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    Camptothecin Analogs

    BOXED WARNING

    Anemia, bone marrow suppression, herpes infection, infection, neutropenia, thrombocytopenia, varicella, viral infection

    Topotecan can cause severe bone marrow suppression, including neutropenia, thrombocytopenia, and anemia. Administer the first cycle of topotecan only to patients with baseline neutrophil counts of 1,500 cells/mm3 or greater and platelet counts of 100,000 cells/mm3 or greater. Frequently monitor blood counts during treatment. Subsequent courses of topotecan should not be administered until the neutrophil count is greater than 1,000 cells/mm3, the platelet count is greater than 100,000 cells/mm3, and the hemoglobin concentration is greater than 9 g/dL (transfusion may be necessary); a dose reduction of topotecan may be necessary. After treatment with oral topotecan, the median day for neutrophil and platelet nadirs occurred on day 15. Grade 4 neutropenia occurred most commonly in cycle 1 of therapy for both oral and intravenous topotecan, for a median duration of 7 days. Patients with active infection should be treated prior to receiving topotecan. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.[33536] [46322]

    DEA CLASS

    Rx

    DESCRIPTION

    A camptothecin derivative, topoisomerase I inhibitor
    Used for the treatment of small cell lung cancer, cervical cancer, and ovarian cancer
    Can cause severe myelosuppression; closely monitor complete blood counts

    COMMON BRAND NAMES

    Hycamtin

    HOW SUPPLIED

    Hycamtin Oral Cap: 0.25mg, 1mg
    Hycamtin/Topotecan/Topotecan Hydrochloride Intravenous Inj Pwd F/Sol: 4mg
    Topotecan/Topotecan Hydrochloride Intravenous Inj Sol: 1mg, 1mL

    DOSAGE & INDICATIONS

    For the treatment of patients with metastatic ovarian cancer with disease progression on or after initial or subsequent chemotherapy.
    NOTE: Patients must have a baseline neutrophil count greater than 1,500 cells/mm3 and a baseline platelet count greater than 100,000 cells/mm3 before the first cycle of topotecan. Do NOT give subsequent courses of topotecan until the neutrophil count is greater than 1,000 cells/mm3, the platelet count is greater than 100,000 cells/mm3, and the hemoglobin concentration is greater than 9 g/dL (transfusion may be necessary).
    Intravenous infusion dosage
    Adults

    1.5 mg/m2 IV (maximum dose, 4 mg) once daily over 30 minutes on days 1, 2, 3, 4, and 5, every 21 days until disease progression or unacceptable toxicity. In a multicenter, randomized, phase 3 clinical trial, women with ovarian cancer that progressed during or after platinum-based chemotherapy were randomized to receive either topotecan or paclitaxel 175 mg/m2 IV over 3 hours on day 1 every 21 days. The overall response rate (ORR) was 21% vs. 14% (not significant) in patients treated with topotecan (n = 112) compared with paclitaxel (n = 114), including complete responses in 5% versus 3%, respectively; the median time to response was 7.6 weeks vs. 6 weeks, respectively. Patients who received topotecan also had nonsignificant improvements in duration of response (6 months vs. 5 months), time to progression (4.4 months vs. 3.4 months), and overall survival (14.5 months vs. 12.2 months) compared with paclitaxel. Studies concluded topotecan is active in ovarian patients who had developed resistance to platinum-containing therapy, defined as tumor progression while on or tumor relapse within 6 months after completion of, a platinum-containing regimen.[28677] [46322]

    For the treatment of small cell lung cancer (SCLC).
    NOTE: Patients must have a neutrophil count > 1500 cells/mm3 and a platelet count > 100,000 cells/mm3 before topotecan initiation. Do NOT give subsequent courses of topotecan until the neutrophil count is > 1000 cells/mm3, the platelet count is > 100,000 cells/mm3, and the hemoglobin concentration is > 9 g/dL (transfusion may be necessary).
    For platinum-sensitive small cell lung cancer (SCLC) who progressed at least 60 days after initiation of first-line chemotherapy.
    Intravenous infusion dosage
    Adults

    1.5 mg/m2/day IV over 30 minutes on days 1, 2, 3, 4, and 5, every 21 days. In a randomized, phase III clinical trial, patients with recurrent or progressive SCLC treated with topotecan (n = 107) had a non-significant improvement in overall response (24% vs. 18%) compared with CAV (n = 104; cyclophosphamide 1000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg IV every 21 days), including mostly partial responses (24% vs. 17%); the median time to response was 6 weeks in each arm. Patients treated with topotecan also had non-significant improvements in duration of response (3.3 months vs. 3.5 months), time to progression (3.1 months vs. 2.8 months; HR 0.92; 95% CI, 0.69—1.22), and overall survival (5.8 months vs. 5.7 months; HR 1.04; 95% CI, 0.78—1.39). Patients who received topotecan noted improvement in disease-related symptoms such as dyspnea, fatigue, hoarseness, cough, insomnia, anorexia, and chest pain. Additionally, patients who received topotecan reported significant improvements in their ability to complete activities of daily living when compared to those treated with CAV.

    For relapsed small cell lung cancer (SCLC) in patients with a prior complete or partial response and who are at least 45 days from the end of first-line chemotherapy.
    Oral dosage
    Adults and Geriatric

    2.3 mg/m2/day PO on days 1, 2, 3, 4, and 5, every 21 days. Round the calculated oral daily dose to the nearest 0.25 mg, and prescribe the minimum number of 1 mg and 0.25 mg capsules. Prescribe the same number of capsules for each of the 5 dosing days. Do not give a replacement dose if the patient vomits. In a randomized, controlled, open-label clinical trial of patients with relapsed small cell lung cancer (SCLC), median overall survival was 6 months (95% CI, 4.2—7.3 months) for patients treated with topotecan capsules plus best supportive care (BSC) (n = 71), compared with 3.2 months (95% CI, 2.6—4.3 months) for patients who received BSC alone (n = 70).

    For chemotherapy-naive, extensive-stage SCLC in combination with paclitaxel†.
    Intravenous infusion dosage
    Adults

    Topotecan 1 mg/m2 IV days 1, 2, 3, 4, and 5, every 28 days in combination with paclitaxel (135 mg/m2 IV as a 24-hour infusion on day 5 following topotecan) was evaluated in a phase II trial for the treatment of chemotherapy-naive extensive stage SCLC. Initially, topotecan dosing was 1.25 mg/m2 IV on days 1—5; however, due to excessive hematologic toxicity in the first 3 patients, the dose was reduced as above. Patients received an average of 4 cycles of chemotherapy. The overall response rate was 69%, overall median survival was 54 weeks with a 1-year survival rate of 50%. Despite the use of prophylactic G-CSF, the incidence of grade 4 neutropenia was 31%, which may have been increased due to the 24-hour administration of paclitaxel. Overall, response rates and tolerability of this regimen were comparable to platinum/etoposide.

    For chemotherapy-naive, extensive-stage SCLC sequentially after treatment with cisplatin and etoposide†.
    Intravenous infusion dosage
    Adults

    Following the completion of 4 cycles of cisplatin/etoposide, topotecan 1.5 mg/m2 IV on days 1, 2, 3, 4, and 5, every 21 days for 4 courses was compared to observation in a phase III trial in chemotherapy-naive extensive-stage SCLC patients. Of the 402 patients who received 4 cycles of cisplatin/etoposide, patients with stable or responding disease (n = 223) were subsequently randomized to receive topotecan or observation. Complete response and partial response rate for the cisplatin/etoposide portion were 3% and 32%, respectively. Response rate for the topotecan arm was 7% (CR 2%, PR 5%). Progression-free survival was significantly better with topotecan compared to observation (3.7 months versus 2.3 months; p < 0.001). Overall survival was not significantly different (9.3 months versus 8.9 months for topotecan versus observation; p = 0.43). Although topotecan improved progression-free survival, no improvement was found in overall survival or quality of life measures. Subsequent phase II and phase III trials produced clinical outcomes for cisplatin/etoposide with sequential topotecan that were consistent with these results.

    For the treatment of stage IV-B recurrent or persistent cervical cancer that is not amendable to curative treatment with surgery and/or radiation therapy.
    NOTE: Patients must have a neutrophil count > 1500 cells/mm3 and a platelet count > 100,000 cells/mm3 before topotecan initiation. Do NOT give subsequent courses of topotecan until the neutrophil count is > 1000 cells/mm3, the platelet count is > 100,000 cells/mm3, and the hemoglobin concentration is > 9 g/dL (transfusion may be necessary).
    Intravenous infusion dosage
    Adults

    0.75 mg/m2 IV on days 1, 2, and 3 in combination with cisplatin (50 mg/m2 IV day 1 only) every 3 weeks. Dosage adjustments for subsequent courses are specific for each drug. In a phase III, trial topotecan in combination with cisplatin (TP) (n=147) was compared to cisplatin alone (n=146) and MVAC in the management of advanced cervical cancer. The MVAC arm was closed prematurely due to excessive toxicity; data from this arm were not evaluated for response. Patients receiving TP had statistically better outcomes as compared to those receiving cisplatin alone with overall response rates of 27% vs. 13%, progression-free survival of 4.6 months vs. 2.9 months, and median survival of 9.4 months vs. 6.5 months, respectively. Patients receiving TP did experience an increased incidence of Grade 3 and 4 hematologic toxicity as compared to those treated with cisplatin alone. Additionally quality of life (QOL) was evaluated for patients on this phase III trial. Adjusting for age, baseline scores, and effects of time, there were no statistically significant differences in QOL between the 2 groups despite the increased incidence of hematologic toxicity in the combination arm.

    For the treatment of metastatic rhabdomyosarcoma† in combination with cyclophosphamide and vincristine alternating with VAC.
    Intravenous infusion dosage
    Adults, Adolescents, Children, and Infants

    Dosage not established. 0.75 mg/m2/day IV on days 1—5 immediately following cyclophosphamide 250 mg/m2/day IV on days 1—5 (TC) in combination with vincristine (age > 3 years: 1.5 mg/m2 ; age 1—3 years: 0.05 mg/kg; age < 1 year: 0.025 mg/kg) IV day 1 (VTC) in weeks 3, 9, 21, 27, 33, and 39 alternating with vincristine (age > 3 years: 1.5 mg/m2; age 1—3 years: 0.05 mg/kg; age < 1 year: 0.025 mg/kg; max 2 mg) IV day 1, dactinomycin (age >= 1 years: 0.045 mg/kg; age < 1 year: 0.025 mg/kg; max 2.5 mg) IV day 1, and cyclophosphamide (age > 3 years: 2200 mg/m2 ; age 1—3 years: 73 mg/kg; age < 1 years: 36 mg/kg) IV day 1 (VAC) in weeks 0, 6, 12, 24, 30, 36; vincristine 1.5 mg/m2 IV was given alone in weeks 1, 2, 4, 5, 7, 8, 10, 11, 19, 20, 22, 23, 34, and 35. To prevent hemorrhagic cystitis, mesna 250 mg/m2/day IV on days 1—5 was given immediately prior to cyclophosphamide administration. During the VAC segment, mesna 450 mg/m2 IV was given immediately before cyclophosphamide and every 3 hours for 3 additional doses after cyclophosphamide. In a phase III clinical trial, VAC/VTC was compared to VAC in 617 patients with previously untreated intermediate-risk rhabdomyosarcoma. The primary endpoint, failure-free survival (FFS), was not significantly different between the two treatment arms (68% VAC/VTC vs 73% VAC, p = 0.3) when measured at 4 years. In addition, the estimated overall survival (OS) at 4 years was 79% for both treatment groups. Neutropenia occurred significantly more often in patients who received VAC only (78% v. 85%, p = 0.04). In a phase II trial of newly diagnosed metastatic rhabdomyosarcoma, 61 patients under the age of 21 received VTC alternating with VAC. After 41 weeks of therapy, 34% achieved a CR. Disease-free survival at 3 years was 10% while 3-year overall survival was 20%. No unexpected toxicities occurred during treatment.

    For the treatment of non-small cell lung cancer (NSCLC)†.
    For the treatment of previously untreated advanced non-small cell lung cancer (NSCLC) in combination with gemcitabine†.
    Intravenous dosage
    Adults

    1 mg/m2 IV on days 1—5 plus gemcitabine (1000 mg/m2 IV on days 1 and 15). The cycle was repeated every 28 days. In a phase II study of 51 patients with previously untreated advanced NSCLC, 17% of patients had a partial response while 23% had stable disease. The 1-year survival rate was 39% with median survival of 7.6 months. There were no treatment related deaths in the study, however, grade 3 and 4 neutropenia (53%), anemia (18%), and thrombocytopenia (10%) were observed.

    For the second-line treatment of advanced non-small cell lung cancer in combination with gemcitabine†.
    Intravenous dosage
    Adults

    0.75 mg/m2 IV on days 1—5 in combination with gemcitabine (400 mg/m2 IV on days 1 and 5). The cycle was repeated every 21 days. In a phase II trial, 35 patients with advanced non-small cell lung cancer received topotecan/gemcitabine in the second-line setting. Partial response was observed in 11% of patients while 23% had stable disease. Of the 17 patient with refractory disease, the partial response rate was 18%, and 18% had stable disease. For all patients, the median survival was 7 months with a 1-year survival rate of 20%.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Intravenous: 4 mg IV
    Oral: 2.3 mg/m2 per day PO

    Geriatric

    Intravenous: 4 mg IV
    Oral: 2.3 mg/m2 per day PO

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    The threshold creatinine clearance rate for reduced oral or intravenous doses is different.
    For the oral formulation:
    CrCL 50 to 80 mL/min: No dosage adjustment needed.
    CrCL 30 to 49 mL/min: Reduce the dose of topotecan to 1.5 mg/m2 PO once daily.
    CrCL less than 30 mL/min: Reduce the dose of topotecan to 0.6 mg/m2 PO once daily.[33536]
     
    For the intravenous formulation:
    Monotherapy, CrCL 40 to 60 mL/min: No dosage adjustment needed.
    Monotherapy, CrCL 20 to 39 mL/min: Reduce the dose of topotecan to 0.75 mg/m2 IV once daily.
    Monotherapy, CrCL less than 20 mL/min: Insufficient data are available to provide a dosage recommendation.[46322]
     
    Intermittent hemodialysis
    In a case report, a patient underwent a 4-hour hemodialysis (HD) procedure using a Fresenius HD machine which utilized a Terumo 220 cuperammonium Rayon H dialysis filter. Approximately 60% of the total drug amount was removed by HD.[28673]

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 1
    NIOSH (Draft) 2020 List: Table 1
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Oral Doses: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
    Injectable Doses: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
    If direct contact of the capsule contents or the topotecan solution with the skin or mucous membranes occurs, thoroughly wash the exposed area with soap and water or wash the eyes immediately with gently flowing water for at least 15 minutes.
    Emetic Risk
    Pediatrics:
    Oral Doses 0.4 to 2.3 mg/m2/day: Moderate
    Administer routine antiemetic prophylaxis prior to treatment.
    Adults:
    Oral Doses: Minimal/Low
    Administer prn antiemetics as necessary.
    IV Doses: Low
    Administer routine antiemetic prophylaxis prior to treatment.]
    Extravasation Risk
    Irritant

    Oral Administration

    Do not open, chew, divide, or crush the capsules. The capsules need to be intact when swallowed.
    The capsules may be taken with or without food.
    If a dose is missed or vomiting occurs after taking a dose, do not administer an additional dose. Give the next dose at the scheduled time.[33536]

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Preparation of infusion
    Reconstitute each 4 mg-vial with 4 mL Sterile Water for Injection.
    Because the vials do not contain preservatives, the contents should be used immediately after reconstitution. Discard any unused portion.
    Withdraw the appropriate volume of the reconstituted solution, and further dilute in either 0.9% Sodium Chloride Injection or 5% Dextrose Injection prior to administration.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The reconstituted solution is yellow or yellow-green.
    Stability after dilution: Protect from light. Reconstituted topotecan, diluted for infusion, is stable at 20 to 25 degrees C (68 to 77 degrees F) for 24 hours.[46322]
     
    Intravenous infusion
    Infuse intravenously over 30 minutes.[46322]

    STORAGE

    Generic:
    - Discard 28 days after first use
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in carton until contents are used
    Hycamtin:
    - Refrigerate (between 36 and 46 degrees F)
    - Store in the original carton to protect from light

    CONTRAINDICATIONS / PRECAUTIONS

    Anemia, bone marrow suppression, herpes infection, infection, neutropenia, thrombocytopenia, varicella, viral infection

    Topotecan can cause severe bone marrow suppression, including neutropenia, thrombocytopenia, and anemia. Administer the first cycle of topotecan only to patients with baseline neutrophil counts of 1,500 cells/mm3 or greater and platelet counts of 100,000 cells/mm3 or greater. Frequently monitor blood counts during treatment. Subsequent courses of topotecan should not be administered until the neutrophil count is greater than 1,000 cells/mm3, the platelet count is greater than 100,000 cells/mm3, and the hemoglobin concentration is greater than 9 g/dL (transfusion may be necessary); a dose reduction of topotecan may be necessary. After treatment with oral topotecan, the median day for neutrophil and platelet nadirs occurred on day 15. Grade 4 neutropenia occurred most commonly in cycle 1 of therapy for both oral and intravenous topotecan, for a median duration of 7 days. Patients with active infection should be treated prior to receiving topotecan. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.[33536] [46322]

    Abdominal pain, colitis, diarrhea, fever

    Diarrhea, including severe and life-threatening diarrhea requiring hospitalization, can occur with topotecan capsules. Diarrhea can occur at the same time as drug-induced neutropenia and its sequelae. Fatal typhlitis (neutropenic entero-colitis) has also been reported with both oral and intravenous topotecan; consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain. The median time to onset of grade 2 to 4 diarrhea was 9 days in patients treated with topotecan capsules. Monitor patients for diarrhea and treat with antidiarrheals at the first sign of diarrhea. Hold treatment and reduce the dose of topotecan as recommended based on severity.[46322] [33536]

    Chronic lung disease (CLD), lung cancer, pneumonitis, pulmonary disease, pulmonary fibrosis, radiation therapy

    Cases of interstitial lung disease (ILD) / pneumonitis, including some fatalities, have been reported with the use of topotecan. Patients with a history of ILD, pulmonary disease, chronic lung disease (CLD), pulmonary fibrosis, lung cancer, exposure to thoracic radiation therapy, and the use of pneumotoxic drugs or colony stimulating factors may have an increased risk. Monitor patients for pulmonary symptoms suggestive of ILD including cough, fever, dyspnea, and/or hypoxia. Permanently discontinue topotecan if ILD is confirmed.[33536] [46322]

    Extravasation, serious hypersensitivity reactions or anaphylaxis

    Topotecan is contraindicated in patients who have a history of serious hypersensitivity reactions or anaphylaxis to topotecan; anaphylactoid reactions have been reported.[33536] [46322] Additionally, topotecan is an irritant; avoid extravasation. Should extravasation occur, immediately stop administration of IV topotecan and begin appropriate management procedures.[46322]

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during topotecan treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, topotecan can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving topotecan should be apprised of the potential hazard to the fetus. Maternal toxicity, embryolethality, and reduced fetal body weight occurred when topotecan was given to rabbits at doses roughly equivalent to the 1.5 mg/m2 clinical IV dose based on BSA on days 6 to 20 of gestation. In rats, similar exposure for 14 days prior to mating through day 6 of gestation resulted in fetal resorption, microphthalmia, pre-implant loss, and mild maternal toxicity. Increased post-implantation mortality in rats occurred on days 6 to 17 of gestation at about half of the 1.5 mg/m2 IV dose based on BSA, along with increased fetal malformations including microphthalmia, anophthalmia, rosette formation of the retina, coloboma of the retina, ectopic orbit, dilated lateral and third ventricles, and skull and vertebrae malformations.[46322] [33536]

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during topotecan treatment. Topotecan can be teratogenic if taken by the mother during pregnancy; it may also damage spermatozoa, resulting in possible genetic and fetal abnormalities (male-mediated teratogenicity). Females should avoid pregnancy and use effective contraception during and for 6 months after treatment with topotecan; males with a female sexual partner of reproductive potential should use effective contraception during and for 3 months after completion of topotecan therapy. Females of reproductive potential should undergo pregnancy testing prior to initiation of topotecan. Women who become pregnant while receiving topotecan should be apprised of the potential hazard to the fetus. In addition, based on animal data, topotecan may have both acute and long-term effects on female fertility (infertility). Because of effects on spermatogenesis, males should also be advised of the potential risk for impaired fertility and family planning options prior to treatment.[33536] [46322]

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from topotecan, advise women to discontinue breast-feeding during treatment and for 1 week after the last dose. It is not known whether topotecan is present in human milk, although many drugs are excreted in human milk.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 25.0-80.0
    thrombocytopenia / Delayed / 6.0-44.0
    anemia / Delayed / 25.0-42.0
    vomiting / Early / 1.0-10.0
    nausea / Early / 1.0-10.0
    dyspnea / Early / 0-9.0
    asthenia / Delayed / 0-9.0
    fever / Early / 2.0-8.0
    fatigue / Early / 0-7.0
    abdominal pain / Early / 0-6.0
    diarrhea / Early / 4.4-6.0
    GI obstruction / Delayed / 0-5.0
    infection / Delayed / 2.0-5.0
    elevated hepatic enzymes / Delayed / 0-4.0
    anorexia / Delayed / 0-2.0
    hyperbilirubinemia / Delayed / 0-2.0
    alopecia / Delayed / 0-0.1
    bleeding / Early / Incidence not known
    GI perforation / Delayed / Incidence not known
    typhlitis / Delayed / Incidence not known
    enterocolitis / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    injection site reaction / Rapid / Incidence not known
    pleural effusion / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    acute respiratory distress syndrome (ARDS) / Early / Incidence not known

    Moderate

    bone marrow suppression / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    pneumonitis / Delayed / Incidence not known
    bone pain / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    dyspareunia / Delayed / Incidence not known
    neuropathic pain / Delayed / Incidence not known

    Mild

    myalgia / Early / Incidence not known
    pelvic pain / Delayed / Incidence not known
    dysmenorrhea / Delayed / Incidence not known
    back pain / Delayed / Incidence not known
    headache / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    weight gain / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    malaise / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    lethargy / Early / Incidence not known

    DRUG INTERACTIONS

    Abrocitinib: (Major) Avoid coadministration of abrocitinib with oral topotecan due to increased topotecan exposure; abrocitinib may be administered with intravenous topotecan. Oral topotecan is a substrate of the P-gp and abrocitinib is a P-gp inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Acalabrutinib: (Major) Avoid coadministration of acalabrutinib with oral topotecan due to increased topotecan exposure; acalabrutinib may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and acalabrutinib is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Amiodarone: (Major) Avoid coadministration of amiodarone with oral topotecan due to increased topotecan exposure; amiodarone may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and amiodarone is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin with oral topotecan due to increased topotecan exposure; clarithromycin may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and clarithromycin is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of cobicistat with oral topotecan due to increased topotecan exposure; cobicistat may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); cobicistat is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Berotralstat: (Major) Avoid coadministration of berotralstat with oral topotecan due to increased topotecan exposure; berotralstat may be administered with intravenous topotecan. Oral topotecan is a substrate of the P-glycoprotein (P-gp) and berotralstat is a P-gp inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Brigatinib: (Moderate) Monitor for an increase in topotecan-related adverse reactions if coadministration of oral topotecan with brigatinib is necessary. Oral topotecan is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Cabozantinib: (Major) Avoid coadministration of cabozantinib with oral topotecan due to increased topotecan exposure; cabozantinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp). Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Cannabidiol: (Major) Avoid coadministration of cannabidiol with oral topotecan due to increased topotecan exposure; cannabidiol may be administered with intravenous topotecan. Oral topotecan is a substrate of the P-gp and cannabidiol is a P-gp inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Capmatinib: (Major) Avoid coadministration of capmatinib with oral topotecan due to increased topotecan exposure; capmatinib may be administered with intravenous topotecan. Oral topotecan is a P-glycoprotein (P-gp) and BCRP substrate. Capmatinib is a P-gp and BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Clarithromycin: (Major) Avoid coadministration of clarithromycin with oral topotecan due to increased topotecan exposure; clarithromycin may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and clarithromycin is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Cobicistat: (Major) Avoid coadministration of cobicistat with oral topotecan due to increased topotecan exposure; cobicistat may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); cobicistat is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Conivaptan: (Major) Avoid coadministration of conivaptan with oral topotecan due to increased topotecan exposure; conivaptan may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and conivaptan is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Cyclosporine: (Major) Avoid coadministration of cyclosporine with oral topotecan due to increased topotecan exposure; cyclosporine may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and cyclosporine is a P-gp inhibitor. Oral administration of topotecan within 4 hours of cyclosporine increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Daclatasvir: (Major) Avoid coadministration of daclatasvir with oral topotecan due to increased topotecan exposure; daclatasvir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); daclatasvir is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Darolutamide: (Major) Avoid coadministration of darolutamide with oral topotecan due to increased topotecan exposure; darolutamide may be administered with intravenous topotecan. Coadministration increases the risk of topotecan-related adverse effects. Oral topotecan is a substrate of the breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
    Darunavir; Cobicistat: (Major) Avoid coadministration of cobicistat with oral topotecan due to increased topotecan exposure; cobicistat may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); cobicistat is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of cobicistat with oral topotecan due to increased topotecan exposure; cobicistat may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); cobicistat is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of dasabuvir with oral topotecan due to increased topotecan exposure; dasabuvir may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and dasabuvir is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. (Major) Avoid coadministration of paritaprevir with oral topotecan due to increased topotecan exposure; paritaprevir may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and paritaprevir is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. (Major) Avoid coadministration of ritonavir with oral topotecan due to increased topotecan exposure; ritonavir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ritonavir is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of quinidine with oral topotecan due to increased topotecan exposure; quinidine may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and quinidine is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Dronedarone: (Major) Avoid coadministration of dronedarone with oral topotecan due to increased topotecan exposure; dronedarone may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and dronedarone is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Elagolix: (Major) Avoid coadministration of elagolix with oral topotecan due to increased topotecan exposure; elagolix may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and elagolix is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of elagolix with oral topotecan due to increased topotecan exposure; elagolix may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and elagolix is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Elbasvir; Grazoprevir: (Major) Avoid coadministration of elbasvir with oral topotecan due to increased topotecan exposure; elbasvir may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and elbasvir is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. (Major) Avoid coadministration of grazoprevir with oral topotecan due to increased topotecan exposure; grazoprevir may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and grazoprevir is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Elexacaftor; tezacaftor; ivacaftor: (Major) Avoid coadministration of ivacaftor with oral topotecan due to increased topotecan exposure; ivacaftor may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ivacaftor is a weak P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Eliglustat: (Major) Avoid coadministration of eliglustat with oral topotecan due to increased topotecan exposure; eliglustat may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and eliglustat is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Eltrombopag: (Major) Avoid coadministration of eltrombopag with oral topotecan due to increased topotecan exposure; eltrombopag may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and eltrombopag is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of cobicistat with oral topotecan due to increased topotecan exposure; cobicistat may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); cobicistat is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of cobicistat with oral topotecan due to increased topotecan exposure; cobicistat may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); cobicistat is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Enasidenib: (Major) Avoid coadministration of enasidenib with oral topotecan due to increased topotecan exposure; enasidenib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-gp and BCRP and enasidenib is a P-gp and BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Erythromycin: (Major) Avoid coadministration of erythromycin with oral topotecan due to increased topotecan exposure; erythromycin may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and erythromycin is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of erythromycin with oral topotecan due to increased topotecan exposure; erythromycin may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and erythromycin is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Etravirine: (Major) Avoid coadministration of etravirine with oral topotecan due to increased topotecan exposure; etravirine may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and etravirine is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Flibanserin: (Major) Avoid coadministration of flibanserin with oral topotecan due to increased topotecan exposure; flibanserin may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and flibanserin is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Fostamatinib: (Major) Avoid coadministration of fostamatinib with oral topotecan due to increased topotecan exposure; fostamatinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); fostamatinib is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Fostemsavir: (Major) Avoid concomitant use of fostemsavir with oral topotecan due to increased topotecan exposure; fostemsavir may be administered with intravenous topotecan. Oral topotecan is a substrate of BCRP and fostemsavir is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Gilteritinib: (Major) Avoid coadministration of gilteritinib with oral topotecan due to increased topotecan exposure; gilteritinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Glecaprevir; Pibrentasvir: (Major) Avoid coadministration of glecaprevir with oral topotecan due to increased topotecan exposure; glecaprevir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); glecaprevir is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold. (Major) Avoid coadministration of pibrentasvir with oral topotecan due to increased topotecan exposure; pibrentasvir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); pibrentasvir is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Grapefruit juice: (Major) Avoid taking oral topotecan with grapefruit juice due to increased topotecan exposure; grapefruit juice may be taken with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and grapefruit juice is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Ibrutinib: (Major) Avoid coadministration of ibrutinib with oral topotecan due to increased topotecan exposure; ibrutinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); ibrutinib is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Isavuconazonium: (Major) Avoid coadministration of isavuconazonium with oral topotecan due to increased topotecan exposure; isavuconazonium may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and isavuconazonium is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Istradefylline: (Major) Avoid coadministration of istradefylline with oral topotecan due to increased topotecan exposure; istradefylline may be administered with intravenous topotecan. Oral topotecan is a substrate of P-gp and istradefylline is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Itraconazole: (Major) Avoid coadministration of itraconazole with oral topotecan due to increased topotecan exposure; itraconazole may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); itraconazole is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Ivacaftor: (Major) Avoid coadministration of ivacaftor with oral topotecan due to increased topotecan exposure; ivacaftor may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ivacaftor is a weak P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Ketoconazole: (Major) Avoid coadministration of ketoconazole with oral topotecan due to increased topotecan exposure; ketoconazole may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ketoconazole is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of clarithromycin with oral topotecan due to increased topotecan exposure; clarithromycin may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and clarithromycin is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Lapatinib: (Major) Avoid coadministration of lapatinib with oral topotecan due to increased topotecan exposure; lapatinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and lapatinib is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of ledipasvir with oral topotecan due to increased topotecan exposure; ledipasvir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); ledipasvir is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Leflunomide: (Major) Avoid coadministration of leflunomide with oral topotecan due to increased topotecan exposure; leflunomide may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and leflunomide is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Levoketoconazole: (Major) Avoid coadministration of ketoconazole with oral topotecan due to increased topotecan exposure; ketoconazole may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ketoconazole is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Lomitapide: (Major) Avoid coadministration of lomitapide with oral topotecan due to increased topotecan exposure; lomitapide may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and lomitapide is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Lonafarnib: (Major) Avoid coadministration of lonafarnib with oral topotecan due to increased topotecan exposure; lonafarnib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and lonafarnib is a P-gp inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of ritonavir with oral topotecan due to increased topotecan exposure; ritonavir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ritonavir is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of ivacaftor with oral topotecan due to increased topotecan exposure; ivacaftor may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ivacaftor is a weak P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Maribavir: (Major) Avoid coadministration of maribavir with oral topotecan due to increased topotecan exposure; maribavir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-gp and BCRP and maribavir is a P-gp and BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Mefloquine: (Major) Avoid coadministration of mefloquine with oral topotecan due to increased topotecan exposure; mefloquine may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and mefloquine is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Midostaurin: (Major) Avoid coadministration of midostaurin with oral topotecan due to increased topotecan exposure; midostaurin may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and midostaurin is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Mifepristone: (Major) Avoid coadministration of mifepristone with oral topotecan due to increased topotecan exposure; mifepristone may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and mifepristone is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Mitapivat: (Major) Avoid coadministration of mitapivat with oral topotecan due to increased topotecan exposure; mitapivat may be administered with intravenous topotecan. Oral topotecan is a substrate of the P-gp and mitapivat is a P-gp inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with oral topotecan due to increased topotecan exposure; sirolimus may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and sirolimus is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Nelfinavir: (Major) Avoid coadministration of nelfinavir with oral topotecan due to increased topotecan exposure; nelfinavir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and nelfinavir is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Neratinib: (Major) Avoid coadministration of neratinib with oral topotecan due to increased topotecan exposure; neratinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and neratinib is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Nirmatrelvir; Ritonavir: (Major) Avoid coadministration of ritonavir with oral topotecan due to increased topotecan exposure; ritonavir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ritonavir is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of paritaprevir with oral topotecan due to increased topotecan exposure; paritaprevir may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and paritaprevir is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. (Major) Avoid coadministration of ritonavir with oral topotecan due to increased topotecan exposure; ritonavir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ritonavir is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Osimertinib: (Major) Avoid coadministration of osimertinib with oral topotecan due to increased topotecan exposure; osimertinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); osimertinib is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Pacritinib: (Major) Avoid coadministration of pacritinib with oral topotecan due to increased topotecan exposure; pacritinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-gp and BCRP; pacritinib is a P-gp and BCRP inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Posaconazole: (Major) Avoid coadministration of posaconazole with oral topotecan due to increased topotecan exposure; posaconazole may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and posaconazole is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Propafenone: (Major) Avoid coadministration of propafenone with oral topotecan due to increased topotecan exposure; propafenone may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and propafenone is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Quinidine: (Major) Avoid coadministration of quinidine with oral topotecan due to increased topotecan exposure; quinidine may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and quinidine is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Quinine: (Major) Avoid coadministration of quinine with oral topotecan due to increased topotecan exposure; quinine may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and quinine is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Ranolazine: (Major) Avoid coadministration of ranolazine with oral topotecan due to increased topotecan exposure; ranolazine may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ranolazine is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Regorafenib: (Major) Avoid coadministration of regorafenib with oral topotecan due to increased topotecan exposure; regorafenib may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and regorafenib is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Ritonavir: (Major) Avoid coadministration of ritonavir with oral topotecan due to increased topotecan exposure; ritonavir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ritonavir is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Rolapitant: (Major) Avoid coadministration of rolapitant with oral topotecan due to increased topotecan exposure; rolapitant may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); rolapitant is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Safinamide: (Major) Avoid coadministration of safinamide with oral topotecan due to increased topotecan exposure; safinamide may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and safinamide is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Saquinavir: (Major) Avoid coadministration of saquinavir with oral topotecan due to increased topotecan exposure; saquinavir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and saquinavir is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Sarecycline: (Major) Avoid coadministration of sarecycline with oral topotecan due to increased topotecan exposure; sarecycline may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp); sarecycline is a P-gp inhibitor.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Simeprevir: (Major) Avoid coadministration of simeprevir with oral topotecan due to increased topotecan exposure; simeprevir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); simeprevir is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Sirolimus: (Major) Avoid coadministration of sirolimus with oral topotecan due to increased topotecan exposure; sirolimus may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and sirolimus is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with oral topotecan due to increased topotecan exposure; velpatasvir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); velpatasvir is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with oral topotecan due to increased topotecan exposure; velpatasvir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); velpatasvir is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold. (Major) Avoid coadministration of voxilaprevir with oral topotecan due to increased topotecan exposure; voxilaprevir may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); voxilaprevir is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Sorafenib: (Major) Avoid coadministration of sorafenib with oral topotecan due to increased topotecan exposure; sorafenib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and sorafenib is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Sotorasib: (Major) Avoid coadministration of sotorasib with oral topotecan due to increased topotecan exposure; sotorasib may be administered with intravenous topotecan. Oral topotecan is a substrate of the P-gp and sotorasib is a P-gp inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Sulfasalazine: (Major) Avoid coadministration of sulfasalazine with oral topotecan due to increased topotecan exposure; sulfasalazine may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and sulfasalazine is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Tacrolimus: (Major) Avoid coadministration of tacrolimus with oral topotecan due to increased topotecan exposure; tacrolimus may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and tacrolimus is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Tafamidis: (Major) Avoid coadministration of tafamidis with oral topotecan due to increased topotecan exposure; tafamidis may be administered with intravenous topotecan. Oral topotecan is a substrate of the breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse effects.
    Tedizolid: (Major) Avoid coadministration of tedizolid with oral topotecan due to increased topotecan exposure; tedizolid may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and tedizolid is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Temsirolimus: (Major) Avoid coadministration of temsirolimus with oral topotecan due to increased topotecan exposure; temsirolimus may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and temsirolimus is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Tepotinib: (Major) Avoid coadministration of tepotinib with oral topotecan due to increased topotecan exposure; tepotinib may be administered with intravenous topotecan. Oral topotecan is a substrate of the P-gp and tepotinib is a P-gp inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Teriflunomide: (Major) Avoid coadministration of teriflunomide with oral topotecan due to increased topotecan exposure; teriflunomide may be administered with intravenous topotecan. Oral topotecan is a substrate of the Breast Cancer Resistance Protein (BCRP) and teriflunomide is a BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions.
    Tezacaftor; Ivacaftor: (Major) Avoid coadministration of ivacaftor with oral topotecan due to increased topotecan exposure; ivacaftor may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ivacaftor is a weak P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Ticagrelor: (Major) Avoid coadministration of ticagrelor with oral topotecan due to increased topotecan exposure; ticagrelor may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ticagrelor is a weak P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Tolvaptan: (Major) Avoid coadministration of tolvaptan with oral topotecan due to increased topotecan exposure; tolvaptan may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and tolvaptan is a weak P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Trandolapril; Verapamil: (Major) Avoid coadministration of verapamil with oral topotecan due to increased topotecan exposure; verapamil may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and verapamil is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Tucatinib: (Major) Avoid coadministration of tucatinib with oral topotecan due to increased topotecan exposure; tucatinib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and tucatinib is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Vemurafenib: (Major) Avoid coadministration of vemurafenib with oral topotecan due to increased topotecan exposure; vemurafenib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); vemurafenib is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
    Venetoclax: (Major) Avoid coadministration of venetoclax with oral topotecan due to increased topotecan exposure; venetoclax may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and venetoclax is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Verapamil: (Major) Avoid coadministration of verapamil with oral topotecan due to increased topotecan exposure; verapamil may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and verapamil is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Voclosporin: (Major) Avoid coadministration of voclosporin with oral topotecan due to increased topotecan exposure; voclosporin may be administered with intravenous topotecan. Oral topotecan is a substrate of the P-gp and voclosporin is a P-gp inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Zonisamide: (Major) Avoid coadministration of zonisamide with oral topotecan due to increased topotecan exposure; zonisamide may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and zonisamide is a weak P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.

    PREGNANCY AND LACTATION

    Pregnancy

    Pregnancy should be avoided by females of reproductive potential during topotecan treatment and for at least 6 months after the last dose. Although there are no adequately controlled studies in pregnant animals or humans, topotecan can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving topotecan should be apprised of the potential hazard to the fetus. Maternal toxicity, embryolethality, and reduced fetal body weight occurred when topotecan was given to rabbits at doses roughly equivalent to the 1.5 mg/m2 clinical IV dose based on BSA on days 6 to 20 of gestation. In rats, similar exposure for 14 days prior to mating through day 6 of gestation resulted in fetal resorption, microphthalmia, pre-implant loss, and mild maternal toxicity. Increased post-implantation mortality in rats occurred on days 6 to 17 of gestation at about half of the 1.5 mg/m2 IV dose based on BSA, along with increased fetal malformations including microphthalmia, anophthalmia, rosette formation of the retina, coloboma of the retina, ectopic orbit, dilated lateral and third ventricles, and skull and vertebrae malformations.[46322] [33536]

    Due to the potential for serious adverse reactions in nursing infants from topotecan, advise women to discontinue breast-feeding during treatment and for 1 week after the last dose. It is not known whether topotecan is present in human milk, although many drugs are excreted in human milk.

    MECHANISM OF ACTION

    All camptothecin analogs, including topotecan, work by inhibiting topoisomerase I, a cellular enzyme involved in maintaining the topographic structure of DNA during translation, transcription, and mitosis. Topoisomerase I relieves the torsional strain in the DNA helix during replication and RNA transcription by inducing single-strand breaks. By binding with the topoisomerase I/DNA complex, topotecan prevents the relegation of the single-strand breaks. However, this activity is not sufficient to cause cytotoxicity because the complexes are easily reversible once the drug is removed. The cytotoxicity of topotecan is thought to be due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. As a result of this complex formation, both the initial cleavage reaction and relegation steps are inhibited. Irreversible DNA damage occurs when a DNA replication fork encounters the topotecan-topoisomerase I complex resulting in double-strand DNA breaks (Replication Collision Model). Camptothecins are highly S-phase specific in their activity due to the requirement of DNA synthesis. Inhibitors of DNA synthesis, such as hydroxyurea, can protect cells from camptothecin-induced cytotoxicity. As with other agents that damage DNA, camptothecins cause cycle arrest in the G2-phase; however, the actual mechanisms of cell death following camptothecin administration has not been determined.[28669]
     
    The 'Transcription Collision Model' has been proposed to explain S-phase-independent cellular activity of camptothecins. In this model, the collision between topoisomerase I-cleavage complexes found on the template strand and elongating RNA polymerase results in transcription arrest and conversion of topoisomerase I cleavage complexes into irreversible single strand breaks. Ultimately, this cascade results in the termination of RNA transcription at the arrested site, causes double-strand breakage, and cell death.[28669] Additional cellular effects exerted by camptothecins include inhibition of RNA synthesis, multi-ubiquitination and degradation of topoisomerase I, chromatin reorganization, and activation of signal transduction molecules. Other effects of camptothecins include radiation sensitization and antiviral effects. Topoisomerase I inhibitors appear to inhibit initial DNA repairs including sealing of broken strands and repair of base damage following radiation therapy. Camptothecins have been shown to decrease HIV-1 replication but the mechanism has not been established. Camptothecins can cause damage at the chromosomal level. However, little is known about the possible long-term toxicities of camptothecins. Other DNA-damaging agents such as alkylating agents and topoisomerase II inhibitors have been associated with mutagenicity and secondary malignancies.
     
    Exposure to topoisomerase I and II inhibitors results in synergistic antitumor effects when administered sequentially. This is secondary to the upregulation of topoisomerase levels and by increasing the topoisomerase II mRNA expression after 24 to 48 hours. These effects have been exemplified utilizing mice tumor-xenografts.[28670]
     
    Mechanisms of resistance to topotecan include inadequate accumulation of drug in the tumor secondary to overexpression of MDR-1, P-glycoprotein, the breast cancer resistance protein (BCRP), and/or other transporters which result in increased activity of efflux mechanisms. Point mutations of topoisomerase I confer resistance to topoisomerase inhibitors via alternations of the minor and major grooves of DNA which results in instability of the topotecan-topoisomerase I-DNA ternary complex. Loss of topoisomerase I nucleolar localization may result in a decrease in the overall amount of topoisomerase I associated with DNA. Overexpression of the X-ray repair cross-complementing gene I protein (XRCC) leads to topotecan resistance in cells. XRCC protein is involved with base-excision repair mechanisms. Overexpression bcl-2 has been associated with relative resistance to topotecan. The clinical implications of these resistance mechanisms are under investigation. [28670] [28671]

    PHARMACOKINETICS

    Topotecan is administered orally and intravenously, with approximately 35% bound to plasma proteins.[33536] [46322] The volume of distribution is approximately 75 liters/m2, indicating that the lactone form is extensively bound to tissue components; topotecan does penetrate the blood-brain barrier and has been measured in the cerebrospinal fluid. Plasma protein binding is about 7% to 35%. Based on a small study (n = 4), the presence or absence of pleural or ascitic fluids does not affect topotecan clearance, terminal disposition half-lives, or AUC ratios of lactone to total drug in plasma.[59812] [59813] It undergoes reversible pH-dependent hydrolysis of its lactone moiety, with an equilibrium existing between the lactone and ring-opened hydroxy-acid (carboxylate) forms. At pH of 4 or less, the pharmacologically active lactone form is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH.[33536] [46322] In vitro studies indicate topotecan is metabolized to an N-demethylated metabolite.[46322] The mean metabolite: parent AUC ratio was less than 10% for total topotecan and topotecan lactone following oral administration and approximately 3% after IV administration.[33536] [46322]
     
    Overall recovery of drug-related material after 5 daily doses of topotecan was 57% after oral administration and 73.4% (+/- 2.3%) after IV administration. A mean value of 20% of the oral dose and 51% (+/- 3%) of the IV dose was recovered in the urine as total topotecan; 2% and 3% (+/- 1%), respectively, were recovered in the urine as N-desmethyl topotecan. Fecal elimination of total topotecan accounted for 33% of the dose after oral administration, and 18% (+/- 4%) after IV administration; 1.5% and 1.7% (+/- 0.6%), respectively, were excreted in the feces as N-desmethyl topotecan.[33536] [46322] An O-glucuronide metabolite of both topotecan and N-desmethyl topotecan have been identified in the urine.[46322] Overall, the N-desmethyl metabolite contributed a mean of less than 6% (range, 4% to 8%) of the total drug-related material accounted for in the urine and feces.[33536]
     
    Affected cytochrome P450 isoenzymes and drug transporters: BCRP, P-glycoprotein (P-gp)
    Topotecan is a substrate of BCRP and P-gp. In vitro inhibition studies indicate that topotecan is not affected by the activity of CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, CYP4A, or dihydropyrimidine dehydrogenase.[46322] [33536]

    Oral Route

    Following doses of 1.2 to 3.1 mg/m2 (0.52 to 1.35 times the recommended dose) daily for 5 days, the area under the curve (AUC) increased proportionally with dose. The time to peak plasma concentrations (Tmax) was 1 to 2 hours, with oral bioavailability of approximately 40%. Following a high-fat meal, the AUC was similar to fed and fasted states, although the Tmax was delayed from 1.5 to 3 hours for topotecan lactone and from 3 to 4 hours for total topotecan. The mean terminal half-life was 3 to 6 hours after oral administration.[33536]

    Intravenous Route

    Hydrolysis of the lactone to the open-ring form of topotecan occurs immediately upon infusion, with a lactone: total topotecan ratio of 0.69 at the end of a 30-minute infusion. Following infusion, topotecan exhibits a two-compartment pharmacokinetic model with a terminal half-life of 2 to 3 hours. At doses of 0.5 to 1.5 mg/m2 (0.1 to 0.3 times the recommended single-agent dose), the AUC is approximately dose-proportional.[46322]