Consumer medicine information

Topotecan Accord

Topotecan

BRAND INFORMATION

Brand name

Topotecan Accord

Active ingredient

Topotecan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Topotecan Accord.

What is in this leaflet

This leaflet answers some of the common questions about Topotecan Accord. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine.

All medicines have risks and benefits. Your doctor will have weighed the risks of you taking Topotecan Accord against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet until you have finished treatment with Topotecan Accord. You may need to read it again.

What Topotecan Accord is used for

Topotecan Accord contains topotecan hydrochloride as the active ingredient.

Topotecan Accord is an anti-cancer medicine. It works by killing cancer cells and preventing cancer cells from reproducing. Topotecan Accord is used to treat patients with ovarian cancer, small cell lung cancer and cervical cancer.

Your doctor may have prescribed Topotecan Accord for another reason.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

Topotecan Accord is not addictive.

Before you are given Topotecan Accord

You must not be given it if:

  • you have had an allergic reaction to topotecan hydrochloride or any of the other ingredients contained in this medicine
  • you are, or think you may be pregnant or if you intend to become pregnant
  • you are breast feeding

If you have been breast feeding prior to receiving Topotecan Accord, do not restart until the doctor tells you it is safe to do so.

  • you have very low blood count.
  • the expiry date printed on the pack has passed
  • the packaging is torn or shows signs of tampering.

Before you are given it

Before you receive Topotecan Accord, tell your doctor if you have any:

  • kidney problems; the dosage of Topotecan Accord may need to be reduced
  • liver problems
  • other medical problems. In particular tell your doctor if you have any of the following:
    - bleeding or bruising; Topotecan Accord may cause a reduction in blood cells which may increase the risk of bleeding.
    - fever or other symptoms of infection; Topotecan Accord may decrease your body’s ability to fight infection.
    - Recent exposure to chickenpox or shingles (Herpes zoster).

Treatment with Topotecan Accord may increase the severity of these infections.

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 Topotecan Accord might affect your ability to have children.

Taking other medicines

Tell your doctor if you are taking any other medicines or have taken other medicines until recently. This includes those medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

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

Some medicines may affect the way other medicines work. Your doctor or pharmacist will be able to tell you what to do when receiving Topotecan Accord with other medicines.

Pregnancy

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

Tell your doctor if you are pregnant or think you could be pregnant before you are given Topotecan Accord.

If you are a woman who could become pregnant, you must use effective birth control (contraception) during treatment with Topotecan Accord.

Ask your doctor for methods of effective birth control.

Breast-feeding

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

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

Male patients

Male patients being treated with Topotecan Accord, 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 Topotecan Accord.

How Topotecan Accord is given

How much is given

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

How Topotecan Accord is given

Your doctor or nurse will inject the necessary dose of Topotecan Accord.

Topotecan Accord is given into the vein by an intravenous drip over a 30-minute period.

Topotecan Accord 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 Topotecan Accord you will need.

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

If you are given too much (overdose)

In the event of a 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 Topotecan Accord.

While you are given Topotecan Accord

Things you must do

Follow your doctor's directions regarding treatment with Topotecan Accord.

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. Topotecan Accord may cause a reduction in blood cells which may make you prone to infection and bleeding.

Tell your doctor immediately if you experience a fever or any other symptoms of infection or any bleeding or bruising.

If you see another doctor or dentist for treatment, tell them that you are being treated with Topotecan Accord.

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. Topotecan Accord may lower your body's resistance to infection. Some vaccines may cause illness in people with decreased resistance to infection.

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.

Check with your doctor before having any dental work done.

  • 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

Things to be careful of

Be careful driving or operating machinery after you have been given Topotecan Accord and you are feeling tired and weak.

Side Effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are receiving Topotecan Accord.

Like most anti-cancer drugs, Topotecan Accord 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.

Topotecan Accord 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, Topotecan Accord may cause you to feel sick or be sick. You will be prescribed medicines to help prevent these side effects.

The most common side effects with Topotecan Accord are infections. Blood disorders are also common, where reduced levels of certain blood cells may cause anaemia, reduced resistance to infections and increased bruising or bleeding. Your doctor will monitor your blood tests for these side effects.

Conditions you need to look out for

Severe allergic reactions

These are very rare in people receiving Topotecan Accord. Signs include:

  • raised and itchy rash (hives)
  • swelling, sometimes of the face or mouth (angioedema), causing difficulty in breathing
  • collapse.

Signs of infection

Topotecan Accord may reduce your white blood cell count, lowering your resistance to infection. This can be life threatening. Signs include:

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

Bowel inflammation

Topotecan Accord can occasionally cause severe stomach pain, fever and diarrhoea (rarely with blood). These could be signs of bowel inflammation (colitis).

Lung inflammation (interstitial lung disease)

This rarely occurs in people taking Topotecan Accord. 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. Signs include:

  • difficulty breathing
  • cough
  • fever.

Tell your doctor immediately if you get any of these symptoms. You may need to be treated in hospital.

Very common side effects (these may affect more than 1 in 10 people):

  • feeling generally weak and tired (anaemia), which can occasionally require blood transfusion
  • weight loss and loss of appetite (anorexia); tiredness; weakness; feeling unwell
  • feeling sick (nausea), being sick (vomiting), stomach pain, diarrhoea, constipation
  • local symptoms such as sore throat or urinary problems (for example a burning sensation when urinating, which may be caused by a urinary infection)
  • inflammation and ulcers of the mouth, tongue or gums
  • high body temperature (fever)
  • hair loss.

Very common side effects that may show up in your blood tests:

  • low numbers of cells needed for blood clotting. This can cause bruising, bleeding, and rarely, severe bleeding (haemorrhage).
  • decrease in the number of white blood cells (neutropenia). This can cause an infection.

Common side effects (these may affect up to 1 in 10 people):

  • allergic or hypersensitivity reactions
  • yellow skin (jaundice)
  • itching sensation.

Rare side effects (these may affect up to 1 in 1000 people):

  • mild pain and inflammation at the site of injection
  • lung inflammation (interstitial lung disease).

Frequency unknown (events from spontaneous reports)

  • Severe stomach pain, nausea, vomiting of blood, black or bloody stools (possible symptoms of gastrointestinal perforation)
  • Mouth sores, difficulty swallowing, abdominal pain, nausea, vomiting, diarrhoea, bloody stool that could be signs and symptoms of inflammation of the inner lining of the mouth, stomach and / or gut (mucosal inflammation).

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

Tell your doctor or nurse if any of these or any other side effects no listed occur during or between treatments with Topotecan Accord.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Storage

Topotecan Accord will be stored in the pharmacy or on the ward. It is kept in a cool dry place where the temperature stays below 25°C.

Product Description

What it looks like

Topotecan Accord containing injections are clear yellow solutions. It is available in vials in packs of 1 and 5.

Not all presentations and pack sizes may be marketed.

Ingredients

Active ingredient:
topotecan (as hydrochloride)

Inactive ingredients:
tartaric acid
sodium hydroxide
hydrochloric acid
water for injections

Name and Address of the Sponsor

Accord Healthcare Pty Ltd
Level 24, 570 Bourke Street
Melbourne, VIC, 3000
Australia

Australian Registration Numbers

1 mg/1 mL: AUST R 310762

4 mg/4 mL: AUST R 310761

Date of Preparation

This leaflet was prepared on 22 July 2020.

Published by MIMS October 2020

BRAND INFORMATION

Brand name

Topotecan Accord

Active ingredient

Topotecan

Schedule

S4

 

1 Name of Medicine

Topotecan hydrochloride.

2 Qualitative and Quantitative Composition

1 mL contains topotecan hydrochloride equivalent to 1 mg topotecan.
Topotecan is a yellow to green powder with a solubility in water of 80.5 mg/mL 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.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Topotecan Accord is a clear, yellow concentrated injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Topotecan Accord concentrated injection is indicated as single agent therapy for the treatment of patients with:
Small cell lung carcinoma after failure of first line chemotherapy.
Metastatic carcinoma of the ovary after failure of first-line or subsequent therapy.
Topotecan Accord 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

Topotecan Accord must be diluted before use (see Instructions for use/handling). Topotecan Accord contains no antimicrobial agent. The product is for single use in one patient only. Discard any residue.
Prior to administration of the first course of Topotecan Accord, 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).

Populations.

Adults and elderly.

Ovarian and small cell lung carcinoma. The recommended dose of topotecan 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 dose reduce to maintain neutrophil counts.
If dosage 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 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 trials, topotecan 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 30 minute intravenous infusion daily 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 re-administered unless the neutrophil count is more than or equal to 1.5 x 109/L, the platelet count is more than or equal to 100 x 109/L, and the haemoglobin level is more than or equal to 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 dose reduce to maintain neutrophil counts.
If dose reduction is chosen for patients who experience severe neutropenia (neutrophil count less than 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 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.

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.

Use in renal impairment.

Monotherapy.

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.

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.

Use in hepatic impairment.

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.

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).

Instructions for use/handling.

For infusion, the appropriate volume of solution is diluted in either 0.9% Sodium Chloride BP intravenous infusion solution or 5% glucose intravenous infusion solution prior to administration.
Diluted solutions are chemically and physically stable for up to 24 hours at temperatures up to 25°C. Topotecan Accord contains no antibacterial preservative. In accordance with good pharmaceutical practice, it is recommended that the product be used as soon as possible after dilution. Otherwise, it should be refrigerated at 2-8°C for not more than 24 hours.
The normal procedures for proper handling and disposal of anticancer medicines should be adopted, including:
Pregnant staff should be excluded from working with this medicine.
Personnel handling this medicine during dilution 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.

4.3 Contraindications

Topotecan Accord is contraindicated in:
Patients with a history of severe hypersensitivity reactions to topotecan or any of its excipients (see Section 6.1 List of Excipients).
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 count including platelets should be monitored regularly (see Section 4.2 Dose and Method of Administration). Prior to administration of the first course of Topotecan Accord, 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).

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 trials 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 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).

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

The use of topotecan in children is not recommended as only limited data are available.

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 co-administration 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 (BCRP) and ABCB1 (P-glycoprotein). Following co-administration of the ABCG2 (BCRP) and the ABCB1 (P-gp) inhibitor, elacridar (GF120918) at 100 to 1,000 mg with intravenous topotecan increased the AUC0-inf of topotecan lactone and total topotecan approximately 1.2-fold, respectively.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Topotecan caused superovulation in female rats when given before mating at 1.36 mg/m2/day. This effect should therefore be taken into account for women of childbearing age. 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 Topotecan Accord.

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 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.
 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 Topotecan Accord.

4.7 Effects on Ability to Drive and Use Machines

There is no evidence that topotecan will affect the ability of a patient to drive or operate machinery. 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 according to indication.

Infections and infestations.

Very common: infection.
Common: sepsis (see Section 4.4 Special Warnings and Precautions for Use).

Blood and lymphatic system disorders.

Very common: anaemia, febrile neutropenia, leucopenia, neutropenia, (see Gastrointestinal disorders), thrombocytopenia.
Common: pancytopenia.
Not known: severe bleeding (associated with thrombocytopenia).

Immune system disorders.

Common: hypersensitivity, including rash.

Metabolism and nutrition disorders.

Very common: anorexia (which may be severe).

Respiratory, thoracic and mediastinal disorders.

Rare: interstitial lung disease.

Gastrointestinal disorders.

Very common: diarrhoea# (see Section 4.4 Special Warnings and Precautions for Use), nausea and vomiting (all of which may be severe), abdominal pain*, constipation and stomatitis.
#Drug-related diarrhoea in patients greater than 65 years of age was 10%.
*Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as a complication of topotecan-induced neutropenia (see Section 4.4 Special Warnings and Precautions for Use).

Hepatobiliary disorders.

Common: hyperbilirubinaemia, elevated ALT and AST.

Skin and subcutaneous disorders.

Very common: alopecia.

General disorders and administrative site conditions.

Very common: asthenia, fatigue, pyrexia.
Common: malaise. Rare: extravasation#.
#These reactions have been mild and have not generally required specific therapy.

Central and peripheral nervous system.

Common: headache, dizziness, paraesthesia.
Uncommon: hypoesthesia, neuropathy, peripheral neuropathy, paresis.

Respiratory.

Common: dyspnoea (4%), coughing, epistaxis, pharyngitis, rhinitis, respiratory disorder.
No evidence of significant cardiotoxicity, neurotoxicity or major organ toxicity has been observed with topotecan. See Table 1.

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. See Table 2 and Table 3.

Postmarketing data.

The following adverse reactions have been reported during post-marketing experience with topotecan 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 4).

Reporting suspected adverse effects.

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 topotecan (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. For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The anti-tumour activity of topotecan involves the 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 religation 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.

Small cell lung carcinoma.

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.

Topotecan 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.

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 5.
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 post-randomisation. 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 intravenous administration, the plasma concentrations decline bi-exponentially. The pharmacokinetics of intravenous 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 intravenous topotecan 1.5 mg/m2 and 4 oral topotecan 2.3 mg/m2 administered once daily for 5 days.
Following intravenous 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.

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

Renal impairment.

Plasma clearance of intravenous 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 intravenous 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

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.

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tartaric acid, hydrochloric acid, sodium hydroxide, water for injections.

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

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Topotecan Accord is available in the following strengths: 1 mg/1 mL and 4 mg/4 mL, in amber type I vials. The 1 mg/1 mL is packs of 1 and the 4 mg/ 4 mL is packs of 1 or 5.
Not all presentations or pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

119413-54-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes