Proleukin Side Effects

Generic Name: aldesleukin

Please note - some side effects for Proleukin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Proleukin - for the Consumer

Proleukin

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Proleukin:

Anxiety; dizziness; general body discomfort; increased cough; infection; loss of appetite; pain; runny nose; weakness.

Seek medical attention right away if any of these SEVERE side effects occur when using Proleukin:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black stools; chest pain; chills; confusion; depression; diarrhea; drowsiness; fainting; fever; heart murmurs or gallops; infrequent urination or inability to urinate; irregular heartbeat; irritability; mood changes; nausea; pain, redness, or swelling at the injection site; pounding in the chest; redness of the tongue; reduced amount of urine; severe dizziness; severe lack of energy; sore throat; sores on the mouth or lips; stomach pain or protrusion; swelling; unusual bruising or bleeding; vomiting; weight gain.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Proleukin Side Effects - for the Professional

Proleukin

The rate of drug-related deaths in the 255 metastatic RCC patients who received single-agent Proleukin® (aldesleukin) was 4% (11/255); the rate of drug-related deaths in the 270 metastatic melanoma patients who received single-agent Proleukin was 2% (6/270).

The following data on common adverse events (reported in greater than 10% of patients, any grade), presented by body system, decreasing frequency and by preferred term (COSTART) are based on 525 patients (255 with renal cell cancer and 270 with metastatic melanoma) treated with the recommended infusion dosing regimen.

TABLE 3: ADVERSE EVENTS OCCURRING IN ≥10% OF PATIENTS (n=525)

Body System	% Patients	Body System	% Patients
Body as a Whole		Metabolic and Nutritional Disorders
Chills	52	Bilirubinemia	40
Fever	29	Creatinine increase	33
Malaise	27	Peripheral edema	28
Asthenia	23	SGOT increase	23
Infection	13	Weight gain	16
Pain	12	Edema	15
Abdominal pain	11	Acidosis	12
Abdomen enlarged	10	Hypomagnesemia	12
Cardiovascular		Hypocalcemia	11
Hypotension	71	Alkaline phosphatase increase	10
Tachycardia	23	Nervous
Vasodilation	13	Confusion	34
Supraventricular tachycardia	12	Somnolence	22
Cardiovascular disordera	11	Anxiety	12
Arrhythmia	10	Dizziness	11
Digestive		Respiratory
Diarrhea	67	Dyspnea	43
Vomiting	50	Lung disorderb	24
Nausea	35	Respiratory disorderc	11
Stomatitis	22	Cough increase	11
Anorexia	20	Rhinitis	10
Nausea and vomiting	19	Skin and Appendages
Hemic and Lymphatic		Rash	42
Thrombocytopenia	37	Pruritus	24
Anemia	29	Exfoliative dermatitis	18
Leukopenia	16	Urogenital
		Oliguria	63

a Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF.

b Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi.

c Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes.

The following data on life-threatening adverse events (reported in greater than 1% of patients, grade 4), presented by body system, and by preferred term (COSTART) are based on 525 patients (255 with renal cell cancer and 270 with metastatic melanoma) treated with the recommended infusion dosing regimen.

TABLE 4: LIFE-THREATENING (GRADE 4) ADVERSE EVENTS (n= 525)

Body System	# (%) Patients	Body System	# (%) Patients
Body as a Whole		Metabolic and Nutritional Disorders
Fever	5 (1%)	Bilirubinemia	13 (2%)
Infection	7 (1%)	Creatinine increase	5 (1%)
Sepsis	6 (1%)	SGOT increase	3 (1%)
Cardiovascular		Acidosis	4 (1%)
Hypotension	15 (3%)	Nervous
Supraventricular tachycardia	3 (1%)	Confusion	5 (1%)
Cardiovascular disordera	7 (1%)	Stupor	3 (1%)
Myocardial infarct	7 (1%)	Coma	8 (2%)
Ventricular tachycardia	5 (1%)	Psychosis	7 (1%)
Cardiac arrest	4 (1%)	Respiratory
Digestive		Dyspnea	5 (1%)
Diarrhea	10 (2%)	Respiratory disorderc	14 (3%)
Vomiting	7 (1%)	Apnea	5 (1%)
Hemic and Lymphatic		Urogenital
Thrombocytopenia	5 (1%)	Oliguria	33 (6%)
Coagulation disorderb	4 (1%)	Anuria	25 (5%)
		Acute kidney failure	3 (1%)

a Cardiovascular disorder: fluctuations in blood pressure.

b Coagulation disorder: intravascular coagulopathy.

c Respiratory disorder: ARDS, respiratory failure, intubation.

The following life-threatening (grade 4) events were reported by <1% of the 525 patients: hypothermia; shock; bradycardia; ventricular extrasystoles; myocardial ischemia; syncope; hemorrhage; atrial arrhythmia; phlebitis; AV block second degree; endocarditis; pericardial effusion; peripheral gangrene; thrombosis; coronary artery disorder; stomatitis; nausea and vomiting; liver function tests abnormal; gastrointestinal hemorrhage; hematemesis; bloody diarrhea; gastrointestinal disorder; intestinal perforation; pancreatitis; anemia; leukopenia; leukocytosis; hypocalcemia; alkaline phosphatase increase; BUN increase; hyperuricemia; NPN increase; respiratory acidosis; somnolence; agitation; neuropathy; paranoid reaction; convulsion; grand mal convulsion; delirium; asthma, lung edema; hyperventilation; hypoxia; hemoptysis; hypoventilation; pneumothorax; mydriasis; pupillary disorder; kidney function abnormal; kidney failure; acute tubular necrosis.

In an additional population of greater than 1,800 patients treated with Proleukin-based regimens using a variety of doses and schedules (e.g., subcutaneous, continuous infusion, administration with LAK cells) the following serious adverse events were reported: duodenal ulceration; bowel necrosis; myocarditis; supraventricular tachycardia; permanent or transient blindness secondary to optic neuritis; transient ischemic attacks; meningitis; cerebral edema; pericarditis; allergic interstitial nephritis; tracheo-esophageal fistula.

In the same clinical population, the following fatal events each occurred with a frequency of <1%: malignant hyperthermia; cardiac arrest; myocardial infarction; pulmonary emboli; stroke; intestinal perforation; liver or renal failure; severe depression leading to suicide; pulmonary edema; respiratory arrest; respiratory failure. In patients with both metastatic RCC and metastatic melanoma, those with ECOG PS of 1 or higher had a higher treatment-related mortality and serious adverse events.

Most adverse reactions are self-limiting and, usually, but not invariably, reverse or improve within 2 or 3 days of discontinuation of therapy. Examples of adverse reactions with permanent sequelae include: myocardial infarction, bowel perforation/infarction, and gangrene.

Immunogenicity

Fifty-seven of 77 (74%) metastatic renal cell carcinoma patients treated with an every 8-hour Proleukin regimen and 33 of 50 (66%) metastatic melanoma patients treated with a variety of IV regimens developed low titers of non-neutralizing anti-Proleukin antibodies. Neutralizing antibodies were not detected in this group of patients, but have been detected in 1/106 (<1%) patients treated with IV Proleukin using a wide variety of schedules and doses. The clinical significance of anti-Proleukin antibodies is unknown.

Post Marketing Experience

The following adverse reactions have been identified during post-approval use of Proleukin.  Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Blood and lymphatic system: neutropenia, febrile neutropenia, eosinophilia, lymphocytopenia
• Cardiac: cardiomyopathy, cardiac tamponade
• Endocrine: hyperthyroidism
• Gastrointestinal: gastritis, intestinal obstruction, colitis
• General and administration site conditions: injection site necrosis
• Hepatobiliary: hepatitis, hepatosplenomegaly, cholecystitis
• Immune system: anaphylaxis, angioedema, urticaria
• Infections and infestations: pneumonia (bacterial, fungal, viral), fatal endocarditis, cellulitis
• Musculoskeletal and connective tissue: myopathy, myositis, rhabdomyolysis
• Nervous system: cerebral lesions, encephalopathy, extrapyramidal syndrome, neuralgia, neuritis, demyelinating neuropathy
• Psychiatric: insomnia
• Vascular: hypertension, fatal subdural and subarachnoid hemorrhage, cerebral hemorrhage, retroperitoneal hemorrhage

Exacerbation or initial presentation of a number of autoimmune and inflammatory disorders have been reported. Persistent but nonprogressive vitiligo has been observed in malignant melanoma patients treated with interleukin-2. Synergistic, additive and novel toxicities have been reported with Proleukin used in combination with other drugs. Novel toxicities include delayed adverse reactions to iodinated contrast media and hypersensitivity reactions to antineoplastic agents.

Experience has shown the following concomitant medications to be useful in the management of patients on Proleukin therapy: a) standard antipyretic therapy, including nonsteroidal anti-inflammatories (NSAIDs), started immediately prior to Proleukin to reduce fever. Renal function should be monitored as some NSAIDs may cause synergistic nephrotoxicity; b) meperidine used to control the rigors associated with fever; c) H2 antagonists given for prophylaxis of gastrointestinal irritation and bleeding; d) antiemetics and antidiarrheals used as needed to treat other gastrointestinal side effects. Generally these medications were discontinued 12 hours after the last dose of Proleukin.

Patients with indwelling central lines have a higher risk of infection with gram positive organisms.9-11 A reduced incidence of staphylococcal infections in Proleukin studies has been associated with the use of antibiotic prophylaxis which includes the use of oxacillin, nafcillin, ciprofloxacin, or vancomycin. Hydroxyzine or diphenhydramine has been used to control symptoms from pruritic rashes and continued until resolution of pruritus. Topical creams and ointments should be applied as needed for skin manifestations. Preparations containing a steroid (e.g., hydrocortisone) should be avoided. NOTE: Prior to the use of any product mentioned, the physician should refer to the package insert for the respective product.

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Side Effects by Body System - for Healthcare Professionals

Cardiovascular

Cardiovascular side effects from aldesleukin have been reported. Many of the adverse cardiovascular events from aldesleukin result from a capillary or vascular leak syndrome. Shifting of fluid into the interstitial spaces results in hypotension, tachycardia, and sometimes congestive heart failure, or myocardial infarction. Besides the vascular leak syndrome and hypotension, direct effects on the myocardium have been noted. These effects include hemodynamic changes as well as myocardial injury with creatine phosphokinase (CPK) elevations and myocarditis secondary to lymphocyte infiltration.

Hypotension resulting from aldesleukin-induced capillary leak syndrome should be managed with careful fluid administration and institution of low-dose dopamine infusions.

Respiratory

Respiratory side effects including respiratory distress resulting from fluid weight gain attributed to the vascular leak syndrome has been reported. Other respiratory effects reported include dyspnea, pulmonary congestion with rales and rhonchi, unspecified pulmonary changes with infiltrates on X-ray, increased cough, and rhinitis.

Nervous system

Nervous system side effects including both acute and chronic neurologic and neuropsychiatric findings have been reported during aldesleukin administration. Patients receiving high-dose therapy have been reported to have become agitated, disoriented, and sometimes comatose. These effects have typically resolved upon discontinuation of the drug. Neuropsychiatric effects including a decrease in cognitive function and memory impairment have been reported in patients receiving continuous-infusion aldesleukin therapy.

Renal

Renal damage attributed to aldesleukin results from the decrease in vascular resistance. Low-dose dopamine helps maintain adequate renal perfusion during aldesleukin therapy and may decrease the incidence of renal failure.

Renal side effects including oliguria and anuria are the predominant adverse events that have been reported in the majority of patients. Acute kidney failure with an increase in creatinine has been reported in 1% of patients.

Hepatic

Hepatic side effects reported with aldesleukin therapy include bilirubinemia, SGOT increase, and alkaline phosphatase increase and hepatosplenomegaly.

Hematologic

Hematopoietic side effects which have been reported include anemia, thrombocytopenia, and leukopenia.

Gastrointestinal

Antiemetics and antidiarrheals are helpful in treating the gastrointestinal side effects and H2-antagonists are often given for prophylaxis of gastrointestinal irritation and bleeding. Mucositis requires diligent oral care, including sodium bicarbonate mouthwashes and nystatin.

Gastrointestinal side effects have included nausea, vomiting, diarrhea, and mucositis. Colon dilatation, perforation, and ischemic necrosis have also been reported but are uncommon.

Dermatologic

Rashes have been treated with either hydroxyzine or diphenhydramine, which can be continued until resolution of the rash. Nonalcoholic-based creams and ointments as well as aloe vera gels may also be applied to skin conditions. Application may begin as early as 48 hours before treatment. Preparations containing steroids should be avoided.

Dermatologic side effects such as erythema, pruritus, and generalized erythroderma have been reported with aldesleukin therapy. In patients with preexisting dermatologic conditions such as psoriasis, exacerbation of the underlying condition has been reported.

General

Meperidine may be helpful for the chills and rigors associated with this flu-like syndrome. Scheduled nonsteroidal anti-inflammatory drugs like acetaminophen and indomethacin can substantially relieve the other symptoms.

General side effects including a flu-like syndrome have been reported in patients receiving aldesleukin. Symptoms include fever, chills, rigors, joint pain, myalgias, malaise, and anorexia.

Other

Other side effects including infection have been reported with aldesleukin treatment (which may be due to the initial drop in lymphocyte levels).

Endocrine

Endocrine side effects including hypothyroidism and hyperthyroidism have been reported with aldesleukin therapy.

Metabolic

Metabolic side effects seen with aldesleukin treatment have included acidosis, hypomagnesemia, hypocalcemia, and hyperuricemia.

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