By

Salah Mabruok Khalaf

South Egypt Cancer Institute2013

Clinical Pharmacy Medical Oncology course

ChemotherapyChemotherapy: Topoisomerase Topoisomerase inhibitorsinhibitors

Classification of Chemotherapeutic AgentsClassification of Chemotherapeutic Agents• Alkylating Agents Alkylating Agents AntimetabolitesAntimetabolites:

• Antitumor AntibioticsAntitumor Antibiotics Anti-microtubulesAnti-microtubules:

• Topoisomerase inhibitorsTopoisomerase inhibitors:

– Topoisomerase I inhibitors Topoisomerase I inhibitors

• Camptothecin: Topotecan, Etoposide

– Topoisomerase II inhibitors Topoisomerase II inhibitors

• Anthracyclines

• Epipodophyllotoxin: Irinotecan, topotecan

• Miscellaneous:

DNA topoisomerases

• These are enzymes that alter DNA topology by causing and resealing DNA strand breaks. Topoisomerases bind to DNA domains, forming a “cleavable complex,” which allows DNA to unwind in preparation for cell division.

• Topoisomerase I relaxes supercoiled single-stranded DNA.

• Topoisomerase II catalyzes the double-stranded breaking and resealing of DNA

Irinotecan Indications

1. Colorectal cancer2. Lung cancer3. Pancreatic Cancer 4. Ovarian Cancer

Form– 100-mg vials

Irinotecan • Dose

– Start at 125 mg/m2 IV weekly for 4 weeks followed by a 2-week rest.

• Dose modification. – Use with caution for hepatic insufficiency

Irinotecan Administration• Administer as a 90-minute infusion.

– If diarrhea, abdominal cramps (mostly cholinergic in nature) develops during the infusion of the drug, administer atropine, 0.25 to 1.0 mg IV.

– For the first poorly formed stool preceding delayed diarrhea, administer loperamide (Imodium), 4 mg PO, then 2 mg every 2 hours (4 mg PO every 4 hours at night) until the patient is free of diarrhea for 12 hours.

Irinotecan Administration• If administered in combination with fluorouracil &

leucovorin, administer leucovorin immediately after irinotecan, & administer fluorouracil immediately after leucovorin– Irinotecan >>> leucovorin >>> fluorouraci

• Premedication with antiemetics (dexamethasone plus ondansetron/granisetron) is recommended, at least 30 min prior to infusion.

Irinotecan • IV Preparation

– Dilute in D5W to a final concentration of 0.12-2.8 mg/mL (most commonly in 500 mL D5W)

– NS can be used, but precipitation under refrigeration is more likely with NS, so D5W is generally preferred

Irinotecan • Toxicity

– Dose-limiting. • Profuse diarrhea (especially in patients 65 years of

age and older) and myelosuppression– Common.

• Neutropenia; mild nausea, vomiting, abdominal cramps; flushing during administration; mild alopecia.

– Occasional. • LFT abnormalities, headache, fever, dyspnea

TopotecanIndications

1. Lung cancer2. Ovarian Cancer3. Cervical cancer

Form– 4-mg vials – 0.25- and 1-mg capsules

Topotecan • Dose

– Usual dose is 1.25 mg/m2 IV over 30 minutes for 5 consecutive days every 3 weeks

– 2.3 mg/m2 PO for 5 days of 21-day cycle

• Dose modification. – None for impaired hepatic function. – Reduce dosage by 50% for creatinine

clearance levels of 20 to 40 mL/minute..

Topotecan Administration• IV Infusion

– Administer 1.5mg/m² by IV infusion over 30 minutes• Capsules

– Administer 2.3mg/m² PO QD x5days; repeat at 21-day cycles

Topotecan • IV Preparation

– Reconstitute in 4 mL SWI to obtain a 1 mg/mL solution– Dilute in 50-250 mL NS or D5W

• Storage– Store intact vials at room temp protected from light

Topotecan • Toxicity

– Dose-limiting. • Myelosuppression

– Common. • Nausea and vomiting; diarrhea, constipation,

abdominal pain; alopecia; headache, fatigue, fever; arthralgias and myalgias.

– Occasional. • Transient elevation of LFTs; paresthesia; rash;

microscopic hematuria

EtoposideIndications

1. Testicular carcinoma2. lung cancer3. Lymphoma4. Other malignancies

Form– 100-mg vials – 50mg capsules

Etoposide• Dose

– 50 mg/m2 PO daily for 21 days, or– 100 mg/m2 IV daily for 3 to 5 days, depending on

the regimen• Dose modification

– Administer with caution in the presence of renal dysfunction; reduce doses by 25% or 50% for creatinine clearance levels of <50 mL/minute and <10 mL/minute, respectively.

– Dose reduction is also recommended for patients with abnormal liver function..

EtoposideAdministration• IV Infusion

– Administer IV infusion over 30 minutes

Etoposide• IV Preparation

– Concs >0.4 mg/mL are very unstable– Lower dose regimens (<1 g/dose): doses may be diluted

in 100-1000 mL of D5W or NS– High dose regimens (>1 g/dose): draw total dose into an

empty Viaflex container & add appropriate amount of diluent for a final concentration of 1 mg/mL

Etoposide• Toxicity

– Dose-limiting. • Myelosuppression

– Common. • Nausea and vomiting (with oral dosing, but

uncommon with intravenous dosing); alopecia (usually mild); hypotension if rapidly infused; metallic taste during drug infusion.

– Occasional. • Anemia, thrombocytopenia, pain at injection site,

phlebitis, abnormal LFTs

TeniposideIndications

Acute lymphoblastic leukemia

Form–50-mg vials

Teniposide• Dose

– 150 to 250 mg/m2 once or twice weekly• Dose modification

– Dose reduction is recommended for patients with abnormal liver function..

TeniposideAdministration• IV Infusion

– Administer IV infusion over 30 minutes

Teniposide• IV Preparation

– Must be diluted with either D5W or NS to a final concentration of 0.1, 0.2, 0.4 or 1 mg/mL

– Administer 1 mg/mL solutions within 4 hr of preparation to reduce potential for precipitation

– Precipitation may occur at any concentration

Teniposide• Toxicity

– Dose-limiting. • Myelosuppression

– Common. • Hypotension with too rapid infusion

– Occasional. • Nausea and vomiting, alopecia, abnormal LFTs,

phlebitis