blood and lymphatic system disorders (see additional information below the table)*
Very common:	Anaemia, thrombocytopenia.
Common:	Leucopenia, coagulation disorders including disseminated intravascular coagulation.
Rare:	Agranulocytosis, aplastic anaemia, haemolytic anaemia.
Not known:	Neutropenia, neutropenic fever, eosinophilia (see additional information below the table).
Immune system disorders
Uncommon:	Hypersensitivity reactions.
Rare:	Anaphylaxis.
Endocrine disorders
Uncommon:	Hypothyroidism, hyperthyroidism
Metabolism and nutrition disorders
Very common:	Anorexia.
Common:	Hyperglycaemia, hypocalcaemia, hyperkalaemia, dehydration.
Uncommon:	Hypercalcaemia.
Rare:	Diabetes mellitus, hypoglycaemia.
Psychiatric disorders
Very common:	Anxiety, confusion.
Common:	Mental status changes including irritability, agitation, depression, hallucinations, insomnia.
Nervous system disorders
Very common:	Dizziness, headache, somnolence.
Common:	Nervous system disorder, not otherwise specified (including paraesthesia and neuropathy), syncope, speech disorders.
Uncommon:	Convulsions, paralysis, myasthenia, taste loss.
Rare:	Lethargy, coma, central nervous system lesion.
Not known:	Intracranial/cerebral haemorrhage, cerebrovascular accident, leukoencephalopathy (see additional information below the table).
Eye disorders
Common:	Conjunctivitis.
Rare:	Optic neuropathy.
Cardiac disorders
Very common:	Tachycardia; chest pain, angina pectoris.
Common:	Arrhythmia, cyanosis.
Uncommon:	Myocardial infarction, cardiovascular disorders including heart failure, myocarditis, transient ECG changes, cardiomyopathy, palpitations, myocardial ischaemia.
Rare:	Ventricular hypokinesia.
Not known:	Cardiac arrest, pericardial effusion, cardiac tamponade.
Vascular disorders
Very common:	Hypotension.
Common:	Phlebitis, hypertension.
Uncommon:	Thrombosis, haemorrhage.
Rare:	Thrombophlebitis.
Respiratory, thoracic and mediastinal disorders
Very common:	Dyspnoea, cough.
Common:	Pulmonary oedema, pleural effusions, hypoxia, nasal congestion.
Uncommon:	Haemoptysis, epistaxis.
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.
Uncommon:	Cheilitis, gastritis.
Rare:	Activation of quiescent Crohn's disease, pancreatitis, intestinal obstruction.
Not known:	Gastrointestinal perforation including necrosis/gangrene.
Hepatobiliary disorders
Common:	Elevation of hepatic transaminases and alkaline phosphatase, elevation of lactic dehydrogenase, hyperbilirubinaemia.
Rare:	Cholecystitis, liver failure with fatal outcome.
Skin and subcutaneous tissue disorders
Very common:	Erythema/rash, skin exfoliation, pruritus.
Common:	Sweating, alopecia.
Uncommon:	Vitiligo, Quincke's oedema.
Rare:	Vesiculobullous rash, Stevens-Johnson syndrome.
Musculoskeletal and connective tissue disorders
Common:	Myalgia, arthralgia.
Renal and urinary disorders
Very common:	Oliguria with elevated serum urea and serum creatinine.
Common:	Haematuria.
Uncommon:	Renal failure.
General disorders and administration site conditions
Very common:	Injection site reaction**, injection site pain**, injection site inflammation**, fever with or without chills, malaise and fatigue, pain, oedematous weight gain, weight loss.
Common:	Oedema, mucositis, injection site nodule, hypothermia.
Rare:	Injection site necrosis.