Topotecan

L01X - Other antineoplastic agents ATC L01XX17 Small molecule approved 1996 Oral Parenteral First-in-class Natural product Black-box warning

JFDA label: Topotecan Hospira

⚠ Black-Box Warning

Bone marrow suppression:

Mechanism of Action

Binds to topoisomerase I and stabilizes the cleavable complex so that religation of the cleaved DNA strand cannot occur. This results in the accumulation of cleavable complexes and single-strand DNA breaks. Topotecan acts in S phase of the cell cycle.

Indications

Approved

Cervical cancer, recurrent or resistant
Injection
Oral
Ovarian cancer, metastatic
Small cell lung cancer, relapsed

Off-label

Acute myeloid leukemia (induction in older adults)
CNS malignancy, relapsed/refractory
Ewing sarcoma
Neuroblastoma, relapsed/refractory
Ovarian cancer, metastatic (off-label [weekly] dosing)
Primary CNS lymphoma, relapsed or refractory
Rhabdomyosarcoma

Class profile

mechanismClass	Plant alkaloid (camptothecin, topoisomerase I inhibitor)
targetMolecule	Topoisomerase I
targetPathway	DNA replication
generation	Classic
primaryTumors	Ovarian,SCLC,Cervical
resistanceMechanisms	ABCG2/BCRP efflux,MDR1/P-gp efflux,Topoisomerase I downregulation
source	NCCN/OncoKB/Goodman&Gilman13ed

Contraindications

Source: Lexicomp

Additional contraindications (not in the US labeling): Severe renal impairment (CrCl Absolute
Severe hypersensitivity to topotecan or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (1)

Very Common Fatigue

Hepatobiliary disorders (1)

Common Increased liver enzymes

Blood and lymphatic system disorders (5)

Very Common Anemia · febrile neutropenia · neutropenia · neutropenic infection · thrombocytopenia

Gastrointestinal disorders (5)

Very Common anorexia · diarrhea · Nausea · vomiting

Common Abdominal pain

Skin and subcutaneous tissue disorders (1)

Very Common Alopecia

Musculoskeletal and connective tissue disorders (1)

Common Weakness

General disorders and administration site conditions (2)

Common Fever · sepsis

Respiratory, thoracic and mediastinal disorders (1)

Common Dyspnea

Dosing

Source: Lexicomp

Note: Baseline neutrophil count should be ≥1,500/mm3 and platelets should be ≥100,000/mm3 prior to treatment; for re-treatment, neutrophil count should be >1,000/mm3; platelets >100,000/mm3 and hemoglobin ≥9 g/dL. IV doses should generally not exceed 4 mg; verify dose prior to administration. Cervical cancer, recurrent or resistant: IV: 0.75 mg/m2/day for 3 days (in combination with cisplatin on day 1 only, [with hydration]) every 21 days Ovarian cancer, metastatic: IV: 1.5 mg/m2/day for 5 consecutive days every 21 days or (off-label dosing) 1.25 mg/m2/day for 5 days every 21 days until disease progression or unacceptable toxicity or a maximum of 12 months (Sehouli 2011) or (weekly administration; off-label dosing) 4 mg/m2 on days 1, 8, and 15 every 28 days until disease progression or unacceptable toxicity or a maximum of 12 months (Sehouli 2011) Small cell lung cancer (SCLC), relapsed: IV: 1.5 mg/m2/day for 5 consecutive days every 21 days Oral: 2.3 mg/m2/day for 5 consecutive days every 21 days (round dose to the nearest 0.25 mg); if patient vomits after dose is administered, do not give a replacement dose. Ewing sarcoma, relapsed/refractory or metastatic (off-label use): IV: 0.75 mg/m2/day for 5 consecutive days every 21 days (in combination with cyclophosphamide) (Hunold 2006; Saylors 2001) Primary CNS lymphoma, relapsed or refractory (off-label use): IV: 1.5 mg/m2 for 5 days every 21 days for a maximum of 10 cycles or until disease progression or unacceptable toxicity (Voloschin 2008). Additional data may be necessary to further define the role of topotecan in this condition. Rhabdomyosarcoma, metastatic (off-label use): Adults 2/day for 5 consecutive days every 21 days for 2 cycles (window therapy; in combination with cyclophosphamide); if objective response occurred by week 6, follow with alternating cycles of vincristine, topotecan, and cyclophosphamide (VTC) with vincristine, dactinomycin, and cyclophosphamide (VAC) (Walterhouse 2004)

(For additional information see "Topotecan: Pediatric drug information") Note: Baseline neutrophil count should be ≥1,500/mm3 and platelets should be ≥100,000/mm3 prior to treatment; for re-treatment, neutrophil count should be >1,000/mm3; platelets >100,000/mm3 and hemoglobin ≥9 g/dL. IV doses should generally not exceed 4 mg; verify dose prior to administration. CNS malignancy, relapsed/refractory (off-label use; based on limited data): Oral: 0.8 mg/m2/day for 21 consecutive days every 4 weeks for ≥12 cycles (Minturn 2011); additional data may be necessary to further define the role of topotecan in this condition Ewing sarcoma, relapsed/refractory or metastatic (off-label use): IV: 0.75 mg/m2/day for 5 consecutive days every 21 days (in combination with cyclophosphamide) (Hunold 2006; Saylors 2001) Neuroblastoma, relapsed/refractory (off-label use): IV: 0.75 mg/m2/day for 5 days every 21 days (in combination with cyclophosphamide) (Ashraf 2013; London 2010) or 2 mg/m2/day for 5 days every 21 days (monotherapy) (London 2010) Rhabdomyosarcoma, metastatic (off-label use): IV: 0.75 mg/m2/day for 5 consecutive days every 21 days for 2 cycles (window therapy; in combination with cyclophosphamide); if objective response occurred by week 6, follow with alternating cycles of vincristine, topotecan, and cyclophosphamide (VTC) with vincristine, dactinomycin, and cyclophosphamide (VAC) (Walterhouse 2004)

Refer to adult dosing.

Manufacturer's labeling: IV (single agent topotecan): CrCl ≥40 mL/minute: No dosage adjustment necessary. CrCl 20 to 39 mL/minute: Reduce dose to 0.75 mg/m2/dose CrCl Oral: CrCl ≥50 mL/minute: No dosage adjustment necessary. CrCl 30 to 49 mL/minute: Reduce dose to 1.5 mg/m2/day; may increase after the 1st cycle by 0.4 mg/m2/day if no severe hematologic or gastrointestinal toxicities occur. CrCl 2/day; may increase after the 1st cycle by 0.4 mg/m2/day if no severe hematologic or gastrointestinal toxicities occur. Alternate recommendations: Aronoff 2007: IV: Adults: CrCl >50 mL/minute: Administer 75% of dose CrCl 10 to 50 mL/minute: Administer 50% of dose CrCl Hemodialysis: Avoid use Continuous ambulatory peritoneal dialysis (CAPD): Avoid use Continuous renal replacement therapy (CRRT): 0.75 mg/m2 Children: CrCl 30 to 50 mL/minute: Administer 75% of dose CrCl 10 to 29 mL/minute: Administer 50% of dose CrCl Continuous renal replacement therapy (CRRT): Administer 50% of dose Kintzel 1995: IV: CrCl 46 to 60 mL/minute: Administer 80% of dose CrCl 31 to 45 mL/minute: Administer 75% of dose CrCl ≤30 mL/minute: Administer 70% of dose

Manufacturer's labeling: IV: Bilirubin 1.7 to 15 mg/dL: There are no dosage adjustments provided in the manufacturer's labeling, although clearance is reduced up to 33%. Oral: There is no dosage adjustment provided in the manufacturer's labeling; however, dosage adjustment is likely not necessary as the pharmacokinetics of topotecan do not differ significantly based on serum bilirubin, ALT, or AST.

Warnings & Precautions

Source: Lexicomp

Bone marrow suppression

May cause severe myelosuppression. Monitor blood counts frequently. Do NOT administer to patients with baseline neutrophils 3 and platelets 3. The dose-limiting toxicity is bone marrow suppression (primarily neutropenia); may also cause thrombocytopenia and anemia. Grade 3 and 4 events were common. Severe myelotoxicity has also been reported when used in combination with cisplatin. Neutropenia is not cumulative over time. The median duration of neutropenia and thrombocytopenia was 7 days and 5 days, respectively. Nadir neutrophil and platelet counts occurred at a median of 15 days (when administered orally). In a clinical study comparing IV to oral topotecan, G-CSF support was administered in a higher percentage of patients receiving oral topotecan (Eckardt 2007). Bone marrow suppression may require dosage reduction and/or growth factor support.

Extravasation

Extravasation injuries have been reported (some severe); if extravasation occurs, discontinue infusion immediately and manage appropriately. Ensure proper needle or catheter placement prior to and during infusion. Avoid extravasation.

Gastrointestinal toxicity

Diarrhea has been reported with oral topotecan; may be severe (requiring hospitalization); educate patients on early recognition and proper management, including diet changes, increase in fluid intake, antidiarrheals, and antibiotics. The median time to onset of diarrhea (grade 2 or worse) was 9 days. The incidence of diarrhea may be higher in the elderly. Do not administer in patients with grade 3 or 4 diarrhea; reduce dose upon recovery to ≤ grade 1 toxicity.

Interstitial lung disease (ILD)

ILD (with fatalities) has been reported; monitor for pulmonary signs/symptoms (eg, dyspnea, fever, cough, hypoxia) and discontinue use in patients with confirmed ILD diagnosis. Risk factors for ILD include a history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and the use of colony-stimulating factors or medication with pulmonary toxicity.

Neutropenic enterocolitis

Topotecan-induced neutropenia may lead to typhlitis (neutropenic enterocolitis), including fatalities; should be considered in patients presenting with neutropenia, fever, and abdominal pain. Disease-related concerns:

Renal impairment

Use with caution in patients with renal impairment; may require dose adjustment. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Topotecan exposure is increased when oral topotecan is used concurrently with P-glycoprotein inhibitors; avoid concurrent use. Other warnings/precautions:

Safety issue

Topotecan overdoses have been reported; potential causes include omission of the leading zero and missing the decimal point when prescribing, preparing, and administering. Recommended intravenous doses should generally not exceed 4 mg in adults; verify dose prior to administration.

Pregnancy & Lactation

Pregnancy

FDA category D

Adverse effects were observed in animal reproduction studies. May cause fetal harm in pregnant women. Women of childbearing potential should use highly effective contraception to prevent pregnancy during treatment and for at least 1 month after therapy discontinuation. Males with female partners of childbearing potential should use highly effective contraception during treatment and for 3 months after therapy discontinuation. Topotecan may have both acute and long-term effects on fertility in women; fertility in males may be impaired due to effects on spermatogenesis.

Lactation

It is not known if topotecan is present in breast milk. Due to the potential for serious adverse reactions in the breastfeeding infant, the manufacturer recommends to discontinue breastfeeding in women who are receiving topotecan.

Monitoring

Efficacy	Tumour response (RECIST criteria, tumour markers, imaging); progression-free survival; performance status (ECOG/Karnofsky)
Toxicity	CBC with differential (nadir timing depends on agent); LFTs; renal function; ECG (QT for relevant agents); echocardiogram for cardiotoxic agents (anthracyclines, trastuzumab); cumulative dose tracking for dose-limited toxicities
Clinical pearl	Treatment response is assessed after 2–3 cycles. Grade 3–4 toxicities typically require dose reduction or interruption per protocol-defined criteria.
Counseling	Attend all scheduled blood tests and imaging appointments. Report fever > 38°C (risk of neutropaenic sepsis — medical emergency), unusual bleeding, or new pain immediately.

Chemistry & Properties

Formula	C23H23N3O5
Molecular weight	421.45 g/mol
IUPAC name	(19S)-8-[(dimethylamino)methyl]-19-ethyl-7,19-dihydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaene-14,18-dione
CAS	123948-87-8
PubChem CID	60700
InChIKey	`UCFGDBYHRUNTLO-QHCPKHFHSA-N`
logP	1.85 (XLogP 0.5)
Polar surface area	104.89 Å²
H-bond acceptors / donors	8 / 2
Drug-likeness (QED)	0.49
Lipinski violations	0

SMILES

CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CN(C)C)c(O)ccc3nc2-1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB -0.42)

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP3A4	Inhibitor	IC₅₀ 1.5211000000000006 µM
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)MATE1 (Inhibitor)MATE2 (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT2 (Inhibitor)P-gp (Inhibitor)BCRP (Substrate)MATE1 (Substrate)MATE2 (Substrate)MDR1 (Substrate)MRP1 (Substrate)MRP2 (Substrate)MRP4 (Substrate)OATP1B1 (Substrate)P-gp (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Carboplatin	major
Certolizumab pegol	major
Cisplatin	major
Clozapine	major
Deferiprone	major
Etanercept	major
Fingolimod	major
Golimumab	major
Infliximab	major
Leflunomide	major
Measles virus vaccine live attenuated	major
Mumps virus strain B level jeryl lynn live antigen	major
Natalizumab	major
Oxaliplatin	major
Ozanimod	major
Rotavirus vaccine	major
Rubella virus vaccine	major
Samarium (153Sm) lexidronam	major
Siponimod	major
Smallpox (Vaccinia) Vaccine, Live	major
Talimogene laherparepvec	major
Teriflunomide	major
Thalidomide	major
Tofacitinib	major
Typhoid vaccine (live)	major
Upadacitinib	major
Varicella Zoster Vaccine (Recombinant)	major
Yellow Fever Vaccine	major
Abemaciclib	moderate
Acalabrutinib	moderate
Aflibercept	moderate
Aldesleukin	moderate
Alefacept	moderate
Alemtuzumab	moderate
Alpelisib	moderate
Altretamine	moderate
Anakinra	moderate

Showing 40 of 100+.

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Hycamtin 4mg Powder For Solution For Infusion	Infusion 4 mg	5	Nabulsi Drug Store	—
Topotecan Hospira	Vial 4 mg/4 ml	5 vial	Petra Drug Store	—