proleukin rnmt zion last revision

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Proleukin® (aldesleukin for injection)for High-Dose I.V. Bolus Administration

Clinical Practice Guide

Rusti Portillas, MSN, RN, Duke University- Doctor of Nursing PracticePLK-900136

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Disclaimer

This presentation contains specific guidelines relating to administering Proleukin, and criteria for delaying or discontinuing Proleukin, which may or may not be included in or differ from the Proleukin prescribing information. The Proleukin prescribing information is included with this presentation and also provided to you at the time of this presentation.

This presentation is not all-encompassing of medical practice and should not replace medical care or clinical judgment for individual patient care.

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*For questions regarding Proleukin, please call the NOVARTIS Pharmaceuticals Proleukin Hotline at 1-866-9PROLEUKIN (977-6538).

Objectives

• To review the FDA-approved indications for the administration of high-dose bolus Proleukin therapy*

• To review Proleukin prescribing information with health professionals

• To review physiologic side effects

– Tolerability– Safety

• To discuss practice guidelines for managing high-dose (HD) interleukin-2 (IL-2) patients

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What Is Proleukin?

• IL-2 is one of a group of cytokines that mediate signals between cells during an immune response

• Can invoke an anti-tumor response in some patients

• Proleukin is a recombinant form of IL-2

• Proleukin (i.e., recombinant IL-2, or rIL-2) helps the immune system fight cancer cells by causing widespread immune activation

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Indications for Proleukin

• The FDA-approved indications for IV bolus Proleukin therapy in adult patients are:

– Metastatic renal cell carcinoma (mRCC) (approved in 1992)– Metastatic melanoma (mM) (approved in 1998)

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Why Proleukin?

• Proleukin may induce a durable, complete response1,2

• Overall response rates (complete responses + partial responses; CR+PR) of 15% to 16% have been obtained with Proleukin therapy3

• Proleukin is the ONLY approved therapy that has shown a complete and durable response in mRCC or mM

• mRCC and mM patients may be candidates for front-line bolus Proleukin if they have normal organ function and are otherwise healthy (Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0 or 1)

1. Fisher et al. Cancer J Sci Am. 2000;6(suppl 1):S55-S57. 2. Atkins et al. Cancer J Sci Am. 2000;6(suppl 1):S11-S14. 3. Proleukin prescribing information. Novartis Pharmaceuticals Corporation.

Please see important safety information on slide 13 and full prescribing information, including boxed warning, on slides 55-56

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Pharmacokinetics of Proleukin

• Distribution half-life is 13 minutes, and the elimination half-life is 85 minutes after a5-minute IV infusion

• Biological effects resulting from a series of cellular responses and cytokine release do not peak until several hours after initial exposure to IL-2

Proleukin prescribing information. Novartis Pharmaceuticals Corporation

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Treatment Regimen

• Administer Proleukin at a dose of 600,000 IU/kg every 8 hours by a 15-minute IV infusion for a maximum of 14 doses (1 cycle)

• Following 9 days of rest, repeat the treatment cycle for another 14 doses for a maximum of 28 doses per course

• Administer Proleukin as tolerated. Dosage modifications should be made by holding a dose or discontinuing treatment for that cycle

• Decision to discontinue, hold, or restart Proleukin therapy must be made after a global patient assessment

• 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


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Treatment Regimen (cont)

1 Course of Treatment

5 daysCycle 1

9 days 5 daysCycle 2

rIL-2 600,000 IU/kg

q8h by 15-min infusionfor a maximum

of 14 doses

Maximum number of doses per course: 28

rIL-2 600,000 IU/kg

q8h by 15-min infusion

for a maximum of 14 doses

REST


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Drug Interactions• Proleukin may affect the CNS, so interactions could occur following concomitant

administration of psychotropic drugs

• Concomitant administration of drugs with nephrotoxic, cardiotoxic, myelotoxic or hepatotoxic effects with Proleukin may increase toxicity in these organ systems

• Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high-dose Proleukin and antineoplastic agents

• Reduced kidney and liver function secondary to Proleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs

• Myocardial injury appears to be increased in patients receiving Proleukin and IFN-alpha concurrently

• Exacerbation or initial presentation of several autoimmune and inflammatory disorders has been observed following concurrent use of IFN-alpha and Proleukin

• Concomitant administration of glucocorticoids with Proleukin should be avoided (may reduce antitumor effectiveness)

• Beta-blockers and other antihypertensives may potentiate hypotension seen with Proleukin

Abridged from Proleukin prescribing information. Novartis Pharmaceuticals Corporation.

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Proleukin Side Effects: Physiologic Categories

• Flu-like • Hepatic (constitutional symptoms)

• Capillary leak syndrome • Neurologic(CLS)

• Cardiovascular • Dermatologic

• Pulmonary • Hematologic

• Renal • Metabolic

• Gastrointestinal

Proleukin prescribing information. Novartis Pharmaceuticals Corporation.

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Suggested Pretherapy Interventions

• Discontinue antihypertensive medications

• Start acetaminophen, indomethacin, and H2 blocker before administering IL-2

• Start maintenance IV fluids (ie, lactated Ringer’s solutions) as 50-100 mL/h immediately before administering IL-2

• Premedicate the patient for nausea before administering IL-2

Schwartzentruber. J Immunother. 2001;24:287-293.

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Flu-Like Effects

• Chills/rigors may occur within 1 to 2 hours of each dose. If they persist, consider increasing premedication before the next dose

• Fever occurs 1 to 2 hours after the onset of chills/rigors. If fever occurs at times other than after the first or second dose of IL-2, an infectious source should be investigated

• Nursing interventions for rigors (Dilaudid, Ativan)

• Fatigue is typically dose-dependent

Schwartzentruber. Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. 2000:32-50.

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Capillary Leak Syndrome (CLS)

• IL-2 therapy is associated with CLS

• CLS is an escape of protein and fluid from the vascular system into the extravascular space

• Assess cardiopulmonary status and risk factors prior to each dose of therapy

• Monitor blood pressure, heart/lung sounds, pulse, and organ function, including mental status and urine output prior to each dose of therapy

• CLS and other adverse events often resolve with interruption of therapy

• If adverse events persist, the treatment cycle may be discontinued

Gale et al. Biotherapy: A Comprehensive Overview. 2nd ed. 2001:195-244.

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Cardiovascular Effects

• Fully assess patient’s cardiac status and risk factors prior to therapy

• Monitor blood pressure, heart sounds, and pulse regularly

• Fluid replacement should be performed judiciously, as this may potentially worsen CLS

• Symptoms often resolve with interruption or discontinuation of therapy


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Cardiovascular Effects

Normal BP for Patient

<100 mm Hg

100-120 mm Hg

>120 mm Hg

Target BP for Patient

>80 mm Hg

>85 mm Hg

>90 mm Hg


The target blood pressure (BP) during HD IL-2 therapy

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Relative and Absolute Criteria for Corrective Measures

Any relative criterion

Initiate corrective measure and/or delay IL-2

≥3 relative criteria

Initiate corrective measures and delay IL-2

Stop IL-2 if adverse events are not easily reversed

Any absolute criterion

Initiate corrective measures and delay IL-2

Stop IL-2 if adverse events are not easily reversed


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Cardiovascular Effects: Criteria for Corrective Measures

Relative criteria

Sinus tachycardia (120-130 BPM)

Absolute criteria

Sustained sinus tachycardia

Atrial fibrillation

Supraventricular tachycardia

Ventricular arrhythmias

Elevated cardiac isoenzymes or troponin

Electrocardiogram changes indicative of ischemia


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Relative criteria

Maximum neosynephrine 1-1.5 microgram/kg/min

Minimum neosynephrine >0.5 microgram/kg/min

Absolute criteria

Maximum neosynephrine 1.5-2 microgram/kg/min

Minimum neosynephrine >0.8 microgram/kg/min

Hemodynamic Effects: Criteria for Corrective Measures


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Pulmonary Effects

• Fully assess patient’s pulmonary status andrisk factors prior to therapy

• Monitor respiratory rate and lung sounds frequently

• Assess for cough or increased sputum production

• Minimize anxiety during respiratory distress

• Elevating the head, limiting activity, and administering low-dose oxygen may help

• Symptoms often resolve with interruption or discontinuation of therapy


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Relative criteria

Resting shortness of breath

Requiring 3-4 L O2 for saturation >95%

Rales 1/3 way up the chest

Absolute criteria

>4 L O2 per nasal cannula (40% mask) to achieve O2 saturation >95%

Endotracheal intubation

Moist rales ½ way up the chest

Effusion requiring thoracentesis or chest tube while on therapy

Pulmonary Effects: Criteria for Corrective Measures


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Renal Effects

• Oliguria (low urine output)

• Monitor patients with nephrectomies or renal dysfunction frequently to assess renal perfusion status

• Measure fluid intake/output and blood urea nitrogen (BUN) and creatinine often

• Weigh patients daily

Gale et al. Biotherapy: A Comprehensive Overview. 2nd ed. 2001:195-244.

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Relative criteria

Urine 80-160 mL/8-hour shift

Urine 10-20 mL/hr

Creatinine 2.5-2.9 mg/dL

Absolute criteria

Urine output <80mL/8-hour shift

Urine output rate <10 mL/hr

Creatinine level >3 mg/dL

Renal Effects: Criteria for Corrective Measures


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Neurological Effects

• Mental status changes, drowsiness and trouble sleeping

• Most symptoms are dose dependent and occur later in treatment cycle

• Concomitant psychotropic agents may increase the potential risk for CNS toxicity

• Neurologic effects can worsen before getting better

• Monitor patients often for any changes in mental status


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Relative criteria

Vivid dreams

Emotional lability

Absolute criteria

Hallucinations

Persistent crying

Mental status changes not reversible within 2 hours

Inability to subtract serial 7s or spell “world” backwards

Disorientation

Neurological Effects: Criteria for Corrective Measures


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Dermatologic Effects

• Generalized erythematous rash with or without pruritus is common

• Dry desquamation of palms and soles may occur

• Apply nonsteroidal and nonalcoholic emollients/lotions

• Rarely require interruption of treatment

• Consider judicious use of topical steroids

• Discontinue IL-2 if there is moist desquamation of skin


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Hematologic Effects

• Leukopenia, thrombocytopenia, anemia, lymphocytosis, and/or eosinophilia can occur

• Monitor complete blood cell (CBC), differential,platelet count

• Upon treatment discontinuation, a rapid rebound of white cells may be anticipated prior to stabilization of blood counts

• Proleukin can increase patients’ risk of sepsis. Patients with indwelling catheters have higher risk of infections with gram-positive (staph) organisms.

• Prophylactic antibiotics have been shown to decrease the incidence of staphylococcal infections


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Relative criteria

Guaiac+ sputum, emesis, and/or stool

Platelets 30,000-50,000/mm3

Absolute criteria

Frank blood in sputum, emesis, and/or stool

Platelet count <30,000/mm3

Hematologic Effects: Criteria for Corrective Measures


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Gastrointestinal Effects

• Nausea, vomiting, and anorexia are usually mild to moderate in severity and generally dose dependent

• Small, frequent meals may mitigate GI distress

• Observe for and report any GI bleeding

• Premedication for nausea, emesis, and/or diarrhea may be required


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Hepatic Effects

• Transient changes in liver function tests are most common

• Monitor patient’s bilirubin, alkaline phosphatase, and liver enzymes (SGOT/AST, SGPT/ALT)

• Use caution when concomitantly administering medications that are metabolized by the liver


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Relative criteria

Diarrhea >1,000 mL/8-hour shift

Ileus and/or abdominal distension

Bilirubin >7 mg/dL

Absolute criteria

Diarrhea >1000 mL for 2 consecutive shifts

Vomiting unresponsive to medication

Severe abdominal distension affecting breathing

Severe abdominal pain, unrelenting

Gastrointestinal Effects: Criteria for Corrective Measures


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Endocrine and Metabolic Effects

• Thyroid dysfunction is manifested most commonly by subclinical hypothyroidism, but hyperthyroidism has occurred

• Thyroid function tests before and routinely during therapy is recommended, with replacement therapy as indicated

• Electrolyte imbalance, including low serumlevels of potassium and magnesium

• Electrolyte and mineral serum levels should be monitored routinely, with replacement therapyfor low levels


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Relative criteria

-

Absolute criteria

Strong clinical suspicion or documented

Infection: Criteria for Corrective Measures


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Proleukin Side Effects

Remember that Proleukin adverse events are typically

• Predictable, manageable, and generally reversible

• Dose- and schedule-dependent

• Usually resolve within 2 to 3 days after discontinuation of therapy

– Fatigue, skin toxicity, anorexia, and neurologic toxicity may persist longer

• Long-term sequelae associated with Proleukin are extremely rare


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Conditions That Require Holding a Dose

Body system

Cardiovascular

Hold dose for:

Atrial fibrillation, supraven-tricular tachycardia, brady-cardia that requires therapy or is recurrent or persistent

Systolic BP <90 mm Hg with increasing requirements for pressors

Any ECG change consistent with MI, ischemia, or myocarditis with or without chest pain; suspicion of cardiac ischemia

Subsequent doses may be given if:

Asymptomatic with full recovery to normal sinus rhythm

Systolic BP ≥90 mm Hg and stable or improving requirements for pressorsAsymptomatic, MI and myocarditis ruled out; clinical suspicion of angina is low; there is no evidence of ventricular hypokinesia


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Conditions That Require Holding a Dose (cont)

Body system

Respiratory

Neurologic

Hold dose for:

O2 saturation <90%

Mental status changes, including moderate confusion or agitation


O2 saturation >90%

Mental status changes completely resolved


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Body system

Body as a whole

Skin

Hold dose for:

Sepsis syndrome, patient is clinically unstable

Bullous dermatitis or marked worsening of preexisting skin condition; avoid topical steroid therapy


Sepsis syndrome has resolved, patient is clinically stable, infection is under treatment

Resolution of all signs of bullous dermatitis


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Body system

Digestive

Hold dose for:

Signs of hepaticfailure, including encephalopathy, increasing ascites, liver pain, hypoglycemia

Stool guaiacrepeatedly >3-4+

Subsequent dosesmay be given if:

Discontinue all further doses of current course. A new course of treatment, if warranted, may be initiated in no sooner than 7 weeks if all signs of hepatic failure have resolved

Stool guaiac negative


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Body system

Urogenital

Hold dose for:

Serum creatinine (Cr) >4.5 mg/dL or of ≥4 mg/dL in the presence of severe volume overload, acidosis, or hyperkalemia

Persistent oliguria, urine output of <10 mL/hr for 16-24 hrs with rising Cr


Cr <4 mg/dL and fluid and electrolyte status is stable

Urine output >10 mL/hr with a decrease in Cr >1.5 mg/dL or normalization of Cr


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Retreatment

• Additional courses should be consideredfor those with tumor shrinkage following last course of therapy, unless contraindicated

• Each treatment course should be separated by a rest period of at least 7 weeks from the date of hospital discharge


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Treatment Plan

• Telemetry VS ICU

• Developing highly specialized RN group

• PICC insertion

• Lab Values prior to treatment (see order set)

• IVF 8-10 liters possibly/increasing IVF when bolusing, encouraging oral intake

• Aggressive phosphorous replacement

• Skipping doses vs discontinuing

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Discharge Interventions

• Standard discharge instructions

• Usually RX are written eg: Lasix & Potassium, Zyrtec, Sarna Lotion

• Discharge instructions IL-2 sheet

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THANK-YOU

QUESTIONS?

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BibliographyAtkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with

metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(suppl 1):S11-S14.

Balch CM, Buzaid AC, Soong SG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635-3648.

Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am. 2000;6(suppl 1):S55-S57.

Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13(3):688-696

Flaherty LE. Rationale for intergroup trial E-3695 comparing concurrent biochemotherapy with cisplatin, vinblastine, and DTIC alone in patients with metastatic melanoma. Cancer J Sci Am. 2000;6(suppl 1):S15-S20.

Gale DM, Sorokin P. In: Rieger PT, ed. Biotherapy: A Comprehensive Overview. 2nd ed. Sudbury, MA: Jones and Bartlett; 2001:195-244.

Griffin-Brown J. In: Yarbro C, Frogge M, Goodman M, et al, eds. Cancer Nursing: Principles and Practice. 5th ed. Sudbury, MA: Jones and Bartlett; 2000:214-240.

Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006;56:106-130.

Lindsey KR, Rosenberg SA, Sherry RM. Impact of the number of treatment courses on the clinical response of patients who receive high-dose bolus interleukin-2. J Clin Oncol. 2000;18:1954-1959.


Rini BI, Vogelzang NJ. Prognostic factors in renal carcinoma. Semin Oncol. 2000;27:213-220.

Schwartzentruber DJ. Guidelines for the safe administration of high-dose interleukin-2. J Immunother. 2001;24:287-293.

Schwartzentruber DJ. In: Rosenberg SA, ed. Principles and Practice of the Biologic Therapy of Cancer. 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins. 2000:32-50.

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