Topotecan Hydrochloride

HYCAMTIN (topotecan hydrochloride) is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitory activity.

HYCAMTIN for Injection is supplied as a sterile, lyophilized, buffered, light yellow to greenish powder available in single-dose vials. Each vial contains topotecan hydrochloride equivalent to 4 mg of topotecan as free base. The reconstituted solution ranges in color from yellow to yellow-green and is intended for administration by intravenous infusion.

Inactive ingredients are mannitol, 48 mg, and tartaric acid, 20 mg. Hydrochloric acid and sodium hydroxide may be used to adjust the pH. The solution pH ranges from 2.5 to 3.5.

The chemical name for topotecan hydrochloride is (S)-10-[(dimethylamino)methyl]-4- ethyl-4,9-dihydroxy-1#-pyrano[3',4':6,7] indolizino [1,2-6]quinoline-3,14-(4#,12#)-dione monohydrochloride. It has the molecular formula C23H23N3O5*HCl and a molecular weight of 457.9.

Topotecan hydrochloride has the following structural formula:

It is soluble in water and melts with decomposition at 213° to 218°C.

Do not use topotecan if you are pregnant. It could harm the unborn baby.

Topotecan can lower blood cells that help your body fight infections. This can make it easier for you to bleed from an injury or get sick from being around others who are ill. Your blood may need to be tested often. Visit your doctor regularly.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using topotecan, and avoid coming into contact with anyone who has recently received a live vaccine. There is a chance that the virus could be passed on to you.

Call your doctor at once if you have fever, chills, body aches, flu symptoms, pale skin, easy bruising or bleeding, severe diarrhea with fever or stomach pain, unusual weakness, white patches or sores inside your mouth or on your lips, or other signs of infection.

Does not inhibit CYP isoenzymes 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E, 3A, or 4A or dihydropyrimidine dehydrogenase in vitro.1 c

Specific Drugs

Absorption

Bioavailability

Rapidly absorbed following oral administration, with peak plasma concentrations attained within 1–2 hours. c

Bioavailability is approximately 40%.c

Food

Extent of absorption following oral administration similar in fed and fasted states, however tmax delayed; capsules can be given without regard to food.c

Distribution

Plasma Protein Binding

Approximately 35%.1 c

Elimination

Metabolism

Principally undergoes reversible pH-dependent hydrolysis.1 c Minor metabolic pathway in the liver to an N-demethylated metabolite.1 c

Elimination Route

Following IV administration, excreted in urine (51%) and in feces (18%) mainly as total topotecan.1

Following oral administration, excreted in urine (20%) and in feces (33%) mainly as total topotecan.c

Half-life

Terminal elimination half-life following IV administration: 2–3 hours.1

Terminal elimination half-life following oral administration: 3–6 hours.c

Special Populations

In male patients, increased clearance.1

In patients with renal impairment, clearance is decreased and half-life is 5 hours.1

In patients with hepatic impairment, clearance is decreased; however, half-life is increased only slightly.1

Storage

Oral

20–25°C (may be exposed to 15–30°C); protect from light.c

Parenteral

20–25°C; protect from light.1 Use immediately after reconstitution.1 Following dilution with infusion solution, use drug within 24 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

• A type I DNA topoisomerase inhibitor.1 3 4 5 6 7 8 9 10 11 13 17

• Exerts cytotoxic effects during the S-phase of DNA synthesis through an interaction with the DNA-DNA topoisomerase cleavable complex.1 2 3 5 7 8 9 11 13 17 21 23 24

• Stabilizes cleavable complex and prevents the topoisomerase from religating the single-strand breaks.2 3 5 7 8 11 13 17 21 23

• Interferes with the moving replication fork, inducing replication arrest and lethal double-stranded breaks in DNA.1 2 4 7 8 9 10 11 13 17 23 This DNA damage is not efficiently repaired and apparently leads to apoptosis (programmed cell death).9 23

• Importance of recognizing and reporting adverse effects including myelosuppressive effects and infectious complications.1

• Risk of weakness or fatigue; use caution when driving or operating machinery until effects on individual are known.1

• Importance of not chewing, crushing, dividing, or opening the capsule.c Capsules must be swallowed whole.c

• Risk of potentially severe diarrhea with oral topotecan.c Importance of contacting clinician if severe diarrhea occurs.c

• If vomiting occurs following a dose of oral topotecan, do not take a replacement dose.c

• Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.1

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.