Proleukin
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Questions & Answers
Side Effects & Adverse Reactions
See boxed “WARNINGS”
Because of the severe adverse events which generally accompany PROLEUKIN® (aldesleukin) therapy at the recommended dosages, thorough clinical evaluation should be performed to identify patients with significant cardiac, pulmonary, renal, hepatic, or CNS impairment in whom PROLEUKIN is contraindicated. Patients with normal cardiovascular, pulmonary, hepatic, and CNS function may experience serious, life threatening or fatal adverse events. Adverse events are frequent, often serious, and sometimes fatal.
Should adverse events, which require dose modification occur, dosage should be withheld rather than reduced (see “DOSAGE AND ADMINISTRATION” section, “Dose Modifications” subsection).
PROLEUKIN has been associated with exacerbation of pre-existing or initial presentation of autoimmune disease and inflammatory disorders. Exacerbation of Crohn’s disease, scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome and bullous pemphigoid, has been reported following treatment with IL-2.
All patients should have thorough evaluation and treatment of CNS metastases and have a negative scan prior to receiving PROLEUKIN therapy. New neurologic signs, symptoms, and anatomic lesions following PROLEUKIN therapy have been reported in patients without evidence of CNS metastases. Clinical manifestations included changes in mental status, speech difficulties, cortical blindness, limb or gait ataxia, hallucinations, agitation, obtundation, and coma. Radiological findings included multiple and, less commonly, single cortical lesions on MRI and evidence of demyelination. Neurologic signs and symptoms associated with PROLEUKIN therapy usually improve after discontinuation of PROLEUKIN therapy; however, there are reports of permanent neurologic defects. One case of possible cerebral vasculitis, responsive to dexamethasone, has been reported. In patients with known seizure disorders, extreme caution should be exercised as PROLEUKIN may cause seizures.
Legal Issues
There is currently no legal information available for this drug.
FDA Safety Alerts
There are currently no FDA safety alerts available for this drug.
Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
PROLEUKIN® (aldesleukin) is indicated for the treatment of adults with metastatic renal cell carcinoma (metastatic RCC).
PROLEUKIN is indicated for the treatment of adults with metastatic melanoma.
Careful patient selection is mandatory prior to the administration of PROLEUKIN. See “CONTRAINDICATIONS”, “WARNINGS” and “PRECAUTIONS” sections regarding patient screening, including recommended cardiac and pulmonary function tests and laboratory tests.
Evaluation of clinical studies to date reveals that patients with more favorable ECOG performance status (ECOG PS 0) at treatment initiation respond better to PROLEUKIN, with a higher response rate and lower toxicity (see “CLINICAL PHARMACOLOGY” section, “Clinical Experience” subsection and “ADVERSE REACTIONS” section). Therefore, selection of patients for treatment should include assessment of performance status.
Experience in patients with ECOG PS >1 is extremely limited.
History
There is currently no drug history available for this drug.
Other Information
PROLEUKIN® (aldesleukin) for injection, a human recombinant interleukin-2 product, is a highly purified protein with a molecular weight of approximately 15,300 daltons. The chemical name is des-alanyl-1, serine-125 human interleukin-2. PROLEUKIN, a lymphokine, is produced by recombinant DNA technology using a genetically engineered E. coli strain containing an analog of the human interleukin-2 gene. Genetic engineering techniques were used to modify the human IL-2 gene, and the resulting expression clone encodes a modified human interleukin-2. This recombinant form differs from native interleukin-2 in the following ways: a) PROLEUKIN is not glycosylated because it is derived from E. coli ; b) the molecule has no N-terminal alanine; the codon for this amino acid was deleted during the genetic engineering procedure; c) the molecule has serine substituted for cysteine at amino acid position 125; this was accomplished by site specific manipulation during the genetic engineering procedure; and d) the aggregation state of PROLEUKIN is likely to be different from that of native interleukin-2.
The in vitro biological activities of the native nonrecombinant molecule have been reproduced with PROLEUKIN.1,2
PROLEUKIN is supplied as a sterile, white to off-white, lyophilized cake in single-use vials intended for intravenous (IV) administration. When reconstituted with 1.2 mL Sterile Water for Injection, USP, each mL contains 18 million IU (1.1 mg) PROLEUKIN, 50 mg mannitol, and 0.18 mg sodium dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic sodium phosphate to a pH of 7.5 (range 7.2 to 7.8). The manufacturing process for PROLEUKIN involves fermentation in a defined medium containing tetracycline hydrochloride. The presence of the antibiotic is not detectable in the final product. PROLEUKIN contains no preservatives in the final product.
PROLEUKIN biological potency is determined by a lymphocyte proliferation bioassay and is expressed in International Units (IU) as established by the World Health Organization 1st International Standard for Interleukin-2 (human). The relationship between potency and protein mass is as follows:
18 million (18 x 106) IU PROLEUKIN = 1.1 mg protein
Sources
Proleukin Manufacturers
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Novartis Pharmaceuticals Corporation
![Proleukin (Aldesleukin) Injection [Novartis Pharmaceuticals Corporation]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Proleukin | Novartis Pharmaceuticals Corporation
The recommended PROLEUKIN® (aldesleukin) for injection treatment regimen is administered by a 15-minute IV infusion every 8 hours. Before initiating treatment, carefully review the “INDICATIONS AND USAGE”, “CONTRAINDICATIONS”, “WARNINGS”, “PRECAUTIONS”, and “ADVERSE REACTIONS” sections, particularly regarding patient selection, possible serious adverse events, patient monitoring and withholding dosage. The following schedule has been used to treat adult patients with metastatic renal cell carcinoma (metastatic RCC) or metastatic melanoma. Each course of treatment consists of two 5-day treatment cycles separated by a rest period.
600,000 IU/kg (0.037 mg/kg) dose administered every 8 hours by a 15-minute IV
Retreatment
infusion for a maximum of 14 doses. Following 9 days of rest, the schedule is
repeated for another 14 doses, for a maximum of 28 doses per course, as tolerated.
During clinical trials, doses were frequently withheld for toxicity (see “Clinical
Experience” and “Dose Modifications” subsections). Metastatic RCC patients
treated with this schedule received a median of 20 of the 28 doses during the first
course of therapy. Metastatic melanoma patients received a median of 18 doses
during the first course of therapy.Patients should be evaluated for response approximately 4 weeks after completion of a course of therapy and again immediately prior to the scheduled start of the next treatment course. Additional courses of treatment should be given to patients only if there is some tumor shrinkage following the last course and retreatment is not contraindicated (see “CONTRAINDICATIONS” section). Each treatment course should be separated by a rest period of at least 7 weeks from the date of hospital discharge.
Dose ModificationsDose modification for toxicity should be accomplished by withholding or interrupting a dose rather than reducing the dose to be given. Decisions to stop, hold, or restart PROLEUKIN therapy must be made after a global assessment of the patient. With this in mind, the following guidelines should be used:
Retreatment with PROLEUKIN is contraindicated in patients who have experienced the following toxicities:
Body System Cardiovascular Sustained ventricular tachycardia (≥5 beats) Cardiac rhythm disturbances not controlled or unresponsive to management Chest pain with ECG changes, consistent with angina or myocardial infarction Cardiac tamponade Respiratory Intubation for >72 hours Urogenital Renal failure requiring dialysis >72 hours Nervous Coma or toxic psychosis lasting >48 hours Repetitive or difficult to control seizures Digestive Bowel ischemia/perforation GI bleeding requiring surgeryDoses should be held and restarted according to the following:
Body System Hold dose for Subsequent doses may be given if Cardiovascular Atrial fibrillation, supraventricular tachycardia or bradycardia that requires treatment or is recurrent or persistent Patient is asymptomatic with full recovery to normal sinus rhythm Systolic bp <90 mm Hg with increasing requirements for pressors Systolic bp ≥90 mm Hg and stable or improving requirements for pressors Any ECG change consistent with MI, ischemia or myocarditis with or without chest pain; suspicion of cardiac ischemia Patient is asymptomatic, MI and myocarditis have been ruled out, clinical suspicion of angina is low; there is no evidence of ventricular hypokinesia Respiratory O2 saturation <90% O2 saturation >90% Nervous Mental status changes, including moderate confusion or agitation Mental status changes completely resolved Body as a Whole Sepsis syndrome, patient is clinically unstable Sepsis syndrome has resolved, patient is clinically stable, infection is under treatment Urogenital Serum creatinine >4.5 mg/dL or a serum creatinine of ≥4 mg/dL in the presence of severe volume overload, acidosis, or hyperkalemia Serum creatinine <4 mg/dL and fluid and electrolyte status is stable Persistent oliguria, urine output of <10 mL/hour for 16 to 24 hours with rising serum creatinine Urine output >10 mL/hour with a decrease of serum creatinine >1.5 mg/dL or normalization of serum creatinine Digestive Signs of hepatic failure including encephalopathy, increasing ascites, liver pain, hypoglycemia All signs of hepatic failure have resolved* Stool guaiac repeatedly >3-4+ Stool guaiac negative Skin Bullous dermatitis or marked worsening of pre-existing skin condition, avoid topical steroid therapy Resolution of all signs of bullous dermatitis * Discontinue all further treatment for that course. A new course of treatment, if warranted, should be initiated no sooner than 7 weeks after cessation of adverse event and hospital discharge.Reconstitution and Dilution Directions: Reconstitution and dilution procedures other than those recommended may alter the delivery and/or pharmacology of PROLEUKIN and thus should be avoided.
1. PROLEUKIN® (aldesleukin) is a sterile, white to off-white, preservative-free, lyophilized powder suitable for IV infusion upon reconstitution and dilution. EACH VIAL CONTAINS 22 MILLION IU (1.3 MG) OF PROLEUKIN AND SHOULD BE RECONSTITUTED ASEPTICALLY WITH 1.2 ML OF STERILE WATER FOR INJECTION, USP. WHEN RECONSTITUTED AS DIRECTED, EACH ML CONTAINS 18 MILLION IU (1.1 MG) OF PROLEUKIN. The resulting solution should be a clear, colorless to slightly yellow liquid. The vial is for single-use only and any unused portion should be discarded.
2. During reconstitution, the Sterile Water for Injection, USP should be directed at the side of the vial and the contents gently swirled to avoid excess foaming. DO NOT SHAKE.
3. The dose of PROLEUKIN, reconstituted with Sterile Water for Injection, USP (without preservative) should be diluted aseptically in 50 mL of 5% Dextrose Injection, USP (D5W) and infused over a 15-minute period.
In cases where the total dose of PROLEUKIN is 1.5 mg or less (e.g., a patient with a body weight of less than 40 kilograms), the dose of PROLEUKIN should be diluted in a smaller volume of D5W. Concentrations of PROLEUKIN below 30 µg/mL and above 70 µg/mL have shown increased variability in drug delivery. Dilution and delivery of PROLEUKIN outside of this concentration range should be avoided.
4. Glass bottles and plastic (polyvinyl chloride) bags have been used in clinical trials with comparable results. It is recommended that plastic bags be used as the dilution container since experimental studies suggest that use of plastic containers results in more consistent drug delivery. In-line filters should not be used when administering PROLEUKIN.
5. Before and after reconstitution and dilution, store in a refrigerator at 2° to 8°C (36° to 46°F). Do not freeze. Administer PROLEUKIN within 48 hours of reconstitution. The solution should be brought to room temperature prior to infusion in the patient.
6. Reconstitution or dilution with Bacteriostatic Water for Injection, USP, or 0.9% Sodium Chloride Injection, USP should be avoided because of increased aggregation. PROLEUKIN should not be coadministered with other drugs in the same container.
7. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
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Prometheus Laboratories Inc.
Proleukin | Actavis Pharma, Inc.
2.1 Adult HypertensionThe recommended starting dose of valsartan tablets is 80 mg or 160 mg once daily when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions may be started at the higher dose. Valsartan tablets may be used over a dose range of 80 mg to 320 mg daily, administered once a day.
The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks. If additional antihypertensive effect is required over the starting dose range, the dose may be increased to a maximum of 320 mg or a diuretic may be added. Addition of a diuretic has a greater effect than dose increases beyond 80 mg.
No initial dosage adjustment is required for elderly patients, for patients with mild or moderate renal impairment, or for patients with mild or moderate liver insufficiency. Care should be exercised with dosing of valsartan tablets in patients with hepatic or severe renal impairment.
Valsartan tablets may be administered with other antihypertensive agents.
Valsartan tablets may be administered with or without food.
2.2 Pediatric Hypertension 6 to 16 Years of AgeFor children who can swallow tablets, the usual recommended starting dose is 1.3 mg/kg once daily (up to 40 mg total). The dosage should be adjusted according to blood pressure response. Doses higher than 2.7 mg/kg (up to 160 mg) once daily have not been studied in pediatric patients 6 to 16 years old.
For children who cannot swallow tablets, or children for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths of valsartan, the use of a suspension is recommended. Follow the suspension preparation instructions below (see Preparation of Suspension) to administer valsartan as a suspension. When the suspension is replaced by a tablet, the dose of valsartan may have to be increased. The exposure to valsartan with the suspension is 1.6 times greater than with the tablet.
No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate less than 30 mL/min/1.73 m2[see Pediatric Use (8.4)].
Valsartan tablets are not recommended for patients less than 6 years old see Adverse Reactions (6.1), Clinical Studies (14.1)].
Preparation of Suspension (for 160 mL of a 4 mg/mL suspension)
Add 80 mL of Ora-Plus®* oral suspending vehicle to an amber glass bottle containing 8 valsartan 80 mg tablets, and shake for a minimum of 2 minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of 1 additional minute. Add 80 mL of Ora-Sweet SF®* oral sweetening vehicle to the bottle and shake the suspension for at least 10 seconds to disperse the ingredients. The suspension is homogenous and can be stored for either up to 30 days at room temperature (below 30ºC/86ºF) or up to 75 days at refrigerated conditions (2° to 8°C/35° to 46°F) in the glass bottle with a child-resistant screw-cap closure. Shake the bottle well (at least 10 seconds) prior to dispensing the suspension.
*Ora-Sweet SF® and Ora-Plus® are registered trademarks of Paddock Laboratories, Inc.
2.3 Heart FailureThe recommended starting dose of valsartan tablets is 40 mg twice daily. Uptitration to 80 mg and 160 mg twice daily should be done to the highest dose, as tolerated by the patient. Consideration should be given to reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical trials is 320 mg in divided doses.
![Proleukin (Aldesleukin) Injection, Powder, Lyophilized, For Solution [Prometheus Laboratories Inc.]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=73733526-aed1-6da2-272b-0921b4b5c160&name=valsartan-tablets-10.jpg)
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