Conventional irinotecan:

Available in single-dose vials in 2-mL, 5-mL, and 15-mL sizes with a concentration of 20 mg/mL. Must be diluted for infusion with D5W (preferred) or NS to concentrations between 0.12 and 2.8 mg/mL. Usually diluted in 250 to 500 mL D5W.

Onivyde:

Available in a single-dose vial containing 43 mg irinotecan free base at a concentration of 4.3 mg/mL. It is a slightly yellow, opaque, liposomal dispersion. Withdraw the calculated volume from the vial and dilute in 500 mL D5W or NS. Mix by gentle inversion. Protect diluted solution from light.

Conventional irinotecan:

Specific information not available. ONIVYDE: Do not use in-line filters.

Conventional irinotecan:

Packaged in a blister pack to protect against accidental breakage and leakage. Store in carton protected from light at CRT. When mixed with D5W, is chemically and physically stable for 48 hours if refrigerated and in ambient fluorescent lighting and for 24 hours at CRT. Do not refrigerate if mixed with NS; a precipitate may form. Stable for 24 hours at CRT when mixed in NS. Because of the risk of microbial contamination, the manufacturer recommends that solutions mixed in D5W or NS be used within 4 hours if kept at RT. However, if reconstitution and dilution are performed under strict aseptic conditions (e.g., on a laminar air flow bench), the solution should be used (i.e., infusion completed) within 12 hours at RT or 24 hours (D5W) if refrigerated. Avoid freezing.

Onivyde:

Refrigerate in carton at 2° to 8° C (36° to 46° F) to protect from light. Do not freeze. Administer diluted solution within 4 hours of preparation when stored at RT or within 24 hours if refrigerated. Allow diluted solution to come to RT before administration. Do not freeze. Discard unused portion.

Conventional irinotecan:

A semi-synthetic derivative of camptothecin. An alkaloid extract from plants such as Camptotheca acuminata. A class of antineoplastic agent that inhibits the enzyme topoisomerase I required for DNA replication. Together with its active metabolite SN-38 it causes cell death by damaging DNA produced during the S-phase of cell synthesis. Maximum plasma SN-38 levels are reached within 1 hour of infusion end. Extensively distributed to body tissues. Terminal half-life of irinotecan is about 6 to 12 hours; SN-38 is 10 to 20 hours. Irinotecan is moderately bound to plasma proteins (30% to 68%), but SN-38 is highly bound (95%). Metabolic conversion of irinotecan to SN-38 primarily occurs in the liver. SN-38 is conjugated to a glucuronide metabolite by the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1). Approximately 25% to 50% excreted through bile and urine.

Onivyde:

A topoisomerase 1 inhibitor encapsulated in a lipid bilayer vesicle or liposome. Topoisomerase 1 relieves torsional strain in DNA by inducing single-strand breaks. Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase 1–DNA complex and prevent re-ligation of the single-strand breaks, leading to cell death. 95% of irinotecan remains liposome-encapsulated. Terminal elimination half-life is approximately 25.8 hours. Protein binding is less than 0.44% of the total irinotecan in ONIVYDE. Metabolism and excretion of irinotecan liposome have not been evaluated.

Conventional irinotecan:

As a component of first-line therapy in combination with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic carcinoma of the colon or rectum. ■ For patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.

Onivyde:

Treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Used in combination with fluorouracil and leucovorin.

Conventional irinotecan:

Can induce both early and late forms of diarrhea that appear to be mediated by different mechanisms. Both forms may be severe. Interrupt therapy and reduce subsequent doses if severe diarrhea occurs; see Dose Adjustments. Late diarrhea may be complicated by colitis, ulceration, bleeding, ileus, obstruction, and infection. Cases of megacolon and intestinal perforation have been reported. Patients must not be treated with irinotecan until resolution of any bowel obstruction. ■ Hepatic dysfunction may impair the metabolism of both irinotecan and SN-38. Patients with a bilirubin of 1 to 2 mg/dL are at increased risk for developing Grade 3 or 4 neutropenia. The manufacturer does not recommend a dose for patients with a bilirubin greater than 2 mg/dL and states that insufficient information is available. ■ May cause severe myelosuppression. Deaths due to sepsis following severe neutropenia have been reported. ■ Use with caution in patients with renal impairment. Has not been studied. Not recommended for use in patients on dialysis. ■ Use caution in the elderly (may have an increased incidence and severity of diarrhea) and in patients who have had previous cytotoxic therapy or previous pelvic/abdominal irradiation (likely to have an increased incidence and severity of myelosuppression). Monitor closely. ■ Use caution in patients with poor performance status. Patients with a baseline performance status of 2 had higher rates of hospitalization, neutropenic fever, thromboembolism, first-cycle treatment discontinuation, and early deaths than patients with a performance status of 0 or 1. ■ Contains sorbitol. Do not use in patients with hereditary fructose intolerance. ■ The Mayo Clinic regimen of 5-FU/LV (administered for 4 to 5 days every 28 days) should not be used in combination with irinotecan outside a carefully controlled, well-designed clinical study. Regimen has caused increased toxicity and death. ■ See Monitor.

Onivyde:

Severe or life-threatening neutropenia, neutropenic fever or sepsis, and fatal neutropenic sepsis have occurred. The incidence of Grade 3 or 4 neutropenia was higher among Asian patients compared with Caucasian patients in clinical trials. Withhold ONIVYDE for absolute neutrophil count below 1,500/mm³ or neutropenic fever; see Monitor. ■ Severe diarrhea has occurred in patients receiving liposomal irinotecan in combination with fluorouracil and leucovorin. Withhold ONIVYDE for diarrhea of Grade 2 to 4 severity. An individual patient may experience both early- and late-onset diarrhea; see Monitor. ■ Do not administer ONIVYDE to patients with bowel obstruction. ■ Not studied in patients with hepatic impairment. ■ No pharmacokinetic effects noted in patients with mild to moderate renal impairment. Data for severe renal impairment are insufficient.

Both formulations:

Prophylactic antiemetics are recommended; see Usual Dose. To reduce nausea and vomiting and increase patient comfort after initial dosing, additional antiemetics should be available (e.g., prochlorperazine [Compazine], ondansetron [Zofran], granisetron [Kytril]). ■ Monitor vital signs. ■ Obtain an accurate bowel history to evaluate changes in bowel habits after administration of irinotecan. ■ Monitor for “early” diarrhea. Occurs during or within 24 hours of irinotecan administration and is cholinergic in nature. Usually transient and only infrequently is severe. May be accompanied by other cholinergic symptoms (e.g., abdominal cramping, bradycardia, diaphoresis, flushing, increased salivation, lacrimation, miosis, rhinitis). Patients who have a cholinergic reaction to irinotecan will probably have similar reactions to subsequent doses. Atropine 0.25 to 1 mg IV or SC may be considered for treatment or for prophylactic use unless clinically contraindicated. ■ Monitor for “late” diarrhea (more than 24 hours after irinotecan administration), which probably results from cytotoxic effects on GI epithelium. May be prolonged; may cause dehydration, electrolyte imbalances, or sepsis; and can be life threatening. At first onset, give loperamide (Imodium) 4 mg; give 2 mg every 2 hours (4 mg every 4 hours during the night) until diarrhea-free for a minimum of 12 hours. Monitor carefully; replace fluids and electrolytes as needed; see Patient Education. ■ Maintain adequate hydration. Orthostatic hypotension or dizziness may indicate dehydration. ■ Initiate antibiotic therapy in patients who develop ileus, fever, or severe neutropenia. ■ Be alert for signs of bone marrow suppression or infection. Prophylactic antibiotics may be indicated pending results of C/S in a febrile or nonfebrile neutropenic patient. ■ Monitor for thrombocytopenia (platelet count less than 50,000/mm³). Initiate precautions to prevent excessive bleeding (e.g., inspect IV sites, skin, and mucous membranes; use extreme care during invasive procedures; test urine, emesis, stool, and secretions for occult blood). ■ Monitor for S/S of a hypersensitivity reaction (e.g., chest pain, chills, dizziness, dyspnea, fever, flushing, hypotension, nausea, pruritus, rash, urticaria) or an infusion reaction (e.g., asthenia, chills, fatigue, fever, vomiting). ■ Monitor for S/S of interstitial lung disease. Withhold therapy in patients with new or progressive cough, dyspnea, and fever pending diagnostic evaluation; see Precautions and Antidote. ■ See Dose Adjustments.

Conventional irinotecan:

Obtain a WBC with differential, hemoglobin, and platelet count before each dose. Expected nadir for platelets is 14 days, and 21 days for hemoglobin, neutrophils, and leukocytes. ■ Obtain baseline electrolytes and liver function tests. ■ Not a vesicant, but monitor injection site for inflammation and/or extravasation. ■ If late-onset diarrhea develops, subsequent weekly chemotherapy treatments should be delayed until pretreatment bowel function has returned for at least 24 hours without the need for antidiarrheal medication. If Grade 2, 3, or 4 late diarrhea recurs, subsequent doses of irinotecan should be decreased; see Dose Adjustments. ■ Avoid use of diuretics and laxatives in patients with diarrhea. ■ Monitor renal function and hydration status. Rare cases of renal impairment or acute renal failure have been reported, usually in patients who became dehydrated from vomiting and/or diarrhea.

Onivyde (liposomal irinotecan):

Prophylactic antiemetics and corticosteroids are recommended 30 minutes before ONIVYDE infusion. ■ Monitor CBC on Days 1 and 8 of every cycle and more frequently if clinically indicated. Withhold ONIVYDE if the absolute neutrophil count (ANC) is below 1,500/mm³ or if neutropenic fever occurs. Resume when the ANC is 1,500 mm³ or above; see Dose Adjustments. ■ Monitor for infusion reactions occurring on the day of administration. S/S have included periorbital edema, pruritus, rash, and urticaria.

Both formulations:

Review manufacturer’s medication guide. ■ Report any unusual or unexpected symptoms or side effects as soon as possible. ■ Report black or bloody stools, diarrhea not under control within 24 hours, dry mouth, fever or chills, inability to retain oral fluids due to nausea and vomiting, infections, symptoms of dehydration (e.g., light-headedness, dizziness, fainting), urine changes, or vomiting immediately; each must be treated promptly. Have loperamide (Imodium) available. Dose of loperamide prescribed for late diarrhea is higher than the usual dose recommendation. Limit use at this dose to 48 hours to avoid risk of paralytic ileus. ■ May cause dizziness or visual disturbances (usually within 24 hours of administration); use caution in tasks that require alertness. ■ Compliance with regimen imperative (e.g., taking temperature, obtaining lab work, adequate rest, nourishment, and fluids). ■ Effective birth control required for both women and men; see Maternal/Child. ■ Inform health care professionals of any problems with previous treatments. ■ See Appendix D, p. 1333.

Both formulations:

Safety and effectiveness for use in pediatric patients not established.

Conventional irinotecan:

Category D: avoid pregnancy. May cause fetal harm. ■ Discontinue breast-feeding.

Onivyde:

Can cause fetal harm; avoid pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 1 month after the final dose. Advise males with female partners of reproductive potential to use condoms during treatment and for 4 months after the final dose. ■ Discontinue breast-feeding during treatment and for 1 month after the final dose.

Conventional irinotecan:

Half-life slightly extended. ■ Reduce starting dose by one dose level to 300 mg/M² in patients 70 years and older in the single-agent, once-every-3-weeks regimen. No change in the starting dose is recommended for elderly patients receiving the weekly dose schedule of irinotecan. See Usual Dose and Dose Adjustments. ■ Risk of early and late diarrhea increased in the elderly. ■ Monitor carefully; may dehydrate more quickly from diarrhea. Begin loperamide therapy promptly. Avoid laxatives.

Onivyde:

No overall differences in safety and effectiveness observed between the elderly and younger patients.

Iron-deficiency anemia:

A test dose is required on the first day. The maximum daily dose is 100 mg/day.

Iron replacement for blood loss:

Dose should represent the equivalent amount of iron represented in blood loss. Begin with a test dose of 0.5 mL (25 mg). Wait 1 hour. If no adverse reactions, calculate the desired dose with the following formula and administer the balance of the replacement dose over 2 to 3 daily doses:

Amount of replacement iron (mg) = Blood loss (mL) × Hematocrit

Calculated dose is in mg; convert to mL before administration.

Formula is based on the approximation that 1 mL of normocytic, normochromic red cells contains 1 mg of elemental iron.

Iron-deficiency anemia:

Iron replacement for blood loss:

Calculate dose by formula used for adult dose. Dose should represent the equivalent amount of iron represented in blood loss. Begin with a test dose of 0.5 mL (25 mg) for pediatric patients or 0.25 mL (12.5 mg) for infants over at least 5 minutes on the first day. Wait 1 hour. If no adverse reactions, administer the balance of the replacement dose over 2 to 3 daily doses.

Filters:

No data available from manufacturer.

Storage:

Store unopened vials at CRT, protect from freezing.

Test dose:

25 mg over 5 minutes (DexFerrum) or over 30 seconds (InFeD). Specific rates of test dose infusions not available for other manufacturers.

IV injection:

If no adverse reactions to the test dose, administer 1 mL (50 mg) or a fraction thereof over 1 minute or more. Extend injection time in pediatric patients.

Infusion:

If no adverse reactions to the test dose, infuse remaining dose over 1 to 8 hours (based on amount of dose, amount of diluent, and patient comfort).

Unlabeled uses:

Iron supplementation for patients taking epoetin alfa (Epogen).

Monitor:

Keep patient lying down after injection to prevent postural hypotension. ■ Observe continuously for a hypersensitivity reaction during an infusion. Monitor vital signs. ■ Monitor hemoglobin, hematocrit, reticulocyte count, total iron-binding capacity (TIBC), and percent of saturation of transferrin as indicated to monitor therapy and iron status. May take up to 3 weeks to see response. ■ Monitor serum ferritin assays in prolonged therapy. Consider possibility of false results for months after injection caused by delayed utilization. ■ In patients undergoing chronic renal dialysis who are receiving iron dextran complex, the correlation of body iron stores and serum ferritin may not be valid.

Patient education:

Promptly report S/S of hypersensitivity (e.g., rash, itching, SOB). ■ Promptly report any other side effects, immediate or delayed.

Maternal/child:

Category C: use only if absolutely necessary in pregnancy, breast-feeding, or childbearing years. ■ Injectable iron not normally used in infants younger than 4 months of age.

Major:

Anaphylaxis (fatalities have occurred); arthritic reactivation; dyspnea; febrile episodes; hypotension; leukocytosis; local phlebitis; lymphadenopathy; peripheral vascular flushing, especially with too-rapid injection; tachycardia; urticaria; shock (severe iron toxicity increases vasodilation and venous pooling and decreases circulating blood volume. Results in decreased cardiac output, hypotension, increased peripheral vascular resistance, and shock).

Overdose:

Serum iron levels greater than 300 mcg/dL may indicate iron poisoning. Overdose with iron dextran is unlikely. May result in hemosiderosis, and excess iron may increase susceptibility to infection. If acute toxicity is seen, it may present as:

Test dose (optional):

50 mg. Test dose is not required but was administered in some of the clinical trials. May be given at the physician’s discretion.

Adult patients with hemodialysis-dependent chronic kidney disease (HDD-CKD):

100 mg as a slow IV injection or as a 15-minute infusion during consecutive hemodialysis sessions. Administered early during the dialysis session. Repeat as needed to maintain target levels of hemoglobin, hematocrit, and laboratory parameters of iron stores within acceptable limits. Frequency of dosing should be no more than three times weekly.

Adult patients with non–dialysis dependent chronic kidney disease (NDD-CKD):

200 mg as a slow IV injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of NS over 15 minutes. Administer on 5 different days within a 14-day period to a total cumulative dose of 1,000 mg. Alternately, there is limited experience with administering a 500-mg dose on Day 1 and Day 14 as a 3.5- to 4-hour infusion in a maximum of 250 mL of NS.

Adult patients with peritoneal dialysis–dependent chronic kidney disease (PDD-CKD):

300 mg as an infusion on Day 1 and Day 14. Follow with 400 mg as an infusion on Day 28. A total cumulative dose of 1,000 mg given in 3 doses over 28 days. Each infusion is diluted in a maximum of 250 mL NS and administered over 1.5 to 2.5 hours; see Rate of Administration.

Pediatric patients (2 years of age and older) with hemodialysis-dependent chronic kidney disease (HDD-CKD) for iron maintenance treatment:

The dosing for iron replacement treatment in pediatric patients with HDD-CKD has not been established.

Pediatric patients (2 years of age and older) with non–dialysis dependent chronic kidney disease (NDD-CKD) or peritoneal dialysis–dependent chronic kidney disease (PDD-CKD) who are undergoing erythropoietin therapy for iron maintenance treatment:

The dosing for iron replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

Test dose (optional):

50 mg should be diluted in 50 mL of NS.

Adult patients with hemodialysis-dependent chronic kidney disease (HDD-CKD):

100-mg dose may be given undiluted or may be further diluted in a maximum of 100 mL of NS and given as an infusion.

Adult patients with non–dialysis dependent chronic kidney disease (NDD-CKD):

200-mg dose may be given undiluted or may be further diluted in a maximum of 100 mL of NS. The 500-mg dose may be further diluted in a maximum of 250 mL of NS and given as an infusion.

Adult patients with peritoneal dialysis–dependent chronic kidney disease (PDD-CKD):

Each 300- or 400-mg dose must be diluted in a maximum of 250 mL NS and given as an infusion.

Pediatric patients receiving iron maintenance treatment:

A single dose may be given undiluted or diluted in 25 mL of NS and given as an infusion; see Usual Dose.

Filters:

No data available from manufacturer.

Storage:

Store unopened vials in original carton at CRT. Do not freeze. Diluted iron infusions should be used immediately after preparation. Discard any unused portion. When diluted with NS to a concentration of 1 to 2 mg/mL in PVC or non-PVC infusion bags, iron sucrose is stable for 7 days at CRT. When undiluted (20 mg/mL) or diluted with NS to a concentration of 2 to 10 mg/mL and stored in a plastic syringe, iron sucrose is stable for 7 days at CRT or refrigerated.

Test dose (optional):

A single dose over 3 to 10 minutes.

Slow IV injection in adults:

A single undiluted dose over 2 to 5 minutes. In dialysis patients, administer into the dialysis line during the dialysis session.

Infusion in adults:

This method of administration may reduce the risk of hypotensive episodes.

Monitor:

Confirm IV placement and avoid extravasation; injection site discoloration has been reported following extravasation. ■ Monitor vital signs during and immediately following administration. Recumbent position during and after administration may help to prevent postural hypotension. Hypotensive effects may be additive to transient hypotension during dialysis and/or from too-rapid rate of administration. ■ Monitor for S/S of hypersensitivity reactions during and after administration for at least 30 minutes and until clinically stable; see Precautions. Reactions may occur after the first dose or subsequent doses of iron sucrose. ■ Periodic monitoring of hematologic and hematinic parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation) is indicated during parenteral iron replacement therapy. Takes about 4 weeks of treatment to see increased serum iron and ferritin and decreased TIBC (total iron-binding capacity). Transferrin saturation values increase rapidly after IV adminstration of iron sucrose; thus serum iron values may be reliably obtained 48 hours after the last IV dose.

Patient education:

Review any possible reactions to past parenteral iron therapy. ■ Report S/S of a hypersensitivity reaction promptly.

Maternal/child:

Category B: use in pregnancy only if clearly needed. ■ Safety for use during breast-feeding not established. ■ Safety and effectiveness for iron replacement treatment in pediatric patients have not been established. Safety and effectiveness for iron maintenance treatment have been established for pediatric patients 2 years of age and older. ■ Necrotizing enterocolitis in 5 premature infants (weight less than 1,250 Gm) with 2 deaths has been reported in one country in which iron sucrose is approved for use in pediatric patients. No causal relationship to drugs could be established; it may be a complication of prematurity in very-low-birth-weight infants.

Elderly:

Differences in response between elderly and younger patients have not been identified. Lower-end initial doses may be appropriate in the elderly; see Dose Adjustments.

Adult patients:

Arthralgia, back pain, chest pain, diarrhea, dizziness, headache, hypotension, injection site burning or pain, muscle cramps, nausea, pain in extremity, peripheral edema, pruritus, and vomiting are most common. Other side effects varied according to the type of chronic kidney disease patient who was receiving iron sucrose (e.g., hemodialysis dependent, peritoneal dialysis–dependent, non–dialysis dependent) and included abdominal pain, altered taste, asthenia, catheter site infection, conjunctivitis, cough, dyspnea, ear pain, fecal occult blood positive, feeling abnormal, fever, fluid overload, gout, graft complications, hyperglycemia, hypersensitivity reactions, hypertension, hypoesthesia, hypoglycemia, injection site extravasation, myalgia, nasal congestion, nasopharyngitis, peritoneal infection, pharyngitis, sinusitis, upper respiratory infection.

Pediatric patients:

Arteriovenous fistula thrombosis, cough, dizziness, fever, headache, hypertension, hypotension, nausea, peritonitis, renal transplant, respiratory tract viral infection, and vomiting occurred.

Overdose:

Serum iron levels greater than 300 mcg/dL may indicate iron poisoning. May result in hemosiderosis. Excess iron may increase susceptibility to infection. If acute toxicity is seen, it may present as abdominal and muscle pain, cardiovascular collapse, dizziness, dyspnea, edema, headache, hemosiderosis, hypotension, joint aches, nausea, pale eyes, paresthesia, sedation, vomiting.

Post-marketing:

Life-threatening hypersensitivity reactions (e.g., anaphylactic shock, angioedema, bronchospasm, collapse, convulsions, dyspnea, loss of consciousness, pruritus, rash, shock, wheezing), bradycardia, chromaturia, confusion, CHF, light-headedness, sweating, swelling of joints.

Loading dose:

372 mg (1 vial) as an infusion every 8 hours for 6 doses.

Maintenance dose:

372 mg (1 vial) as an infusion once daily. Initiate 12 to 24 hours after the last loading dose. Oral formulation (2 capsules = 372 mg) may be substituted when appropriate.

Filters:

Must be administered using an infusion set that contains a sterile, nonpyrogenic, in-line filter (pore size of 0.2 to 1.2 micrometers).

Storage:

Before use, refrigerate at 2° to 8° C (36° to 46° F). Reconstituted solution should be further diluted and used immediately but may be stored below 25° C for a maximum of 1 hour before further dilution. Diluted solution must be used within 6 hours if kept at RT or may be immediately refrigerated. Complete the infusion within 24 hours. Do not freeze.

Monitor:

Obtain specimens for fungal culture and other relevant lab studies (including histopathology) to isolate and identify causative organism(s) before initiating therapy. Institute antifungal therapy and adjust based on results of culture and lab studies. ​■ ​Obtain baseline liver function tests and repeat as necessary. Monitor more frequently in patients who develop abnormal liver function tests and when treating patients with severe hepatic impairment. ​■ ​Monitor for infusion-related reactions (e.g., chills, dizziness, dyspnea, hypoesthesia, hypotension, and paresthesia). ​■ ​Monitor for S/S of hypersensitivity reactions (e.g., hypotension, rash, tightness of the chest, urticaria, wheezing). ​■ ​Monitor for S/S of skin reactions (e.g., rash, blisters).

Patient education:

Review manufacturer’s medication guide. ​■ ​Review of health history and medication profile is imperative. ​■ ​Avoid pregnancy; nonhormonal birth control recommended; see Drug/Lab Interactions. Should pregnancy occur, notify physician and discuss potential hazards. ​■ ​Promptly report S/S of a hypersensitivity/infusion reaction (e.g., itching, hives, shortness of breath, or a serious skin reaction [e.g., rash]).

Maternal/child:

Category C: may cause fetal harm. Use during pregnancy only if the potential benefit to the patient outweighs the risk to the fetus. Report a suspected pregnancy. ​■ ​Discontinue breast-feeding. ​■ ​Safety and effectiveness for use in patients under 18 years of age have not been established.

Elderly:

Response similar to that seen in younger adults.