Consumer medicine information

Hycamtin

Topotecan

BRAND INFORMATION

Brand name

Hycamtin

Active ingredient

Topotecan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Hycamtin.

SUMMARY CMI

HYCAMTIN®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I given Hycamtin?

Hycamtin contains the active ingredient topetecan (as hydrochloride). Hycamtin is used to treat ovarian cancer, small cell lung cancer and cervical cancer.

For more information, see Section 1. Why am I given Hycamtin? in the full CMI.

2. What should I know before I am given Hycamtin?

Do not use if you have ever had an allergic reaction to Hycamtin or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given Hycamtin? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Hycamtin and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is Hycamtin given?

  • Your doctor will decide the dosage of Hycamtin to be given to you. The dosage you receive is based on your height and weight.
  • Your doctor or nurse will inject the necessary dose of Hycamtin. Hycamtin is given into the vein by an intravenous drip over a 30 minute period.
  • Hycamtin is given once daily for five days for the treatment of ovarian and small cell lung cancer and once every day for three days for cervical cancer. This is usually repeated every three weeks from the start of each course. This may vary depending on the results of your blood tests. Your doctor will decide how many courses of Hycamtin you will need.

More instructions can be found in Section 4. How do is Hycamtin given? in the full CMI.

5. What should I know while being given Hycamtin?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Hycamtin.
  • Remember to have your blood tests regularly, as instructed by your doctor.
  • Tell your doctor immediately if you experience a fever or any other symptoms of infection or any bleeding or bruising.
Things you should not do
  • Do not have any vaccinations without your treating doctor's approval. In addition, avoid contact with anyone who has recently received the oral polio vaccine.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Hycamtin affects you.
Looking after your medicine
  • Hycamtin is usually stored at the hospital or at the pharmacy.
  • Store in a cool, dry place where temperatures stay below 30°C.

For more information, see Section 5. What should I know while being given Hycamtin? in the full CMI.

6. Are there any side effects?

Common side effects: feeling generally weak and tired (anaemia), weight loss, loss of appetite, feeling sick (nausea), being sick (vomiting), stomach pain, diarrhoea, constipation, high body temperature (fever)

Serious side effects: sore throat, urinary problems (burning sensation when urinating), severe stomach pain, raised and itchy rash (hives), swelling of face or mouth, difficulty breathing, cough

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

HYCAMTIN®

Active ingredient(s): topotecan (as hydrochloride)

Consumer Medicine Information (CMI)

This leaflet provides important information about using Hycamtin. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Hycamtin.

Where to find information in this leaflet:

1. Why am I using Hycamtin?
2. What should I know before I use Hycamtin?
3. What if I am taking other medicines?
4. How do I use Hycamtin?
5. What should I know while using Hycamtin?
6. Are there any side effects?
7. Product details

1. Why am I using Hycamtin?

Hycamtin contains the active ingredient topetecan hydrochloride. Hycamtin is an anti-cancer medicine that works by killing cancer cells and preventing cancer cells from reproducing.

Hycamtin is used to treat patients with either of the following cancers:

  • ovarian cancer
  • small cell lung cancer
  • cervical cancer.

Your doctor may have prescribed Hycamtin for another reason.

2. What should I know before I use Hycamtin?

Warnings

Do not use Hycamtin if:

  • you are allergic to topetecan (as hydrochloride), or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you have a very low blood count.

Check with your doctor if you:

  • have any other medical conditions
    - kidney problems; the dosage of Hycamtin may need to be reduced
    - liver problems
    - bleeding or bruising; Hycamtin may cause a reduction in blood cells which may increase the risk of bleeding
    - fever or other symptoms of infection; Hycamtin may decrease your body's ability to fight infection
    - recurrent exposure to chickenpox or shingles (Herpes zoster). Treatment with Hycamtin may increase the severity of these infections.
  • take any medicines for any other condition
  • Many medicines used to treat cancer may impair your ability to have children in the future. Talk to your doctor if you are concerned about how Hycamtin might affect your ability to have children

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take if you are pregnant, think you may be pregnant, or if you intend to become pregnant.

Female patients who might become pregnant should make sure they are not pregnant before starting treatment. Hycamtin may harm your unborn baby.

If you are a woman who could become pregnant, you must use effective birth control (contraception) during treatment with Hycamtin. Ask your doctor for methods of effective birth control.

If you are breast-feeding, check with your doctor before you are given Hycamtin.

Do not restart breast-feeding until your doctor tells you that it is safe to do so.

Male patients

  • Male patients being treated with Hycamtin, with female partners who are or may become pregnant, should use condoms during sexual intercourse and for at least three months after stopping treatment with Hycamtin.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

In particular, mention if you are receiving any other medicines to treat cancer.

Some medicines may interfere with Hycamtin and affect how it works. Your doctor or pharmacist will be able to tell you what to do when receiving Hycamtin with other medicines.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Hycamtin.

4. How Hycamtin is given?

How much is given

  • Your doctor will decide the dosage of Hycamtin to be given to you. The dosage you receive is based on your height and weight.

How Hycamtin is given

  • Your doctor or nurse will inject the necessary dose of Hycamtin.
  • Hycamtin is given into the vein by an intravenous drip over a 30 minute period.
  • Hycamtin is given once daily for five days for the treatment of ovarian and small cell lung cancer and once every day for three days for cervical cancer. This is usually repeated every three weeks from the start of each course. This may vary depending on the results of your blood tests. Your doctor will decide how many courses of Hycamtin you will need.

If you have any concerns about Hycamtin, talk to your doctor or pharmacist.

If too much Hycamtin is given

In the event of suspected overdose, you will be monitored by your doctor and treated for any unwanted side effects that may occur.

There is no antidote for an overdose of Hycamtin.

If you think that you have been given too much Hycamtin, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Hycamtin?

Things you should do

  • Follow your doctor's directions regarding treatment with Hycamtin.
  • Remember to keep your appointments with your doctor. If you miss an appointment, contact your doctor for instructions.
    It is very important that your doctor checks your progress at regular visits.
  • Remember to have your blood tests regularly, as instructed by your doctor. Hycamtin may cause a reduction in blood cells which may make you prone to infection and bleeding.
  • If you see another doctor or dentist for treatment, tell them you are being treated with Hycamtin.
  • If you experience low blood counts, there are precautions you can take to reduce the risk of infection or bleeding:
    - Avoid people with infections
    - Take care when using a toothbrush, dental floss or toothpick. Your doctor, dentist or nurse may recommend other ways to clean your teeth and gums.
    - Take care not to cut yourself when using sharp objects such as a safety razor or nail cutters.
    - Avoid contact sports or other situations where bruising or injury could occur.
  • Check with your doctor before having any dental work done.

Call your doctor straight away if you:

  • experience a fever or any other symptoms of infection or any bleeding or bruising

Remind any doctor, dentist or pharmacist you visit that you are using Hycamtin.

Things you should not do

  • Do not have any vaccinations without your treating doctor's approval. In addition, avoid contact with anyone who has recently received the oral polio vaccine.
    Hycamtin may lower your body's resistance to infection. Some vaccines may cause illness in people with decreased resistance to infection.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Hycamtin affects you.

Looking after your medicine

  • Hycamtin is an anti-cancer medicine which requires special care in handling and preparation. It should be given to your pharmacist, doctor or nurse as soon as possible.
  • Hycamtin is usually stored at the hospital or at the pharmacy.

Store it in a cool dry place below 30°C away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date or the packaging is torn or shows signs of tampering.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Like most anti-cancer drugs, Hycamtin may cause some unwanted side effects. Some side effects will have symptoms that you will notice. Your doctor may check for others by doing certain tests. Some side effects may need medical treatment.

Hycamtin may cause other unwanted effects that may not occur until months or years after it is given. These delayed effects may include a decreased ability to have children or certain types of cancer. Discuss these possible effects with your treating doctor.

Like many anticancer medicines, Hycamtin may cause you to feel sick or be sick. You will be prescribed medicines to help prevent these side effects.

Less serious side effects

Less serious side effectsWhat to do
General
  • feeling generally weak and tired (anaemia), which can occasionally require blood transfusion
  • tiredness; weakness; feeling unwell
  • mild pain and inflammation at the site of injection
  • itching sensation
Gastrointestinal or Gut related
  • feeling sick (nausea), being sick (vomiting), stomach pain, diarrhoea, constipation
  • weight loss and loss of appetite (anorexia)
Others
  • inflammation and ulcers of the mouth, tongue or gums
  • high body temperature (fever)
  • hair loss
Speak to your doctor if you have any of these less serious side effects and they worry you.
They are generally mild and do not cause patients to stop taking Hycamtin.

Serious side effects

Serious side effectsWhat to do
Allergy related
  • allergic or hypersensitivity reaction
  • raised and itchy rash (hives)
  • swelling, sometimes of the face or mouth (angioedema), causing difficulty in breathing
  • collapse

These are very rare in people receiving Hycamtin.


Signs of infection
  • local symptoms such as sore throat or urinary problems (for example, a burning sensation when urinating, which may be caused by a urinary infection)
  • fever
  • diarrhoea and vomiting
  • feeling extremely weak

Hycamtin may reduce your white blood cell count (neutropenia), lowering your resistance to infection.


Liver related
  • yellow skin (jaundice)
Signs of gastrointestinal perforation (bowel inflammation)
  • severe stomach pain, nausea, vomiting of blood, black or bloody stools
  • fever
  • diarrhoea (rarely with blood)
Signs of mucosal inflammation
  • Mouth sores, difficulty swallowing, abdominal pain, nausea, vomiting, diarrhoea, bloody stool
Lungs related
  • lung inflammation (interstitial lung disease)
  • difficulty breathing
  • cough
  • fever

This rarely occurs in people taking Hycamtin. You are most at risk if you have existing lung disease, have had radiation treatment to your lungs, or have previously taken medicines that caused lung damage.


Blood related
  • low numbers of cells needed for blood clotting. This can cause bruising, bleeding, and rarely, severe bleeding (haemorrhage).
Call your doctor straight away, or go straight to the Emergency Department nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Your doctor, nurse or pharmacist may be able to tell you about ways to prevent or reduce some of these side effects.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Hycamtin contains

Active ingredient
(main ingredient)		topetecan (as hydrochloride)
Other ingredients
(inactive ingredients)
  • tartaric acid (E334)
  • mannitol
  • hydrochloric acid (E507)
  • sodium hydroxide (E524)
Potential allergens
  • mannitol

Do not take this medicine if you are allergic to any of these ingredients.

What Hycamtin looks like

Hycamtin 4mg powder for infusion – clear glass vials with grey butyl rubber stoppers and aluminium seals with plastic flip-off caps. The vials contain topotecan as a yellow powder (Aust R 58598).

Who distributes Hycamtin

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Tel: 1800 726 369

This leaflet was prepared in November 2022.

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Hycamtin

Active ingredient

Topotecan

Schedule

S4

 

1 Name of Medicine

Topotecan.

2 Qualitative and Quantitative Composition

Active substance.

Each vial contains topotecan as topotecan hydrochloride. When reconstituted as recommended, each millilitre of solution for infusion contains topotecan 1 mg.

Excipients.

See Section 6.1 List of Excipients for the other ingredients in this product.

3 Pharmaceutical Form

Powder for i.v. infusion.

A sterile light yellow to greenish lyophilised powder for intravenous (i.v.) infusion, following reconstitution and further dilution.
The reconstituted solution ranges in colour from yellow to yellow-green. The pH of a 1 mg/mL solution in water is 4.3.

4 Clinical Particulars

4.1 Therapeutic Indications

Hycamtin powder for i.v. infusion is indicated as single agent therapy for the treatment of patients with:
small cell lung carcinoma (SCLC) after failure of first line chemotherapy;
metastatic carcinoma of the ovary after failure of first line or subsequent therapy.
Hycamtin powder for i.v. infusion is indicated in combination with cisplatin for the treatment of patients with:
histologically confirmed stage IV-B, recurrent, or persistent carcinoma of the cervix, which is not amenable to curative treatment with surgery and/or radiation therapy.

4.2 Dose and Method of Administration

Hycamtin powder for i.v. infusion must be reconstituted and further diluted before use (see Instructions for use/handling).
Prior to administration of the first course of Hycamtin, patients must have a baseline neutrophil count of ≥ 1.5 x 109/L, a platelet count of ≥ 100 x 109/L and a haemoglobin level of ≥ 9 g/dL (after transfusion if necessary).

Dosage.

Populations. Adults and elderly.

Ovarian and small cell lung carcinoma.

Initial dose.

The recommended dose of Hycamtin is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, with a 3 week interval between the start of each course. A minimum of 4 courses is recommended in the absence of definite tumour progression since median time to response in clinical trials was 8-11.7 weeks in ovarian cancer and 6.1 weeks in small cell lung cancer.

Subsequent doses.

Topotecan should not be readministered unless the neutrophil count is ≥ 1 x 109/L, the platelet count is ≥ 100 x 109/L, and the haemoglobin level is ≥ 9 g/dL (after transfusion if necessary).
Standard oncology practice for the management of neutropenia is either to administer topotecan with other medications (e.g. G-CSF) or to reduce the dose to maintain neutrophil counts.

Dose reduction.

If dosage reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 x 109/L) for 7 days or more, or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose should be reduced by 0.25 mg/m2/day to 1.25 mg/m2/day (or subsequently down to 1.0 mg/m2/day if necessary).
Doses should be similarly reduced if the platelet count falls below 25 x 109/L.
In clinical studies, Hycamtin powder for i.v. infusion was discontinued if the dose had to be reduced below 1.0 mg/m2.
Cervical cancer.

Initial dose.

The recommended dose of topotecan is 0.75 mg/m2 administered as a 30 minute intravenous infusion on days 1, 2 and 3. Cisplatin is administered as an intravenous infusion on day 1 at a dose of 50 mg/m2 and following the topotecan dose. This treatment schedule is repeated every 21 days for 6 courses or until progressive disease.

Subsequent doses.

Topotecan should not be readministered unless the neutrophil count is ≥ 1.5 x 109/L, the platelet count is ≥ 100 x 109/L, and the haemoglobin level is ≥ 9 g/dL (after transfusion if necessary).
Standard oncology practice for the management of neutropenia is either to administer topotecan with other medications (e.g. G-CSF) or to reduce the dose to maintain neutrophil counts.
During topotecan and cisplatin combination therapy, if the serum creatinine is > 132.6 micromol/L, it is recommended that the cisplatin full product information be consulted for any advice on dose reduction/ continuation.

Dose reduction.

If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count < 0.5 x 109/L) for seven days or more, or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, the dose of topotecan should be reduced by 20% to 0.60 mg/m2 for subsequent courses (or subsequently down to 0.45 mg/m2/day).
Doses should be similarly reduced if the platelet count falls below 25 x 109/L.

Special populations.

Patients with renal impairment.

Monotherapy (ovarian and small cell lung carcinoma).

No dosage adjustment is required in patients with a creatinine clearance ≥ 0.66 mL/s. The recommended dose in patients with creatinine clearance between 0.33 and 0.65 mL/s is 0.75 mg/m2/day. Insufficient data is available to make a recommendation for patients with a creatinine clearance < 0.33 mL/s. Advice on dosing of topotecan for patients with moderate renal impairment (0.33 to 0.65 mL/s) is based on studies involving patients with advanced cancer.

Combination therapy (cervical carcinoma).

It is recommended that topotecan in combination with cisplatin for the treatment of cervical cancer only be initiated in patients with serum creatinine less than or equal to 132.6 micromol/L. If, during topotecan/ cisplatin combination therapy serum creatinine exceeds 132.6 micromol/L, it is recommended that the full prescribing information be consulted for any advice on cisplatin dose reduction/ continuation. If cisplatin is discontinued, there are insufficient data regarding continuing monotherapy with topotecan in patients with cervical cancer.
Patients with hepatic impairment (ovarian and small cell lung carcinoma).

Monotherapy.

No dosage adjustment is required in patients with hepatic impairment (serum bilirubin in the range 25.65 to 171 micromol/L). Hepatically impaired patients were able to tolerate 1.5 mg/m2 for five days every three weeks although a small reduction in topotecan clearance was observed.

Combination therapy (cervical carcinoma).

There is currently insufficient information to make a recommendation with respect to the use of topotecan in combination with other cytotoxics in first line patients. Dose adjustment may be necessary if topotecan is administered in combination with other cytotoxic agents (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Children. Use in children is not recommended as only limited data are available.
Elderly. No overall differences in effectiveness were observed between patients over 65 years and younger adult patients.

Method of administration.

Instructions for use/handling.

The normal procedures for proper handling and disposal of anticancer drugs should be adopted, including:
personnel should be trained to reconstitute the drug;
pregnant staff should be excluded from working with this drug;
personnel handling this drug during reconstitution and dilution for infusion should wear protective clothing including mask, goggles and gloves;
all items for administration or cleaning, including gloves, should be placed in a high risk, waste disposal bag for high temperature incineration;
liquid waste may be flushed with large amounts of water;
accidental contact with the skin or eyes should be treated immediately with copious amounts of water.
Hycamtin 4 mg vials are reconstituted with 4 mL sterile water for injection. Hycamtin 1 mg vials are reconstituted with 1.1 mL sterile water for injections, which ensures that a full 1 mL of solution can be withdrawn from the vial. For infusion, the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride BP intravenous infusion solution or 5% glucose intravenous infusion solution prior to administration.
Reconstituted vials are stable for up to 24 hours at 5°C and 30°C. Diluted solutions are chemically and physically stable for up to 24 hours at temperatures up to 30°C. The lyophilised dosage form contains no antibacterial preservative. In accordance with good pharmaceutical practice, it is recommended that the product be used as soon as possible after reconstitution and dilution. Otherwise, it should be refrigerated at 2-8°C for not more than 24 hours.

4.3 Contraindications

Hycamtin is contraindicated in:
patients with a history of severe hypersensitivity reactions to topotecan or any of its excipients (see Section 6.1);
women who are pregnant or breastfeeding;
persons who already have severe bone marrow depression prior to starting the first course, as evidenced by baseline neutrophil count of < 1.5 x 109/L and/or a platelet count of less than 100 x 109/L.

4.4 Special Warnings and Precautions for Use

Initiation.

Topotecan should be initiated under the direction of a physician experienced in the use of cytotoxic agents.

Haematological toxicity.

Haematological toxicity is dose related and full blood counts including platelets should be determined regularly (see Section 4.2 Dose and Method of Administration). Prior to administration of the first course of Hycamtin, patients must have a baseline neutrophil count of ≥ 1.5 x 109/L, a platelet count of ≥ 100 x 109/L and a haemoglobin (Hb) level of ≥ 9 g/dL (after transfusion if necessary).

Neutropenia.

Severe neutropenia has been seen in some clinical study patients. Fever in a small number of patients, fever and infection have occurred concurrently with severe neutropenia (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients who experience prolonged severe neutropenia, or severe neutropenia associated with fever or infection, or who have had treatment delayed due to neutropenia, should either be given a reduced topotecan dose or prophylactic G-CSF in subsequent courses. If neutropenia is not adequately managed with G-CSF administration, the topotecan dose should be reduced.
Topotecan induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical studies with topotecan. In patients presenting with fever, neutropenia and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered.

Thrombocytopenia.

Moderate and severe thrombocytopenia have been seen in some clinical study patients. There have been infrequent reports of significant sequelae associated with thrombocytopenia, including fatalities due to tumour bleeds (see Section 4.8 Adverse Effects (Undesirable Effects)).

Anaemia.

Moderate to severe anaemia (Hb < 8.0 g/dL) has been seen in some clinical study patients (see Section 4.8 Adverse Effects (Undesirable Effects)).

Myelosuppression.

As with other cytotoxic drugs, topotecan can cause severe myelosuppression. Myelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated with topotecan (see Section 4.8 Adverse Effects (Undesirable Effects)).
As with other myelosuppressive cytotoxics, greater myelosuppression is likely to be seen when topotecan is used in patients who have received extensive previous chemotherapy and when used in combination with other myelosuppressive cytotoxics. Dose reduction of topotecan may be required in these circumstances.

Interstitial lung disease (ILD).

Topotecan has been associated with reports of interstitial lung disease (ILD), some of which have been fatal (see Section 4.8 Adverse Effects (Undesirable Effects)). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation and use of pneumotoxic drugs and/or colony stimulating factors. Patients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoea and/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed.

Use in combination with other cytotoxic agents.

Dose adjustment may be necessary if topotecan is administered in combination with other cytotoxic agents (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

With the exception of the studies looking at the interaction of topotecan with other cytotoxics, possible interactions of topotecan with concomitantly administered medications have not been formally investigated.
As with other myelosuppressive cytotoxics, greater myelosuppression is likely to be seen when topotecan is used in combination with other myelosuppressive cytotoxics, thereby necessitating dose reduction.
In vitro, topotecan did not inhibit human cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A, nor did it inhibit the human cytosolic enzymes dihydropyrimidine or xanthine oxidase. In population studies, the coadministration of granisetron, ondansetron, morphine or corticosteroids did not appear to have a significant effect on the pharmacokinetics of topotecan.
When topotecan (0.75 mg/m2/day for 5 consecutive days) and cisplatin (60 mg/m2/day on day 1) were administered intravenously in 13 patients with ovarian cancer, mean topotecan plasma clearance on day 5 was slightly reduced compared to values on day 1. As a result, systemic exposure of total topotecan, as measured by AUC and Cmax, on day 5 were increased by 12% (95% C.I.: 2%, 24%) and 23% (95% C.I.: -7%, 63%), respectively. No pharmacokinetic data are available following topotecan (0.75 mg/m2/day for 3 consecutive days) and cisplatin (50 mg/m2/day on day 1) in patients with cervical cancer.
Topotecan is a substrate for both ABCG2 (breast cancer resistance protein (BCRP)) and ABCB1 (P-glycoprotein (P-gp)). Following coadministration of the ABCG2 (BCRP) and the ABCB1 (P-gp) inhibitor, elacridar* at 100 to 1,000 mg with intravenous topotecan increased the AUC0-inf of topotecan lactone and total topotecan approximately 1.2-fold, respectively.

Note.

* Elacridar is not registered or commercially available in Australia.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Topotecan is genotoxic and effects on fertility, including male fertility, cannot be excluded.
(Category D)
Topotecan is contraindicated in pregnancy (see Section 4.3 Contraindications).
There is no information on the use of topotecan in pregnant women. As with other cytotoxic drugs, topotecan may cause foetal harm when administered to pregnant women. Women should be advised to avoid becoming pregnant during therapy with topotecan and to inform the treating physician immediately should this occur.

Pregnancy testing.

The pregnancy status for females of reproductive potential should be verified prior to starting treatment with Hycamtin.

Contraception.

As with all cytotoxic chemotherapy, patients being treated with topotecan must be advised that they or their partner must use an effective method of contraception.
 Topotecan is contraindicated during lactation (see Section 4.3 Contraindications).
It is not known whether topotecan is present in human milk, however it has been shown to be excreted in the milk of lactating rats at high concentrations. Because of the potential for serious adverse reactions in nursing infants, nursing mothers must be advised to discontinue breastfeeding before and during therapy with Hycamtin.

4.7 Effects on Ability to Drive and Use Machines

No studies of the effects on the ability to drive or operate machinery have been performed. However, caution should be observed when driving or operating machinery if fatigue and asthenia persist.

4.8 Adverse Effects (Undesirable Effects)

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (greater than or equal to 1/10), common (greater than or equal to 1/100 and less than 1/10), uncommon (greater than or equal to 1/1,000 and less than 1/100), rare (greater than or equal to 1/10,000 and less than 1/1,000) and very rare (less than 1/10,000) including isolated reports and not known (cannot be estimated from the available data). Very common, common and uncommon events were generally determined from clinical trial data.

Clinical trial data.

Topotecan clinical trials usually did not include a placebo arm, therefore background rates were not taken into account when assigning frequency categories and all reports of these adverse events have been used.
The following frequencies are estimated at the standard recommended doses of topotecan. See Table 1.
No evidence of significant cardiotoxicity, neurotoxicity or major organ toxicity has been observed with Hycamtin. See Tables 2, 3 and 4.

Haematologic AEs.

In dose-finding studies, the dose-limiting toxicity was found to be haematological. Toxicity was generally predictable and reversible. No evidence of cumulative toxicity was seen. In patients with small cell lung or ovarian carcinoma the onset of neutropenia and thrombocytopenia was generally within 2 weeks of treatment and in the majority of cases lasted no more than 7 days. In 11% of courses, severe neutropenia lasted more than 7 days.
Among all patients treated in clinical studies (including both those with severe neutropenia and those who did not develop severe neutropenia), 13% (5% of courses) developed fever and 27% (10% of courses) developed infection. In addition 5% of all patients treated (1% of courses) developed sepsis.

Postmarketing data.

The following adverse reactions have been reported during post-marketing experience with Hycamtin via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse reactions are listed according to system organ classes in MedDRA. See Table 5.

Reporting suspected adverse events.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdoses have been reported in patients being treated with intravenous topotecan (up to 10 fold of the prescribed dose).

Signs and symptoms.

The primary anticipated complication of overdosage would consist of bone marrow suppression. The observed signs and symptoms for overdose are consistent with the known adverse reactions associated with Hycamtin (see Section 4.8 Adverse Effects (Undesirable Effects)). In addition, elevated hepatic enzymes and mucositis have been reported following overdose.

Treatment of overdose or accidental poisoning.

There is no known antidote for topotecan overdosage. The mainstay of treatment is symptomatic and supportive care.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Topotecan hydrochloride is a water soluble analogue of camptothecin, a natural substance found in several species of Asian trees. The antitumour activity of topotecan involves the specific inhibition of the enzyme topoisomerase I. This enzyme plays an important role in replication, transcription and DNA damage repair. It is involved in DNA replication, resolving supercoils introduced into DNA by the movement of a replication fork or transcription complex down a double stranded DNA molecule. Topotecan reversibly inhibits the catalytic action of topoisomerase I by reducing the initial velocity of catalysis. It inhibits the relegation reaction of topoisomerase I by stabilising the intermediate covalent complex between topoisomerase I enzyme and strand cleaved DNA. This results in relaxation of supercoiled DNA.
The cytotoxicity of topotecan results from the production of enzyme mediated DNA damage. This DNA damage occurs when a replication complex runs into a topotecan induced cleavable complex. This induces a protein associated single strand DNA break. Consequently, topotecan is an S-phase dependent cytotoxic drug.

Clinical trials.

Powder for i.v. infusion.

Small cell lung carcinoma (SCLC). In a comparative study of topotecan and the treatment regimen CAV (cyclophosphamide, doxorubicin, vincristine) in patients with relapsed small cell lung carcinoma who had been sensitive to first line chemotherapy (n = 107 and 104, respectively), the response rate (95% C.I.) was 22% (15, 30) versus 15% (8, 22). Median time to progression was 13 weeks versus 12 weeks (hazard ratio 0.86 [0.6, 1.2]), median duration of response was 14 weeks versus 15 weeks (hazard ratio 1.3 [0.6, 2.9]) for topotecan and CAV, respectively. Median overall survival was 25 weeks for topotecan versus 22 weeks for CAV (hazard ratio 1.17 [0.8, 1.6]). In a symptom specific questionnaire, patients treated with topotecan experienced significantly greater relief in the following symptoms: dyspnoea*, hoarseness*, fatigue* and interference with daily activities. The time to worsening of the following symptoms was significantly longer for topotecan treated patients than for CAV: dyspnoea*, loss of appetite (* p < 0.05).
In phase II studies the outcomes for refractory patients were response rates 2-7%, median time to progression 6-10 weeks and median survival 16-21 weeks. Symptom improvement in refractory patients was comparable to those in sensitive patients.
The response rate in the overall small cell lung carcinoma population (n = 426) was 14% with a response rate of 4% in refractory patients.
Activity has been observed in cerebral metastases in patients (sensitive and refractory) with brain metastases. Of 23 patients in three studies who had measurable brain metastases, 8 (35%) had objective responses.
In a study in patients with extensive small cell lung cancer who had received no prior therapy, 48 patients were treated with topotecan at a dose of 2.0 mg/m2/day daily for five days and repeated every 21 days. According to the window of opportunity design, patients who did not respond after 2 cycles, or who did not achieve complete response after 4 cycles or who had progressive disease at any stage were treated with cisplatin and etoposide or carboplatin and etoposide. The partial response rate achieved after topotecan therapy was 40% and the overall median survival (after salvage therapy with cisplatin/ carboplatin and etoposide) was 10 months.
Ovarian carcinoma. Hycamtin (topotecan hydrochloride) was studied in four clinical trials of 453 patients with metastatic ovarian carcinoma. All patients had disease that had recurred on, or was unresponsive to, a platinum containing regimen. Patients in these four studies received an initial dose of 1.5 mg/m2 given by intravenous infusion over 30 minutes for 5 consecutive days, starting on day 1 of a 21 day course.
In a comparative study of topotecan and paclitaxel in patients previously treated for ovarian carcinoma with platinum based chemotherapy (n = 112 and 114, respectively), the response rate (95% C.I.) was 21% (18, 28) versus 14% (8, 21) and median time to progression 26 weeks versus 22 weeks (hazard ratio 0.76 [0.6, 1.0]), for topotecan and paclitaxel, respectively. Median overall survival was 63 weeks for topotecan versus 53 weeks for paclitaxel (hazard ratio 0.97 [0.7, 1.3]).
The response rate in the whole ovarian carcinoma programme (n = 392, all previously treated with cisplatin or cisplatin and paclitaxel) was 16%. In patients refractory to, or relapsing within three months after cisplatin therapy (n = 186), the response rate was 10%.
These data should be evaluated in the context of the overall safety profile of the drug, in particular to the important haematological toxicity. (See Section 4.8 Adverse Effects (Undesirable Effects).)
Cervical carcinoma.

Study GOG 0179.

In a randomised, comparative phase III trial conducted by the Gynaecological Oncology Group (GOG 0179), topotecan plus cisplatin (n = 147) was compared with cisplatin alone (n = 146) for the treatment of confirmed stage IV-B or recurrent or persistent carcinoma of the cervix where curative treatment with surgery and/or radiation was not considered appropriate. No patient had received primary chemotherapy with cisplatin or any other cytotoxic agent. Approximately 56% of both treatment groups had received prior cisplatin as a radiotherapy sensitiser. Treatment was planned for a total of 6 cycles. The median number of cycles received was 4 in the combination arm and 3 in the cisplatin arm. The primary efficacy results of this study are presented in Table 6.
There were four (3%) deaths reported as related/ possibly related to treatment in the combination arm and none in the cisplatin arm. In 3 of these cases early progressive disease was reported as the predominant cause of death with treatment related toxicity cited as a contributory factor. The combination arm was associated with increased haematological toxicity (see Section 4.8 Adverse Effects (Undesirable Effects)).
Secondary endpoints of quality of life (QoL) was assessed using the Functional Assessment of Cancer Therapy - Cervix Cancer, Brief Pain Inventory as well as the UNISCALE. QoL readings were taken prior to randomisation, prior to cycles 2 and 5 of treatment and 9 months postrandomisation. Compared to cisplatin alone, the increased haematological toxicity seen with the combination of topotecan and cisplatin, did not significantly reduce the patient QoL outcomes.

5.2 Pharmacokinetic Properties

The pharmacokinetics of topotecan after intravenous administration have been evaluated in adult cancer patients who received single doses of 2.5 to 22.5 mg/m2 given as a 30 minute infusion and 0.5 to 1.5 mg/m2 given as 30 minute infusions on a daily times five schedule.

Absorption.

Not applicable for intravenous administration.

Distribution.

Following intravenous administration, topotecan has a high volume of distribution of about 132 L (80 L/m2), approximately three times total body water, indicating binding to tissues or intracellular uptake.
In vitro studies indicate that binding of topotecan to plasma proteins was low (35%). Distribution between blood cells and plasma was fairly homogenous resulting in a blood to plasma ratio of approximately 1.2.

Metabolism.

In vitro, topotecan did not inhibit human cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A, nor did it inhibit the human cytosolic enzymes dihydropyrimidine or xanthine oxidase.

Elimination.

Following i.v. administration, the plasma concentrations decline biexponentially. The pharmacokinetics of i.v. topotecan is dose proportional within the range of doses administered.
There is little or no accumulation of topotecan with repeated daily dosing, and there is no evidence of a change in the pharmacokinetics with multiple dosing.
Following a single 30 minute intravenous infusion of topotecan, at doses of 0.5 to 1.5 mg/m2 topotecan demonstrated a high plasma clearance with mean value of 62 L/h (SD 22 L/h), corresponding to approximately 2/3 liver blood flow. The mean terminal half-life of topotecan lactone ranged from 2 to 3 hours following intravenous administration.
Topotecan appears to be excreted by both biliary and urinary routes. A major route of clearance of topotecan was by hydrolysis of the lactone ring to form the ring opened hydroxy acid. A variable fraction of the dose (generally 20-60%) was excreted as topotecan or the open ring form in urine.
In an unlabelled mass balance study in patients with advanced solid tumours, 4 patients received i.v. topotecan 1.5 mg/m2 and 4 oral topotecan 2.3 mg/m2 administered once daily for 5 days.
Following i.v. administration, overall recovery of drug related material was 71% to 76% of the administered dose. Approximately 51% was excreted as total topotecan and 2.5% was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted for 18% of the administered dose while faecal elimination of N-desmethyl topotecan was approximately 1.5%. Overall, the N-desmethyl metabolite contributed a mean of less than 7% (range 4-9%) of the total drug related material accounted for in the urine and faeces. The topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide in the urine were less than or equal to 2% of the dose.

Special patient populations.

Age/weight.

In a population study with i.v. topotecan, a number of factors including age, weight and ascites had no significant effect on clearance.

Renal impairment.

Plasma clearance of i.v. topotecan in patients with mild renal impairment (creatinine clearance 0.68-1 mL/s) decreased to about 67% compared with control patients. Volume of distribution was slightly decreased and thus half-life only increased by 14%. In patients with moderate renal impairment (creatinine clearance 0.33-0.67 mL/s) topotecan plasma clearance was reduced to 34% of the value in control patients. Volume of distribution also decreased by about 25% which resulted in an increase in mean half-life from 1.9 hours to 4.9 hours.

Hepatic impairment.

Plasma clearance of topotecan lactone after i.v. administration in patients with hepatic impairment (serum bilirubin in the range 25.65 to 171 micromol/L) decreased to about 67% when compared with a control group of patients. Topotecan half-life was increased by about 30% but no clear change in volume of distribution was observed. Total topotecan plasma clearance in patients with hepatic impairment only decreased by about 10% compared with the control group of patients.

5.3 Preclinical Safety Data

Reproductive toxicity and fertility.

Topotecan caused superovulation in female rats when given before mating at 1.36 mg/m2/day. Topotecan was also shown to cause embryo-foetal toxicity when given to rats (0.59 mg/m2/day) and rabbits (1.25 mg/m2/day) at doses less than the clinical intravenous dose in humans (1.5 mg/m2/day). A dose of 0.59 mg/m2/day was teratogenic in rats (predominantly effects of the eye, brain, skull and vertebrae). These effects have been observed with other topoisomerase-I inhibitors and would therefore appear to be a class effect.

Carcinogenicity.

The carcinogenic potential of topotecan has not been studied. In common with a number of other cytotoxic agents, and resulting from its mechanism of action, topotecan is genotoxic to mammalian cells and must be considered to be carcinogenic.

Genotoxicity.

Topotecan was mutagenic to L5178Y mouse lymphoma cells and clastogenic to cultured human lymphocytes with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tartaric acid, mannitol, hydrochloric acid and sodium hydroxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Vials.

Do not store above 30°C. Keep the vial in the carton in order to protect from light.

Reconstituted solution.

The lyophilised dosage form does not contain an antibacterial preservative.
It is recommended that the product is used immediately after reconstitution or stored in a refrigerator (2°C to 8°C) and discarded after 24 hours. Please see Section 4.2 Dose and Method of Administration, Instructions for use/handling.
Reconstituted solutions have been shown to retain their stability when stored for up to 24 hours at 5°C to 30°C. Please see Section 4.2 Dose and Method of Administration, Instructions for use/handling.

Diluted solution for infusion.

The infusion solution is chemically and physically stable for up to 24 hours at temperatures up to 30°C. It is recommended that diluted solutions are infused immediately or within 24 hours, as Hycamtin powder for i.v. infusion contains no preservative. Please see Section 4.2 Dose and Method of Administration, Instructions for use/handling.

6.5 Nature and Contents of Container

Pack supplied.

Hycamtin powder for i.v. infusion is presented in single use glass vials.
Each Hycamtin 4 mg vial is supplied in clear glass vials with grey butyl rubber stoppers and aluminium seals with plastic flip-off caps. Each vial contains a yellow to green lyophilised topotecan hydrochloride mass, equivalent to 4 mg topotecan as the free base. Five vials per pack.

Other registered packs (not supplied).

Carton of Hycamtin powder for i.v. infusion 4 mg packs containing 1 vial*.
Each Hycamtin 1 mg vial contains a yellow to green lyophilised topotecan hydrochloride mass, equivalent to 1 mg as the free base*. Cartons contain either 1* or 5* vials.
* Not all strengths or pack sizes may be distributed in Australia.

6.6 Special Precautions for Disposal

Unused product should not be disposed in domestic waste or waste water. Please see Section 4.2 Dose and Method of Administration, Instructions for use/handling.

6.7 Physicochemical Properties

Topotecan has the chemical name: (S)-10-[(dimethylamino)methyl]- 4-ethyl-4,9-dihydroxy- 1H-pyrano[3',4':6,7]indolizino [1,2-b]-quinoline-3,14- (4H,12H)-dione.
Empirical formula: C23H23N3O5 (topotecan free base).
Molecular weight: 421.453 (topotecan free base).
Topotecan is a yellow to green powder at room temperature.
Aqueous solubility for topotecan free base is 80.5 g/L at 25°C.
The pKa values obtained for the quinoline, phenol and benzyldimethylamino groups of topotecan hydrochloride were 0.60, 6.99 and 10.50 respectively.
The log P value (calculated) at pH 7.4 is -0.3.

Chemical structure.


CAS number.

123948-87-8.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

Summary Table of Changes