Topotecan is a chemotherapy medication used in the treatment of various types of cancer. It belongs to a class of drugs known as topoisomerase I inhibitors. Topotecan works by interfering with the action of an enzyme called topoisomerase I, which is involved in the replication and repair of DNA in cells. By inhibiting this enzyme, topotecan prevents DNA from unwinding and resealing properly, leading to breaks in the DNA strands and ultimately causing cell death.

Topotecan is a chemotherapeutic drug and acts by inhibiting Topoisomerase 1. It is used in the treatment of lung cancer, ovarian, and cervical cancer.

Indications of Topotecan:

• Recurrent or persistent cervical cancer:
  • It is indicated for treatment (in combination with cisplatin) of stage IVb, recurrent or persistent cervical cancer that is not amenable to curative treatment.
• Metastatic Ovarian cancer:
  • It is used for the treatment of metastatic ovarian cancer (as a single agent) after disease progression on or after initial or subsequent chemotherapy.
• Relapsed or progressive small cell lung cancer:
  • It is used for treating  small cell lung cancer (as a single agent) in patients with a platinum-sensitive disease which has progressed at least 60 days after initiation of first-line chemotherapy.
  • It is also used for relapsed small cell lung cancer in patients with a prior complete or partial response and who are at least 45 days from the end of first-line chemotherapy.
• Off Label Use of Topotecan in Adults:
  • Ewing sarcoma;
  • High-risk Myelodysplastic syndromes;
  • Relapsed or refractory primary CNS lymphoma;
  • Rhabdomyosarcoma

Topotecan dose in Adults

Note:

• Before starting topotecan treatment, make sure your blood counts are at a certain level: your neutrophil count should be at least 1,500 per millimeter, and your platelet count should be at least 100,000 per millimeter.
• If you need to get topotecan again, your neutrophil count should be over 1,000 per millimeter, your platelet count should still be above 100,000 per millimeter, and your hemoglobin should be at least 9 grams per deciliter.
• Usually, the IV dose of topotecan shouldn't go over 4 milligrams, but always double-check the right dose before it's given to you.

Topotecan dose in the treatment of recurrent or persistent Cervical cancer:

• Topotecan is administered intravenously (IV).
• The dose is 0.75 mg/m^2 per day for 3 days, with treatment given on days 1, 2, and 3.
• It is usually used in combination with cisplatin on day 1 only.
• Cisplatin is given on the same day as topotecan, and hydration is typically provided to prevent kidney damage associated with cisplatin.
• This treatment cycle is repeated every 21 days.
• The maximum number of treatment cycles is typically six unless there is a lack of response to the treatment, disease progression, or unacceptable toxicity.

Topotecan dose in the treatment of relapsed/refractory CNS malignancy:

Adults ≤21 years of age:

• Topotecan is administered orally.
• The dose is 0.8 mg/m^2 per day.
• Treatment is given for 21 consecutive days.
• This treatment cycle is repeated every 4 weeks.
• The goal is to complete at least 12 cycles of this treatment regimen.

It's important to note that the use of topotecan for CNS malignancies in this context is considered off-label and is based on limited data, as mentioned.

Topotecan dose in the treatment of metastatic or relapsed/refractory Ewing sarcoma:

• Topotecan is administered intravenously (IV).
• The dose is 0.75 mg/m^2 per day.
• Treatment is given for 5 consecutive days.
• This treatment cycle is repeated every 21 days.
• Topotecan is used in combination with cyclophosphamide.

Topotecan dose in the treatment of High-risk Myelodysplastic syndromes:

• Topotecan is administered intravenously (IV).
• The dose is 1.25 mg/m^2 per day.
• Treatment is given as a continuous infusion for 5 days.
• Topotecan is typically used in combination with cytarabine.

Topotecan dose in the treatment of metastatic Ovarian cancer:

Standard Dosing:

• Topotecan is administered intravenously (IV).
• The dose is 1.5 mg/m^2 per day.
• Treatment is given for 5 consecutive days.
• This treatment cycle is repeated every 21 days.
• Treatment continues until disease progression or unacceptable toxicity, as reported by Ten Bokkel Huinink in 2004.

Off-Label Dosing 1:

• Topotecan is administered intravenously (IV).
• The dose is 1.25 mg/m^2 per day.
• Treatment is given for 5 consecutive days.
• This treatment cycle is repeated every 21 days.
• Treatment continues until disease progression or unacceptable toxicity, or for a maximum duration of 12 months, as reported by Sehouli in 2011.

Off-Label Dosing 2 (Weekly Administration):

• Topotecan is administered intravenously (IV).
• The dose is 4 mg/m^2.
• Treatment is given on days 1, 8, and 15 of a 28-day cycle.
• Treatment continues until disease progression or unacceptable toxicity, or for a maximum duration of 12 months, as reported by Sehouli in 2011.

Topotecan dose in the treatment of Primary relapsed or refractory CNS lymphoma:

• Topotecan is administered intravenously (IV).
• The dose is 1.5 mg/m^2 per day.
• Treatment is given for 5 consecutive days.
• This treatment cycle is repeated every 21 days.
• The maximum number of treatment cycles is typically 10, or treatment may continue until disease progression or unacceptable toxicity, as reported by Voloschin in 2008.

Topotecan dose in the treatment of metastatic Rhabdomyosarcoma:

For children and young adults is as follows:

• Topotecan is administered intravenously (IV).
• The initial dose is 0.75 mg/m^2 per day.
• Treatment is given for 5 consecutive days.
• This initial treatment cycle is repeated every 21 days for 2 cycles (referred to as "window therapy").
• Topotecan is used in combination with cyclophosphamide during this window therapy phase.
• If there is an objective response (meaning a positive treatment effect) by week 6, the treatment plan is modified as follows:
  • Follow with alternating cycles of:
    • Vincristine
    • Topotecan
    • Cyclophosphamide (VTC)
  • These VTC cycles are alternated with cycles of:
    • Vincristine
    • Dactinomycin
    • Cyclophosphamide (VAC)

Topotecan dose in the treatment of relapsed or progressive small cell lung cancer:

Intravenous (IV) Administration:

• The dose is 1.5 mg/m^2 per day.
• Treatment is given for 5 consecutive days.
• This treatment cycle is repeated every 21 days.

Oral Administration:

• The dose is 2.3 mg/m^2 per day.
• Treatment is given for 5 consecutive days (days 1 to 5).
• This treatment cycle is also repeated every 21 days.
• The dose should be rounded to the nearest 0.25 mg.
• If a patient vomits after the dose is administered, do not give a replacement dose.

Topotecan dose in Childrens

Note:

• In adults, before starting this treatment, doctors check your blood to make sure you have enough infection-fighting white blood cells (neutrophils), enough blood clotting cells (platelets), and a certain level of hemoglobin, which is a substance in your blood that carries oxygen.
• If you're getting this treatment again, they check these levels again, but the requirements are a bit lower.
• Make sure to check the specific guidelines for children, as they might be different.
• How much of the medicine you get and how often you get it can change depending on your treatment plan.
• If you're a child, the dose might be based on either your body size or your weight.
• It's really important to double-check all the dosing instructions carefully to make sure you're getting the right amount of medicine.

Topotecan dose in the treatment of recurrent Acute lymphoblastic leukemia:

In the treatment of recurrent acute lymphoblastic leukemia (ALL) in children and adolescents during the induction therapy phase, the topotecan dose is as follows:

• Topotecan is administered intravenously (IV).
• The dose is 2.4 mg/m^2 per dose.
• Treatment is given once daily for 7 to 9 consecutive days.

This dosing regimen is used as part of the induction therapy for recurrent ALL, as reported by Furman in 2002 and Hijiya in 2008.

Topotecan dose in the treatment of recurrent or refractory Acute myeloid leukemia:

In the treatment of recurrent, refractory acute myeloid leukemia (AML) in children and adolescents, the topotecan dosing regimen is as follows:

• Initial Dose: Topotecan is administered intravenously (IV) at a dose of 4 mg/m^2 once on day 1.
• Subsequent Daily Doses (Days 2 to 5): The specific daily doses for days 2 to 5 are determined by pharmacokinetic analysis. The target area under the curve (AUC) is 140 ± 20 ng/mL/hour. These doses are administered once daily in combination with cladribine.

The median reported topotecan dose was 4 mg/m^2 per day, with a range of 1.7 to 6 mg/m^2 per day, as reported by Inaba in 2010.

Topotecan dose in the treatment of CNS malignancies, including gliomas:

Fixed Dosing:

• For infants, children, and adolescents.
• Topotecan is administered orally using a reconstituted lyophilized parenteral formulation.
• The dose is 0.8 mg/m^2 per dose.
• Treatment is given once daily for 21 consecutive days, followed by a 7-day rest period.
• This treatment cycle is repeated every 28 days.
• This dosing regimen was used in a study involving 25 pediatric patients with recurrent brain tumors, including gliomas, medulloblastoma, and ependymoma.
• The reported median number of treatment cycles was 1.9, with a range of 0.5 to 15 cycles (months), as reported by Minturn in 2011.

Dose Escalation:

• For children aged 3 years and older, as well as adolescents.
• Topotecan is administered orally using a reconstituted lyophilized parenteral formulation.
• The initial dose is 0.4 mg/m^2 per dose once daily.
• Dosage is increased based on patient tolerance and individual dose-limiting toxicity.
• Doses are increased in 0.2 mg/m^2 increments at weekly intervals for the first 2 weeks of therapy.
• Afterward, doses are increased in 0.1 mg/m^2 increments at weekly intervals up to a maximum dose of 2 mg/m^2 per day.
• Once the patient's maximum tolerated dose is reached, the daily dose may be decreased if toxicity becomes unacceptable.
• The reported final median maximum tolerated dose was 0.9 mg/m^2 per day, with a range of 0.6 to 2 mg/m^2 per day.
• The median duration of therapy was 3 months, with a range of 21 days to 1 year, as reported by Wagner in 2004.

Topotecan dose in the treatment of Neuroblastoma:

Induction:

Infants, Children, and Adolescents:

IV Administration:

• For patients with a weight of 12 kg or less:
  • Topotecan is administered intravenously (IV).
  • The dose is 0.04 mg/kg per dose once daily for 5 days.
  • This treatment is given in combination with cyclophosphamide.
  • The treatment cycle is repeated every 21 days for a total of 6 cycles.
• For patients with a weight greater than 12 kg:
  • Initial topotecan dose is 1.2 mg/m^2 per dose once daily for 5 days.
  • This treatment is also given in combination with cyclophosphamide.
  • The treatment cycle is repeated every 21 days for a total of 6 cycles.
• Pharmacokinetic analysis is used to guide topotecan therapy during the first 2 cycles, with a target area under the curve (AUC) of 50 to 70 ng/mL/hour.
• Median doses for cycle 1 and cycle 2 may vary based on individual patient responses.

Recurrent, Refractory, or Untreated Metastatic Disease:

IV Administration:

• In children and adolescents, topotecan can be administered intravenously in combination with cyclophosphamide at a dose of 0.75 mg/m^2 per dose once daily for 5 days.
• The treatment cycle is repeated every 21 days.

Monotherapy:

• Alternatively, topotecan can be used as monotherapy at a dose of 2 mg/m^2 per day for 5 days.
• This treatment cycle is also repeated every 21 days.

Oral Administration (Using Reconstituted Lyophilized Parenteral Formulation):

Children ≥2 years and Adolescents:

• Topotecan is administered orally in combination with oral cyclophosphamide.
• The dose is 0.8 mg/m^2 per dose once daily for 14 days.
• The treatment cycle can be repeated every 21 to 28 days.

It's important to note that the specific dosing regimen may vary depending on factors such as the patient's age, weight, and the treatment phase (induction or recurrent/refractory disease). Additionally, individual patient responses may guide dose adjustments during therapy.

Topotecan dose in the conditioning of Hematopoietic stem-cell transplant:

For children and adolescents:

Dosing Regimen 1:

• IV Administration:
  • Topotecan is administered intravenously (IV).
  • The dose is 2 mg/m^2 per dose.
  • Treatment occurs on days -8 through -4 prior to stem cell transfusion.
  • The total cumulative dose of topotecan over this period is 10 mg/m^2.
  • Topotecan is used in combination with carboplatin and thiotepa.
  • This regimen was used in patients with refractory solid tumors, including neuroblastoma.

Dosing Regimen 2:

• IV Administration:
  • Initially, topotecan is given at a dose of 3 mg/m^2 per dose on day -11.
  • Subsequent doses (on days -10 through -2) are determined by pharmacokinetic analysis.
  • The target area under the curve (AUC) is 100 ± 20 ng/mL/hour.
  • Topotecan is administered once daily.
  • It is given in combination with cyclophosphamide on days -6 through -2.
  • The median reported topotecan dose in this regimen was 3.1 mg/m^2 per day, with a range of 1.1 to 4.6 mg/m^2 per day.
  • This dosing regimen was used in a clinical trial involving pediatric patients.

Topotecan dose in the treatment of Pediatric solid tumors, recurrent or refractory or untreated metastatic including rhabdomyosarcoma and Ewing sarcoma:

IV Administration:

• Combination Therapy:
  • Infants, children, and adolescents receive topotecan at a dose of 0.75 mg/m^2 per dose.
  • Treatment is given once daily for 5 consecutive days.
  • This treatment cycle is repeated every 21 days.
  • Topotecan can be used in combination with cyclophosphamide, cyclophosphamide and vincristine (VTC regimen), or in combination with temozolomide in 28-day cycles (TOTEM regimen).
• Single-Agent Therapy (Window Therapy):
  • For single-agent therapy, topotecan is administered at a dose ranging from 2 to 2.4 mg/m^2 per dose.
  • Treatment is given once daily for 5 consecutive days.
  • This treatment cycle is repeated every 21 days.

Oral Administration:

• For Children ≥3 Years and Adolescents:
  • Topotecan is given orally.
  • The dose is 1.8 mg/m^2 per dose once daily for 5 days.
  • This is followed by a 2-day rest period, and then another 5 days of therapy.
  • One complete cycle consists of 10 doses over 12 days.
  • The treatment cycle is repeated every 28 days.
  • In some cases, oral capsules may be used for patients who can swallow the medication.
  • When using oral capsules, doses should be rounded to the nearest 0.25 mg.

Topotecan Dosing adjustment for toxicity in Adults:  

For Cervical Cancer:

• IV Administration:
  • If a patient experiences severe febrile neutropenia (neutrophil count below 1000/mm^3 with a temperature of 38°C) or a platelet count below 25,000/mm^3, the topotecan dose should be reduced to 0.6 mg/m^2 per day for subsequent cycles.
  • Consider the use of G-CSF (granulocyte colony-stimulating factor) support starting on day 4 before instituting a dose reduction for neutropenic fever.
  • If a patient experiences neutropenic fever despite G-CSF use, further reduce the dose to 0.45 mg/m^2 per day for subsequent cycles.

For Ovarian Cancer:

• IV Administration:
  • If a patient experiences severe neutropenia (neutrophil count below 500/mm^3) or a platelet count below 25,000/mm^3, the topotecan dose should be reduced to 1.25 mg/m^2 per day for subsequent cycles.
  • Consider the use of G-CSF support starting on day 6 before instituting a dose reduction for neutropenia.

For Small Cell Lung Cancer:

• IV Administration:
  • If a patient experiences severe neutropenia (neutrophil count below 500/mm^3) or a platelet count below 25,000/mm^3, the topotecan dose should be reduced to 1.25 mg/m^2 per day for subsequent cycles.
  • Consider the use of G-CSF support starting on day 6 before instituting a dose reduction for severe neutropenia.
• Oral Administration:
  • If a patient experiences severe neutropenia (neutrophils below 500/mm^3 associated with fever or infection, or lasting ≥7 days), prolonged neutropenia (neutrophils ≥500/mm^3 to ≤1000/mm^3 lasting beyond day 21), or if platelets drop below 25,000/mm^3, or experiences grades 3 or 4 diarrhea, the dose should be reduced by 0.4 mg/m^2 per day for subsequent cycles.
  • A similar dosage reduction may be considered for grade 2 diarrhea if clinically indicated.

Pregnancy Risk Category: D

• Topotecan can harm an unborn baby if a pregnant woman is exposed to it.
• So, before starting treatment, it's important to make sure that women who can become pregnant are not pregnant.
• During treatment and for at least 6 months after the last dose of topotecan, these women should use effective birth control methods.
• Men who have female partners who can become pregnant should also use effective birth control during treatment and for 3 months after their last topotecan dose.
• Topotecan can affect fertility in both women and men, both in the short term and possibly in the long term, based on studies in animals.

Use of topotecan while breastfeeding

• It's uncertain whether topotecan can be found in breast milk.
• To avoid any potential harm to the baby, the manufacturer advises that breastfeeding should not be done by lactating women during their treatment with topotecan and for one week after their last dose of topotecan.
• This is because there is a risk of serious side effects in the breastfeeding infant.

Topotecan Dose adjustment in renal disease:

IV (Single-Agent Topotecan):

• For patients with a creatinine clearance (CrCl) of 40 mL/minute or higher, no dosage adjustment is necessary.
• If CrCl is between 20 and 39 mL/minute, the dose should be reduced to 0.75 mg/m^2 per dose.
• There are no specific dosage adjustments provided for patients with a CrCl less than 20 mL/minute due to insufficient data.

IV (When Used in Combination with Cisplatin):

• The manufacturer's labeling does not provide specific dosage adjustments for this combination therapy.

Oral:

• For patients with a CrCl of 50 mL/minute or higher, no dosage adjustment is necessary.
• If CrCl is between 30 and 49 mL/minute, the dose should be reduced to 1.5 mg/m^2 per dose.
• For patients with a CrCl less than 30 mL/minute, the dose should be reduced to 0.6 mg/m^2 per dose.

In addition to these manufacturer-recommended adjustments, other dosing recommendations have been proposed:

Kintzel 1995:

• For patients with a CrCl of 46 to 60 mL/minute, administer 80% of the usual dose.
• For patients with a CrCl of 31 to 45 mL/minute, administer 75% of the usual dose.
• For patients with a CrCl of 30 mL/minute or lower, administer 70% of the usual dose.

O’Reilly 1996b:

• For patients with a CrCl of 40 mL/minute or higher (minimally pretreated patients), no dosage adjustment is necessary.
• For patients with a CrCl of 20 to 39 mL/minute (minimally pretreated patients), reduce the dose to 0.75 mg/m^2 or lower, depending on the degree of pretreatment.
• There is insufficient data to make recommendations for patients with a CrCl less than 20 mL/minute.

Hemodialysis and Continuous Ambulatory Peritoneal Dialysis (CAPD):

• Topotecan is generally recommended to be avoided in patients undergoing hemodialysis or CAPD.

Continuous Renal Replacement Therapy (CRRT):

• In patients undergoing CRRT, a dose of 0.75 mg/m^2 has been recommended.

Dose adjustment in liver disease:

• For intravenous (IV) administration of topotecan, the manufacturer's labeling does not provide specific dosage adjustments based on hepatic impairment. However, a small phase I study in patients with hepatic impairment (total bilirubin >1.2 mg/dL) found no significant alterations in pharmacokinetics or pharmacodynamics, suggesting that dosage adjustment may not be necessary in this context (O'Reilly 1996a).

 

• For oral administration of topotecan, the manufacturer's labeling does not offer specific dosage adjustments related to hepatic impairment.

Common Side Effects of Topotecan:

• Central Nervous System:
  • Fatigue
• Dermatologic:
  • Alopecia
• Gastrointestinal:
  • Nausea
  • Diarrhea
  • Vomiting
  • Anorexia
• Hematologic & Oncologic:
  • Anemia
  • Neutropenia
  • Thrombocytopenia
  • Febrile Neutropenia
  • Neutropenic Infection

Rare Side Effects Of Topotecan:

• Central Nervous System:
  • Pain
• Gastrointestinal:
  • Abdominal Pain
  • Constipation
  • Intestinal Obstruction
• Hepatic:
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Bilirubin
• Neuromuscular & Skeletal:
  • Asthenia
• Respiratory:
  • Dyspnea
  • Pneumonia
• Miscellaneous:
  • Fever
  • Sepsis

Uncommon side effects of Topotecan:

• Hematologic & Oncologic:
  • Bone Marrow Depression

Contraindications to Topotecan:

• Topotecan should not be used if a person has a severe allergy to topotecan or any part of the medication.
• In Canada, there are some additional reasons not to use topotecan, including severe kidney problems (when the kidney's filtering function is very low), being pregnant, breastfeeding, or having a severe existing problem with bone marrow (where blood cells are made).

Warnings and precautions

Suppression of bone marrow: [US Boxed Warning]

• Topotecan can cause a significant drop in blood cell counts, which is a serious side effect.
• It's crucial to regularly check the patient's blood counts while they are on this medication.
• In the first treatment cycle, it's given only to patients with a certain level of white blood cells (neutrophils) and platelets to reduce the risk of severe blood cell reduction.
• Neutropenia (low neutrophil count) and thrombocytopenia (low platelet count) are common, and they can be severe, especially during the first treatment cycle.
• These conditions can lead to infections, fever, and even sepsis (a severe infection).
• In some cases, they can be fatal.
• Anemia (low red blood cell count) has also been reported.
• Depending on the severity, the treatment might need to be adjusted, or medications that boost blood cell production may be given to help manage these side effects.

Extravasation

• When administering topotecan intravenously (IV), it's important to be cautious as it can irritate the tissues.
• There have been reports of injuries, including severe ones, when topotecan leaks from the vein into the surrounding tissues (extravasation).
• If this happens, stop the IV infusion right away and take appropriate steps to manage the situation.
• To minimize the risk of extravasation, ensure that the needle or catheter is correctly placed before and during the infusion and take steps to prevent any leakage.
• It's crucial to be vigilant and take prompt action if extravasation occurs during topotecan treatment.

Gastrointestinal toxicities:

• Gastrointestinal issues can occur with topotecan treatment, including diarrhea, which can be severe and even life-threatening, particularly when taking topotecan orally.
• If diarrhea develops, it's essential to monitor for it and start using anti-diarrhea medications as soon as you notice it.
• Severe diarrhea associated with oral topotecan might require hospitalization and can happen at the same time as low white blood cell counts (neutropenia).
• On average, grade 2 or worse diarrhea with oral topotecan starts around 9 days after treatment begins.
• Older patients may be more likely to experience diarrhea.
• Oral topotecan should not be given to patients with grade 3 or 4 diarrhea, and the dose should be reduced if the patient recovers to less severe (grade 1) diarrhea.
• There have been reports of gastrointestinal perforation in some cases.
• To prevent nausea and vomiting, anti-nausea medications may be recommended, especially when taking oral topotecan.
• The likelihood of nausea and vomiting in pediatric patients can vary depending on the dose.

Hypersensitivity

• Some individuals may experience hypersensitivity reactions when taking topotecan.
• These reactions can include allergic reactions, anaphylactoid reactions, and angioedema.
• It's important for healthcare providers to be vigilant and monitor for signs of hypersensitivity during topotecan treatment, and if such reactions occur, appropriate steps should be taken to manage them.

Neutropenic enterocolitis

• Topotecan can lead to a condition called neutropenic enterocolitis, which can be fatal.
• Neutropenic enterocolitis is characterized by neutropenia (low white blood cell count), fever, and abdominal pain.
• Healthcare providers should consider the possibility of this condition in patients who have neutropenia, fever, and abdominal pain while on topotecan treatment.
• Timely diagnosis and management are crucial in such cases to prevent severe complications.

Toxicity in the lungs:

• Pulmonary toxicity, including interstitial lung disease (ILD), which can be a severe and sometimes fatal lung condition, has been reported in individuals taking topotecan.
• Healthcare providers should carefully monitor patients for any signs or symptoms of lung problems while on topotecan treatment.
• If ILD is confirmed, topotecan should be permanently discontinued.
• Certain factors may increase the risk of ILD, including a history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation therapy, or the use of colony-stimulating factors or medications known to have pulmonary toxicity.
• Awareness of these risk factors is important in the management of patients receiving topotecan.

Renal impairment:

• Renal impairment, which refers to kidney problems, may necessitate adjustments in the dose of topotecan.
• Patients with compromised kidney function may require a different dosing regimen to ensure the medication is used safely and effectively.

Topotecan: Drug Interaction

Risk Factor C (Monitor therapy)
Chloramphenicol (Ophthalmic)	May enhance the adverse/toxic effect of Myelosuppressive Agents.
CloZAPine	Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased.
Coccidioides immitis Skin Test	Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test.
Denosumab	May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
Mesalamine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Ocrelizumab	May enhance the immunosuppressive effect of Immunosuppressants.
Pidotimod	Immunosuppressants may diminish the therapeutic effect of Pidotimod.
Promazine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Siponimod	Immunosuppressants may enhance the immunosuppressive effect of Siponimod.
Tafamidis	May increase the serum concentration of BCRP/ABCG2 Substrates.
Tertomotide	Immunosuppressants may diminish the therapeutic effect of Tertomotide.
Trastuzumab	May enhance the neutropenic effect of Immunosuppressants.
Risk Factor D (Consider therapy modification)
Baricitinib	Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted.
Deferiprone	Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely.
Echinacea	May diminish the therapeutic effect of Immunosuppressants.
Fingolimod	Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections).
Fosphenytoin-Phenytoin	May decrease the serum concentration of Topotecan. Management: Monitor topotecan response closely, and consider alternatives to phenytoin when possible. No specific guidelines for topotecan dose adjustment are available.
Granulocyte Colony-Stimulating Factors	May enhance the adverse/toxic effect of Topotecan. Specifically, the risk for the development of interstitial lung disease may be increased. Granulocyte Colony-Stimulating Factors may enhance the myelosuppressive effect of Topotecan. Management: Avoid use of granulocyte colony-stimulating factors (G-CSFs) until at least 24 hours after the last dose of topotecan. Additionally, monitor patients closely for the development of interstitial lung disease with this combination.
Lenograstim	Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy.
Lipegfilgrastim	Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy.
Nivolumab	Immunosuppressants may diminish the therapeutic effect of Nivolumab.
Palifermin	May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy.
Platinum Derivatives	May enhance the adverse/toxic effect of Topotecan.
Roflumilast	May enhance the immunosuppressive effect of Immunosuppressants.
Sipuleucel-T	Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T.  Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy.
Tofacitinib	Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants.
Tolvaptan	May increase the serum concentration of BCRP/ABCG2 Substrates.
Vaccines (Inactivated)	Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation.
Risk Factor X (Avoid combination)
BCG (Intravesical)	Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical).
BCG (Intravesical)	Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical).
BCRP/ABCG2 Inhibitors	May increase the serum concentration of Topotecan.
Cladribine	May enhance the immunosuppressive effect of Immunosuppressants.
Cladribine	May enhance the myelosuppressive effect of Myelosuppressive Agents.
Dipyrone	May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
Natalizumab	Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
P-glycoprotein/ABCB1 Inhibitors	May increase the serum concentration of Topotecan.
Pimecrolimus	May enhance the adverse/toxic effect of Immunosuppressants.
Tacrolimus (Topical)	May enhance the adverse/toxic effect of Immunosuppressants.
Vaccines (Live)	Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants.
Velpatasvir	May increase the serum concentration of Topotecan.
Voxilaprevir	May increase the serum concentration of BCRP/ABCG2 Substrates.

Monitoring parameters:

Blood Counts:

• Regularly check Complete Blood Count (CBC) with differential and platelet count to monitor for any changes in blood cell levels.
• This helps ensure that the patient's blood cell counts stay within safe ranges during treatment.

Kidney Function:

• Conduct renal function tests to assess the patient's kidney health.
• Adjust the dose as needed in patients with renal impairment to prevent complications.

Bilirubin Levels:

• Monitor bilirubin levels to assess liver function.
• This can help detect any potential liver issues related to topotecan treatment.

Pregnancy Test:

• Before starting treatment, perform a pregnancy test in females of reproductive potential to confirm pregnancy status.
• It's crucial to know if a patient is pregnant before initiating topotecan therapy.

Interstitial Lung Disease Symptoms:

• Keep an eye out for symptoms of interstitial lung disease, such as breathing difficulties or cough.
• Early detection and management of lung issues are essential for patient safety.

Diarrhea and Hydration:

• Monitor for symptoms of diarrhea and assess the patient's hydration status.
• Severe diarrhea can be a side effect of topotecan, and proper hydration is important.

Infusion Site:

• Regularly inspect the infusion site if topotecan is administered intravenously.
• This helps detect any signs of extravasation or other issues related to the infusion.

Adherence (Oral Therapy):

• If the patient is on oral topotecan, monitor their adherence to the prescribed treatment regimen.
• Ensuring consistent dosing is important for treatment effectiveness.

How to administer Topotecan?

Intravenous (IV) Administration:

• Administer topotecan IV as a piggyback infusion over a 30-minute period.
• When using topotecan in combination with cisplatin, provide hydration as pretreatment.
• Be aware that IV topotecan can be irritating to the veins and tissues.
• Ensure proper placement of the IV needle or catheter before and during the infusion.
• Take measures to prevent extravasation (leakage of the medication from the vein into surrounding tissues).
• If extravasation occurs, immediately stop the infusion and manage the situation appropriately.

Oral Administration:

• Administer oral topotecan with or without food, as directed.
• If a dose is missed or the patient vomits after taking the dose, do not give an additional dose. Instead, continue with the next scheduled dose.
• Swallow the oral capsules whole; do not crush, open, chew, or divide them.
• For patients who have difficulty swallowing capsules, topotecan solution for injection (1 mg/mL) can be mixed with up to 30 mL of acidic fruit juice (such as apple, orange, or grape) just before oral administration.

These administration guidelines help ensure the safe and effective use of topotecan, whether administered intravenously or orally. Proper administration techniques, caution against extravasation, and adherence to dosing instructions are essential for patient well-being during topotecan treatment.

Mechanism of action of Topotecan:

• Topotecan works by binding to a protein called topoisomerase I.
• It forms a complex with this protein and prevents it from reconnecting the broken strands of DNA.
• This leads to the accumulation of broken DNA strands and single-strand DNA breaks in the cells.
• Topotecan primarily acts during the S phase of the cell cycle, a stage where DNA is being replicated.

Note: It's worth noting that in pediatric patients and young adults, the way their bodies process topotecan can vary significantly from person to person. There can be differences in how the drug is absorbed, distributed, and eliminated, both between individuals and within the same individual over time. This variability makes it important to carefully monitor and adjust dosages as needed to achieve the desired therapeutic effect while minimizing side effects.

Distribution:

• In pediatric patients and young adults (0.4 to 22 years of age), the volume of distribution (Vd) for topotecan ranges from 32.2 to 32.7 L/m². This indicates how the drug spreads throughout the body.
• In adults, the Vd for topotecan can range from 25 to 75 L/m², showing some variability based on individual factors.
• About 35% of topotecan in the bloodstream is bound to proteins.

Metabolism:

• Topotecan undergoes a reversible pH-dependent hydrolysis of its active lactone ring in the plasma. In an acidic environment (pH ≤4), the active ring form is dominant, while at physiologic pH, the ring-opened hydroxy acid form becomes more prevalent.
• In the liver, topotecan is metabolized into its N-demethylated metabolite.

Bioavailability:

• The bioavailability of oral topotecan capsules in adults is approximately 40%. Data from pediatric patients (1 to 18 years of age) indicate that the bioavailability with the oral reconstituted parenteral solution is similar to that in adults.

Half-life Elimination:

• In pediatric patients (0 to 18 years of age), the half-life of the lactone form of topotecan is approximately 2.58 hours, with some variability.
• In adults, the half-life of topotecan ranges from 2 to 3 hours for intravenous administration and 3 to 6 hours for oral administration.

Time to Peak in Plasma:

• In pediatric patients (1 to 18 years of age), the time to reach peak plasma levels for the parenteral formulation (reconstituted lyophilized formulation) is between 0.75 to 2 hours.
• In adults, oral topotecan reaches peak plasma levels in 1 to 2 hours, and this may be delayed by a high-fat meal (taking 3 to 4 hours).

Excretion:

• Topotecan is excreted primarily through the urine (51% for IV; 20% for oral) and, to a lesser extent, in feces (18% for IV; 33% for oral).
• A portion of topotecan is excreted as its N-desmethyl metabolite.

Clearance:

• In pediatric patients (0.4 to 18 years of age), renal clearance is a significant determinant of topotecan clearance, and a linear model with glomerular filtration rate (GFR) has been observed.
• Body surface area (BSA) also plays a role in clearance, with infants under 6 months having decreased clearance.
• In pediatric patients with severe renal impairment, other mechanisms besides GFR may assist with renal clearance, as overall systemic clearance was shown to be similar to matched controls despite decreased GFR.

Topotecan Brand Names (International):

• Hycamtin
• ACT Topotecan
• Hycamtin
• PMS-Topotecan
• Camtoop
• Canol
• Firotex
• Hycamtin
• Hykamtin
• Oncotecan
• Potactasol
• Potekam
• Topocan
• Topodria
• Topokebir
• Topotel
• Toranex

Topotecan Brand Names in Pakistan:

Topotecan Injection 4 mg
Hycamtin	Glaxosmithkline
Topokebir	Oncogene Pharmaceuticals Karachi
Topotel	Atco Laboratories Limited