Consumer medicine information

Evoltra

Clofarabine

BRAND INFORMATION

Brand name

Evoltra Concentrate for infusion

Active ingredient

Clofarabine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Evoltra.

What is in this leaflet

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

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

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

Keep this leaflet with the medicine.

You may need to read it again.

What EVOLTRA is used for

EVOLTRA is used to treat young patients with Acute Lymphoblastic Leukaemia (ALL) when previous treatments have not worked or have stopped working. ALL is caused by abnormal growth of some types of white blood cells.

This medicine belongs to a group of medicines known as antineoplastic or cytotoxic agents. You may also hear it referred to as a chemotherapy medicine.

This medicine is thought to work by interfering with the growth and/or repair of some cells that are multiplying rapidly, such as cancer cells, which are eventually destroyed.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

This medicine is not addictive.

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

There is not enough information to recommend the use of this medicine for children under the age of one year, or adults over the age of 65 years.

Before you are given EVOLTRA

When you must not be given it

Do not receive treatment with EVOLTRA if you have an allergy to:

  • any medicine containing clofarabine
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not receive treatment with EVOLTRA if you are pregnant or intend to become pregnant.

Like most cytotoxic medicines, EVOLTRA is not recommended for use during pregnancy. If there is any need to consider EVOLTRA during your pregnancy, your doctor or pharmacist will discuss with you the benefits and risks of using it.

Do not breast-feed if you are being treated with this medicine.

If you are breast-feeding, you must stop breast-feeding before starting the treatment, and must not breast-feed either during or after your treatment. Your doctor can advise you when it is safe to breast-feed.

Males: tell your doctor or pharmacist if your partner intends to become pregnant while you are being given EVOLTRA or shortly after you have stopped treatment with EVOLTRA.

EVOLTRA may cause birth defects if either the male or female is using it at the time of conception. It is recommended that you use effective methods of contraception during and after treatment with EVOLTRA. Your doctor can discuss this with you.

Do not receive treatment with EVOLTRA if you have or have had any of the following medical conditions:

  • severe kidney problems
  • severe liver problems

Tell your doctor if you have an infection or high temperature.

Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

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

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • any blood disorders, or conditions which cause a reduced number of red blood cells, white blood cells, or platelets
  • bone marrow disease
  • kidney disease
  • liver disease
  • hypotension (low blood pressure)
  • gout
  • bowel problems such as colitis (inflammation of the colon)
  • lowered immunity due to diseases including HIV/AIDS
  • heart disease.

Tell your doctor if you have been given EVOLTRA before, and you became unwell.

You may need to be given another medicine instead.

Tell your doctor if you are on a controlled sodium diet as it could affect how you will be given your medicine.

EVOLTRA contains 180mg of sodium chloride in each vial. This is equivalent to 3.08 mmol (or 70.77mg) of sodium. You need to allow for this if you are on a controlled sodium diet.

If you have not told your doctor about any of the above, tell him/her before you are given EVOLTRA.

Taking other medicines

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

Some medicines and EVOLTRA may interfere with each other. These may include:

  • other medicines used to treat cancer
  • some vaccines
  • medicines which can affect the kidneys
  • medicines which can affect the liver
  • medicines which can affect blood pressure or the heart.

These medicines may be affected by EVOLTRA or may affect how well it works. You may need different amounts of your medicine, or you may need to use different medicines. Your doctor or pharmacist will advise you.

Your doctor and pharmacist have more information on medicines/vaccinations to be careful with or avoid while being treated with EVOLTRA.

How EVOLTRA is given

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

How much is given

Your doctor will decide what dose of EVOLTRA you will receive. This depends on your condition and other factors, such as your weight, height and other chemotherapy medicines you are being given.

Your doctor will monitor your health and may change your dose depending on your response to the treatment.

EVOLTRA may be given alone or in combination with other drugs.

Several courses of EVOLTRA may be needed depending on your response to treatment.

Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any uncontrolled effects have been controlled.

Ask your doctor if you want to know more about the dose of EVOLTRA you receive.

How it is given

EVOLTRA is given as a slow injection (or infusion) into a vein. EVOLTRA should only be given by a nurse or doctor.

How long it is given

EVOLTRA infusion lasts for two hours and is usually given every day for five days. If you (or your child) weighs less than 20kg, the infusion time may be longer. Your doctor will decide how many of these cycles you will need.

If you receive too much (overdose)

As EVOLTRA is given to you in a hospital under the supervision of your doctor, it is very unlikely that you will receive an overdose. However, if you experience any side effects after being given EVOLTRA, tell your doctor immediately or go to the Accident and Emergency department of your nearest hospital.

Symptoms of an overdose may include the side effects listed below in the 'Side Effects' section but are usually of a more severe nature.

Ask your doctor or pharmacist if you have any concerns.

While you are being given EVOLTRA

Tell your doctor, nurse or pharmacist if you have any concerns before, during or after administration of EVOLTRA.

Things you must do

Be sure to keep all your doctor's appointments so your progress can be checked.

Your doctor may want to check your blood pressure and do some blood and other tests from time to time to check on your progress and detect any unwanted side effects.

Keep follow up appointments with your doctor.

It is important to have your follow-up cycles of EVOLTRA at the appropriate times to get the best effects from your treatment.

Tell any other doctors, dentists, and pharmacists who are treating you that you are being given EVOLTRA.

If you are about to be started on any new medicine, remind your doctor, dentist or pharmacist that you are being given EVOLTRA.

If you become pregnant while you are being treat with EVOLTRA, tell your doctor immediately.

Drink plenty of water while you are being treated with EVOLTRA to avoid dehydration.

EVOLTRA can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding. The following precautions should be taken to reduce your risk of infection or bleeding:

  • Avoid people with infections. Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain, or find it painful or difficult to urinate.
  • Check with your doctor immediately if you notice any unusual bleeding or bruising, black stools, blood in urine or stools or pinpoint red spots on your skin.
  • Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, pharmacist or nurse may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work.
  • Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters.
  • Avoid contact sports or other situations where you may bruise or get injured.

Things to be careful of

Be careful driving or operating machinery until you know how EVOLTRA affects you.

You may feel dizzy or light-headed while you are receiving a cycle of EVOLTRA.

Be careful when drinking alcohol while you are being given this medicine.

If you drink alcohol, dizziness or light-headedness may be worse.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you being treated with EVOLTRA.

Like other medicines that treated cancer, EVOLTRA, may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • Nausea and vomiting
  • Diarrhoea
  • Headache
  • Unusual tiredness or weakness
  • Anxiety or nervousness
  • Fever
  • Flushing, itching and inflamed skin
  • Skin rashes or flaking
  • Inflammation of mucus (moist) linings, such as the mouth
  • Infections
  • Hair loss
  • Decreased or lost appetite, weight loss

The above list includes the more common side effects of EVOLTRA.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • High fever
  • Breathing difficulties, rapid breathing or breathlessness, cough
  • Nosebleeds, bleeding gums, mouth ulcers
  • Changes in your heart beat
  • Dizziness, light-headedness or fainting
  • Hearing problems
  • Fluid retention (oedema)
  • Severe nausea and vomiting
  • Severe diarrhoea
  • Feeling thirsty and producing concentrated (dark) urine
  • Blood in the urine
  • Vomiting blood, stomach ache
  • Bruising, hair loss, changes to skin colour
  • Increased sweating or dry skin
  • Feeling numb
  • Yellowing of the eyes and skin (jaundice)
  • Pain in the chest wall or bones
  • Neck or back pain, pain in the muscles or joints
  • Symptoms of an allergic reaction, such as shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some patients.

The benefits and side effects of EVOLTRA may take some time to occur. Therefore, even after you have finished receiving your EVOLTRA treatment you should tell your doctor immediately if you notice any of the side effects listed in this section.

After being given EVOLTRA

Storage

EVOLTRA will be stored in the pharmacy or on the ward. The injection is kept in a cool, dry place where the temperature stays below 25°C.

Product description

What it looks like

EVOLTRA is a concentrate for solution for infusion (sterile concentrate) that is prepared and diluted before it is used.

It is a clear, colourless solution supplied in a glass vial.

Ingredients

Active ingredients:

EVOLTRA contains 20mg of clofarabine in each 20 mL vial.

Other ingredients:

  • Sodium chloride
  • Water for injections.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Australian Sponsor:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Australia

New Zealand Sponsor:

sanofi-aventis new zealand ltd
Level 8, 56 Cawley Street
Ellerslie
Auckland
New Zealand

EVOLTRA is available in the following sizes:

  • 20mg/20mL vials

This leaflet was updated in August 2016.

AUST R 154991

evoltra-ccdsv9-cmiv2-aug16.

BRAND INFORMATION

Brand name

Evoltra Concentrate for infusion

Active ingredient

Clofarabine

Schedule

S4

 

1 Name of Medicine

Clofarabine.

2 Qualitative and Quantitative Composition

Each 20 mL vial contains 20 mg of clofarabine. Each mL contains 1 mg of clofarabine. The pH of the solution ranges between 4.5 and 7.5 and it has an osmolarity of 270 to 310 mOsm/L.

Excipients of known effect.

Each 20 mL vial contains 180 mg of sodium chloride. This is equivalent to 3.8 mmol (or 70.77 mg) of sodium and should be taken into consideration for patients on a controlled sodium diet.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrate for intravenous infusion.
Evoltra is a sterile, clear, practically colourless liquid which is free from foreign matter.

4 Clinical Particulars

4.1 Therapeutic Indications

Evoltra is indicated for treatment of acute lymphocytic leukaemia (ALL) in paediatric patients who have relapsed or are refractory after receiving at least two prior regimens. This use is based on the induction of complete responses (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Dosage.

Paediatric patients.

Administer the recommended paediatric dose of 52 mg/m2 as an IV infusion over 2 hours daily for 5 consecutive days. Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2 to 6 weeks. The dosage is based on the patient's body surface area (BSA), calculated using the actual height and weight before the start of each cycle.
In clinical trials with clofarabine in paediatric acute leukaemias, the median duration between cycles was 28 days (range of 12-55 days) [see Section 5.1 Pharmacodynamic Properties, Clinical trials].
Provide IV infusion fluids throughout the 5 days of Evoltra administration to reduce the effects of tumour lysis and other adverse effects. Consider prophylactic antiemetic medications as Evoltra is moderately emetogenic. The use of prophylactic steroids may be of benefit in preventing signs or symptoms of SIRS or capillary leak (e.g. hypotension, tachycardia, tachypnoea, and pulmonary oedema).
Most patients who respond to clofarabine do so within 1 to 2 treatment cycles (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The potential benefits and risks of continued therapy should be considered in those not responding after 2 cycles.

Children (weighing < 20 kg).

An infusion time of > 2 hours should be considered to help reduce symptoms of anxiety and irritability, and to avoid unduly high maximum concentrations of clofarabine (see Section 5.2 Pharmacokinetic Properties).

Children (< 1 year old).

There are no data on the pharmacokinetics, safety or efficacy of clofarabine in infants. Therefore, a safe and effective dosage recommendation for patients (< 1 year old) has yet to be established.

Dose reduction for patients experiencing haematological toxicities.

Administer subsequent cycles no sooner than 14 days from the starting day of the previous cycle provided the patient's ANC is ≥ 0.75 x 109/L.
If a patient experiences a grade 4 neutropenia (ANC < 0.5 x 109/L) lasting ≥ 4 weeks, reduce dose by 25% for the next cycle.

Dose reduction for patients experiencing nonhaematological toxicities.

Withhold Evoltra if a patient develops a clinically significant infection, until the infection is clinically controlled and then restart at the full dose. In the event of a second clinically significant infection, clofarabine treatment should be withheld until the infection is clinically controlled and may be reinitiated at a 25% dose reduction.
Withhold Evoltra if a grade 3 noninfectious nonhaematologic toxicity (excluding transient elevations in serum transaminases and/or serum bilirubin and/or nausea/vomiting that was controlled by antiemetic therapy) occurs. Reinstitute Evoltra administration at a 25% dose reduction upon resolution or return to baseline.
Should a patient experience the same severe toxicity on a second occasion, treatment should be delayed until the toxicity resolves to baseline parameters or to the point where it is no longer severe and the potential benefit of continued treatment with clofarabine outweighs the risk of such continuation. It is then recommended that clofarabine be administered at a further 25% dose reduction.
Any patient who experiences a severe toxicity on a third occasion, a severe toxicity that does not recover within 14 days (see above for exclusions), or a life threatening or disabling toxicity (US NCI CTC grade 4 toxicity) should be withdrawn from treatment with clofarabine (see Section 4.4 Special Warnings and Precautions for Use).
Evoltra administration should be stopped if the patient develops hypotension for any reason during the 5 days of administration. If hypotension is transient and resolves without pharmacological intervention, Evoltra treatment can be reinstituted generally with a 25% dose reduction.
Discontinue Evoltra administration if a patient shows early signs or symptoms of SIRS or capillary leak (e.g. hypotension, tachycardia, tachypnoea, and pulmonary oedema) occur and provide appropriate supportive measures.
Discontinue Evoltra administration if substantial increases in creatinine or bilirubin are noted. Reinstitute Evoltra when the patient is stable and organ function has returned to baseline, possibly with a 25% dose reduction. If hyperuricaemia is anticipated (tumour lysis), prophylactically administer allopurinol.

Patients with renal insufficiency.

There is no experience in patients with renal insufficiency (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). Close monitoring of renal function during the 5 days of Evoltra administration is advised [see Section 4.4 Special Warnings and Precautions for Use]. Avoid drugs with known renal toxicity during the 5 days of Evoltra administration.

Patients with hepatic impairment.

There is no experience in patients with hepatic impairment (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). Close monitoring of hepatic function during the 5 days of Evoltra administration is advised [see Section 4.4 Special Warnings and Precautions for Use]. Avoid concomitant use of medications known to induce hepatic toxicity.

Method of administration.

Evoltra contains no antimicrobial preservative. Product is for single use in one patient only. Discard any residue. See Section 6.6 Special Precautions for Disposal.
Evoltra must be diluted prior to administration (see Table 1). The recommended dosage should be administered by intravenous infusion although it has been administered via a central venous catheter in ongoing clinical trials. Evoltra must not be mixed with or concomitantly administered using the same intravenous line as other medicinal products.
Evoltra should be filtered through a sterile 0.2 micrometre syringe filter and then diluted with sodium chloride 9 mg/mL (0.9%) intravenous infusion to produce a total volume according to the examples given in Table 1. However, the final dilution volume may vary depending on the patient's clinical status and physician discretion. (If the use of a 0.2 micrometre syringe filter is not feasible, the sterile concentrate should be prefiltered with a 5 micrometre filter, diluted and then administered through a 0.22 micrometre in-line filter).
The diluted sterile concentrate should be a clear, colourless solution. Visually inspect for particulate matter and discolouration prior to administration.
For stability of the diluted sterile solution and associated information, see Stability, below.
Procedures for proper handling of antineoplastic agents should be observed. Cytotoxic medicinal products should be handled with caution.
The use of disposable gloves and protective garments is recommended when handling Evoltra. If the product comes into contact with eyes, skin or mucous membranes, rinse immediately with copious amounts of water.
Evoltra should not be handled by pregnant women.

Stability.

The diluted sterile concentrate is chemically and physically stable for 3 days at 2 to 8°C and at room temperature. From a microbiological point of view, it should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C unless dilution has taken place under controlled and validated aseptic conditions.

4.3 Contraindications

Clofarabine is contraindicated:
in patients with hypersensitivity to clofarabine or to any of the excipients (see Section 6.1 List of Excipients);
in patients with severe renal insufficiency or severe hepatic impairment;
in breastfeeding women.
Breastfeeding should be discontinued prior to, during and following treatment with Evoltra (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).

4.4 Special Warnings and Precautions for Use

Evoltra should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy.

Haematologic toxicity.

Obtain complete blood counts and platelet counts at regular intervals during Evoltra therapy.
Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. Severe bone marrow suppression, including neutropenia, anaemia, and thrombocytopenia, has been observed in patients treated with Evoltra and may be prolonged. Haemorrhage, including cerebral, gastrointestinal and pulmonary haemorrhage, has been reported and may be fatal. The majority of cases were associated with thrombocytopenia (see Section 4.8 Adverse Effects (Undesirable Effects)). At initiation of treatment, most patients in the clinical studies had haematological impairment as a manifestation of leukaemia. Because of the pre-existing immunocompromised condition of these patients and prolonged neutropenia that can result from treatment with Evoltra, patients are at increased risk for severe opportunistic infections.
The most frequently reported haematologic adverse effects in paediatric patients have included febrile neutropenia (55%) and neutropenia (10%). One (1) report of grade 4 bone marrow depression, and 1 report of grade 4 thrombocytopenia were considered related to the study drug.

Infections.

The use of Evoltra is likely to increase the risk of infection, including severe sepsis, as a result of bone marrow suppression. Infections may be associated with fatal outcomes.
At baseline, 48% of the paediatric patients had 1 or more concurrent infections. A total of 83% of patients experienced at least 1 infection after Evoltra treatment, including fungal, viral and bacterial infections. Twenty one (18.3%) infection events were considered to be related to clofarabine of which catheter related infection (1 event), sepsis (2 events) and septic shock (2 events; 1 patient died) were considered to be serious.

Hyperuricaemia (tumour lysis), and capillary leak syndrome/ SIRS.

Administration of Evoltra results in a rapid reduction in peripheral leukaemia cells. Evaluate and monitor patients undergoing treatment with Evoltra for signs and symptoms of tumour lysis syndrome, as well as signs and symptoms of cytokine release (e.g. tachypnoea, tachycardia, hypotension, pulmonary oedema) that could develop into systemic inflammatory response syndrome (SIRS)/capillary leak syndrome and organ dysfunction. Early intervention is recommended. Provide IV infusion fluids throughout the five days of Evoltra administration to reduce the effects of tumour lysis and other adverse effects. Administer allopurinol if hyperuricaemia (tumour lysis) is expected.
Discontinue Evoltra immediately in the event of clinically significant signs or symptoms of SIRS or capillary leak syndrome, either of which can be fatal, and consider use of steroids, diuretics and albumin. Reinstitute Evoltra when the patient is stable and organ function has returned to baseline, generally with a 25% dose reduction. The use of prophylactic steroids (e.g. 100 mg/m2 hydrocortisone on days 1 through 3) may be of benefit in preventing signs and symptoms of SIRS/capillary leak syndrome or cytokine release.
Capillary leak syndrome or SIRS occurred in 6 paediatric patients overall (5 ALL, 1 AML). Several patients developed rapid onset of respiratory distress, hypotension, capillary leak (pleural and pericardial effusions), and multiorgan failure. Other concurrent medical conditions, including sepsis, may also have contributed to the incidence of capillary leak syndrome. In addition, prior therapies and/or disease progression may also make these patients more susceptible to capillary leak syndrome.
Renal failure/acute renal failure has been observed as a consequence of infections, sepsis and tumour lysis syndrome (see Section 4.8 Adverse Effects (Undesirable Effects)). Monitor patients for renal toxicity and interrupt or discontinue Evoltra as necessary.

Hepatobiliary disorders.

Patients who have previously received a hematopoietic stem cell transplant (HSCT) may be at higher risk for hepatotoxicity, suggestive of veno-occlusive disease (VOD) following treatment with clofarabine (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). Veno-occlusive disease has also been observed in patients who had not received HSCT and were treated with clofarabine (52 mg/m2) as the single chemotherapeutic agent. Severe hepatotoxic events have been reported in an ongoing phase I/II combination study of clofarabine in paediatric patients with relapsed or refractory acute leukaemia. Cases of hepatitis and hepatic failure, including fatal incomes, have been reported with Evoltra treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for liver function and signs and symptoms of hepatitis and hepatic failure. Evoltra should be discontinued immediately if substantial increases in liver enzymes and/or bilirubin are observed.
Hepatobiliary toxicities were frequently observed in paediatric patients during treatment with Evoltra. Grade 3 or 4 elevated aspartate aminotransferase (AST) occurred in 36% of patients and grade 3 or 4 elevated alanine aminotransferase (ALT) occurred in 43% of patients. Grade 3 or 4 elevated bilirubin occurred in 13% of patients, with 2 events reported as grade 4 hyperbilirubinaemia (2%), one of which resulted in treatment discontinuation, one patient had multiorgan failure and died. One report (1%) of veno-occlusive disease (VOD) was considered related to the study drug.
For patients with follow-up data, elevations in AST and ALT were transient and typically ≤ 15 days duration. The majority of AST and ALT elevations occurred within 10 days of Evoltra administration and returned to ≤ grade 2 within 15 days. Where follow-up data are available, the majority of bilirubin elevations returned to ≤ grade 2 within 10 days. Eight patients had grade 3 or 4 elevations in serum bilirubin at the last time point measured, these patients died due to sepsis and/or multiorgan failure.

Renal and urinary disorders.

The most prevalent renal toxicity in paediatric patients was elevated creatinine. Grade 3 or 4 elevated creatinine occurred in 8% of patients. Acute renal failure has been reported with Evoltra treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). Nephrotoxic medications, tumour lysis, and tumour lysis with hyperuricaemia may contribute to renal toxicity. Haematuria was observed in 13% of patients overall. This event likely reflects thrombocytopenia that is a pre-existing condition in these patients.

Vascular disorders.

Sixty four patients of 115 (55.7%) experienced at least one vascular disorder adverse effect. Twenty three patients out of 115 experienced a vascular disorder considered to be related to clofarabine, the most frequently reported being flushing (13 events; not serious) and hypotension (5 events; all of which were considered to be serious). However, the majority of these hypotensive events were reported in patients who had confounding severe infections.

Gastrointestinal disorders.

Occurrences of enterocolitis including neutropenic colitis, cecitis and C.difficile colitis have been reported during treatment with Evoltra. Enterocolitis may lead to necrosis, perforation, haemorrhage or sepsis complications and may be associated with a fatal outcome (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for liver function and signs and symptoms of enterocolitis.

Skin and subcutaneous disorders.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Evoltra must be discontinued for exfoliative or bullous rash, or if SJS or TEN is suspected.

Cardiac disorders.

The most frequently reported cardiac disorder was tachycardia (35%), which was, however, already present in 35% of patients at study entry. Most of the cardiac adverse effects were reported in the first 2 cycles. Pericardial effusion was a finding in these patients on post-treatment studies, [9/115 (8%)]. The effusion was almost always minimal to small and in no cases had haemodynamic significance.

Use in cardiac disease.

Patients with cardiac disease and those taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Dehydration/hypotension.

Patients receiving Evoltra may experience vomiting and diarrhea; they should therefore be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, lightheadedness, fainting spells, or decreased urine output. Evoltra administration should be stopped if the patient develops hypotension for any reason during the 5 days of administration. If hypotension is transient and resolves without pharmacological intervention, Evoltra treatment can be reinstituted generally with a 25% dose reduction [see Section 4.2 Dose and Method of Administration].

Use in hepatic or renal impairment.

Evoltra has not been studied in patients with hepatic or renal dysfunction. In severe dysfunction, Evoltra is contraindicated. In mild to moderate dysfunction, Evoltra should be used with the greatest caution [see Section 4.2 Dose and Method of Administration].

Use in adults (> 21 and < 65 years old).

Safety and effectiveness have not been established in adults.

Use in the elderly (≥ 65 years old).

There are currently insufficient data to establish the safety and efficacy of clofarabine in elderly patients.

Paediatric use (> 1 and ≤ 21 years old).

The safety and efficacy have been established in children.

Effects on laboratory tests.

There are no known clinically significant interactions of Evoltra with laboratory tests. No formal drug/laboratory test interaction studies have been conducted with Evoltra.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Although no clinical drug-drug interaction studies have been conducted to date, on the basis of the in vitro studies, cytochrome P450 inhibitors and inducers are unlikely to affect the metabolism of clofarabine. Clofarabine did not significantly inhibit the activity of CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 at clinically relevant concentrations in vitro. Weak induction of CYP1A2 and CYP3A4 occurred in human hepatocytes in vitro at clofarabine concentrations of 0.5 to 12 microgram/mL, which was slightly higher than the clinical Cmax.
Clofarabine is predominately excreted via the kidneys. Hence, the concomitant use of medicinal products that have been associated with renal toxicity and those eliminated by tubular secretion should be avoided particularly during the 5 day clofarabine administration period.
Since the liver is a potential target organ for toxicity, the concomitant use of medicinal products that have been associated with hepatic toxicity should be avoided wherever possible.
Patients taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine.
There are no known clinically significant interactions of Evoltra with other medications or laboratory tests. No formal drug/laboratory test interaction studies have been conducted with Evoltra.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies in mice, rats, and dogs have demonstrated dose-related adverse effects on male reproductive organs. Seminiferous tubule and testicular degeneration and atrophy were reported in male mice receiving intraperitoneal (IP) doses of 3 mg/kg/day (9 mg/m2/day, approximately 17% of clinical recommended dose on an AUC basis). The testes of rats receiving 25 mg/kg/day (approximately 5 times the recommended clinical dose on an AUC basis) in a 6-month IV study had bilateral degeneration of the seminiferous epithelium with retained spermatids and atrophy of interstitial cells. In a 6-month IV dog study, cell degeneration of the epididymis and degeneration of the seminiferous epithelium in the testes were observed in dogs receiving 0.375 mg/kg/day (approximately 30% of the clinical recommended dose on an AUC basis). Ovarian atrophy or degeneration and uterine mucosal apoptosis were observed in female mice at 75 mg/kg/day IP (225 mg/m2/day, approximately 4-fold of recommended human dose on a mg/m2 basis), the only dose administered to female mice. Atrophy of the ovaries, uterus and vagina occurred in female rats receiving 12.5 g/kg/day (approximately 4 times the recommended clinical dose on an AUC basis). As the effect of clofarabine treatment on human fertility is unknown, reproductive planning should be discussed with patients as appropriate.
(Category D1)
1 Drugs which have caused, are expected to have caused or may be expected to cause, an increased risk of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
Evoltra (clofarabine) may cause foetal harm when administered to a pregnant woman.
Clofarabine was teratogenic in rats and rabbits. Developmental toxicity (reduced foetal bodyweight and increased postimplantation loss) and increased incidences of malformations and variations (gross external, soft tissue, skeletal and retarded ossification) were observed in rats receiving 1 mg/kg/day (approximately 40% of the recommended clinical dose on an extrapolated AUC basis), and in rabbits receiving 1 mg/kg/day (12 mg/m2/day; approximately 23% of the recommended clinical dose on a mg/m2 basis).
There are no adequate and well controlled studies in pregnant women using clofarabine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus.
Women of childbearing potential and sexually active males must use effective methods of contraception during treatment.
It is unknown whether clofarabine or its metabolites are excreted in human breast milk. The excretion of clofarabine in milk has not been studied in animals. Because of the potential for tumorigenicity shown for clofarabine in animal studies and the potential for serious adverse effects, women treated with clofarabine should not nurse. Female patients should be advised to avoid breastfeeding during treatment with Evoltra (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of clofarabine on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as dizziness, lightheadedness or fainting spells during treatment and told not to drive or operate machines in such circumstances.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials experience.

The information provided is based on data generated from clinical trials in which 115 patients (> 1 and ≤ 21 years old) with either ALL or acute myeloid leukaemia (AML) received at least one dose of clofarabine at the recommended dose of 52 mg/m2 daily x 5.
Patients with advanced stages of ALL or AML may have confounding medical conditions that make causality of adverse effects difficult to assess due to the variety of symptoms related to the underlying disease, its progression and the coadministration of numerous medicinal products.
Nearly all patients (98%) experienced at least one adverse effect considered by the study investigator to be related to clofarabine. Those most frequently reported were nausea (61% of patients), vomiting (59%), febrile neutropenia (35%), headache (24%), rash (21%), diarrhoea (20%), pruritus (20%), pyrexia (19%), palmar plantar erythrodysaesthesia syndrome (15%), fatigue (14%), anxiety (12%), mucosal inflammation (11%), and flushing (11%). Sixty-eight patients (59%) experienced at least one serious clofarabine related adverse effect. One patient discontinued treatment due to grade 4 hyperbilirubinaemia considered as related to clofarabine after receiving 52 mg/m2/day clofarabine. 3 patients died of adverse effects considered by the study investigator to be related to treatment with clofarabine: one patient died from respiratory distress, hepatocellular damage, and capillary leak syndrome; one patient from VRE sepsis and multiorgan failure; and one patient from septic shock and multiorgan failure.
Table 2 lists adverse effects by system organ class, including severe or life threatening events (NCI CTC grade 3 or grade 4), reported in ≥ 1% of the 115 patients in the 52 mg/m2/day dose group (pooled analysis of paediatric patients with ALL and AML).
Table 3 lists the incidence of treatment emergent laboratory abnormalities after Evoltra administration at 52 mg/m2 among paediatric patients with ALL and AML (n = 115).

Uncommon effects.

Gastrointestinal disorders.

Pancreatitis, serum amylase and lipase elevation.

Skin disorders.

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN).

Eye disorders.

Ocular icterus.

Postmarketing experience.

The following adverse effects have been identified during postapproval use of Evoltra. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labelling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal connection to Evoltra.

Blood and lymphatic system disorders.

Bone marrow failure and prolonged pancytopenia (thrombocytopenia, anaemia, neutropenia and lymphopenia) may occur. Bleeding events have been observed in the setting of thrombocytopenia. Haemorrhage, including cerebral and pulmonary haemorrhage, has been reported and may be fatal.

Gastrointestinal disorders.

Gastrointestinal haemorrhage has been observed and may be associated with a fatal outcome. Enterocolitis, including neutropenic colitis, cecitis and C. difficile colitis may lead to necrosis, perforation or sepsis complications and may be associated with fatal outcomes.

Hepatobiliary disorders.

Serious hepatotoxic events of venoocclusive disease have been reported and may be fatal in patients who had previous HSCT and who received conditioning regimens that included busulfan, melphalan, and/or the combination of cyclophosphamide and total body irradiation. Cases of hepatitis and hepatic failure have been reported, including fatal outcomes (see Section 4.4 Special Warnings and Precautions for Use).

Metabolism and nutrition disorders.

Hyponatremia.

Skin and subcutaneous disorders.

Occurrences of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases, have been reported in patients who were receiving or had recently been treated with Evoltra and other medications (e.g. allopurinol or antibiotics) known to cause these syndromes. Other exfoliative conditions have also been reported (see Section 4.4 Special Warnings and Precautions for Use).

Vascular disorders.

Capillary leak syndrome has been reported and may be fatal (see Section 4.4 Special Warnings and Precautions for Use).

Infections and infestations.

Bacterial, fungal and viral infections have been reported and may be fatal. These infections may lead to septic shock, respiratory failure and/or multi-organ failure (see Section 4.4 Special Warnings and Precautions for Use).
Systemic: neutropenic sepsis, bacterial sepsis (Streptococcus, Enterococcus, Klebsiella), fungal sepsis (Candida), bacteraemia (Streptococcus).
Respiratory: bronchopulmonary aspergillosis, lung abscess, pneumonia bacterial (Klebsiella), lower respiratory tract infection, respiratory tract infection fungal.
GI: tonsillitis, hepatosplenic candidiasis.
Neurological: brain abscess, central nervous system infection.
Musculoskeletal: necrotizing fasciitis.
Skin: wound infection bacterial (Staphylococcus).
Unspecified: Cytomegalovirus, Fusarium, Pseudomonas, central line infection, vaginal cellulitis.

Nervous system disorders.

Syncope.

Psychiatric disorders.

Confusional state.

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 www.tga.gov.au/reporting-problems (Australia).

4.9 Overdose

Symptoms.

No case of overdose has been reported. However, possible symptoms of overdose may include nausea, vomiting, diarrhoea and severe bone marrow depression. To date, the highest daily dose administered to human beings is 70 mg/m2 for 5 consecutive days (2 paediatric ALL patients). The toxicities observed in these patients included vomiting, hyperbilirubinaemia, elevated transaminase levels and maculopapular rash.

Treatment.

No specific antidotal therapy exists. Immediate discontinuation of therapy, careful observation and initiation of appropriate supportive measures are recommended.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antineoplastic agents, antimetabolites, ATC code: L01BB06.

Mechanism of action.

Clofarabine is a purine nucleoside antimetabolite. Its antitumour activity is believed to be due to 3 mechanisms:
DNA polymerase α inhibition resulting in termination of DNA chain elongation and/or inhibition of DNA synthesis/ repair;
Ribonucleotide reductase inhibition with reduction of intracellular deoxynucleotide triphosphate (dNTP) pools;
Disruption of mitochondrial integrity with the release of cytochrome C and other proapoptotic factors leading to programmed cell death even in nondividing cells.
In addition, halogenation of the adenine ring at the 2 position increases resistance to cellular degradation by adenosine deaminase, and substitution of a fluorine at the C-2' position in the arabino configuration decreases the susceptibility to phosphorylic cleavage by acid and bacterial purine nucleoside phosphorylase.

Pharmacodynamic effects.

In vitro studies have demonstrated that clofarabine inhibits cell growth and is cytotoxic to a variety of rapidly proliferating haematological and solid tumour cell lines (clofarabine concentrations inhibiting 50% of cell growth were ≤ 1 micromolar for solid tumours and mostly > 1 micromolar for leukaemia cell lines). It was also active against quiescent lymphocytes and macrophages (50% growth inhibition at > 0.45 micromolar). In addition, clofarabine delayed tumour growth and, in some cases, caused transient tumour regression in an assortment of human tumour xenografts implanted in mice.

Clinical trials.

Seventy-eight (78) paediatric patients with acute lymphocytic leukaemia (ALL) were exposed to Evoltra. Seventy (70) of the patients received the recommended paediatric dose of 52 mg/m2 daily x 5 as an intravenous (IV) infusion.

Phase I study in paediatric patients with haematologic malignancies.

The safety and efficacy of Evoltra were evaluated in paediatric patients with refractory or relapsed haematologic malignancies in an open label, dose escalation, noncomparative study. The starting dose was 11.25 mg/m2/day IV infusion daily x 5 and escalated to 70 mg/m2/day IV infusion daily x 5. This dosing schedule was repeated every 2 to 6 weeks depending on toxicity and response. Nine of 17 ALL patients were treated with 52 mg/m2 daily x 5. In the 17 ALL patients there were 2 complete remissions (12%) and 2 partial remissions (12%) at varying doses. Dose limiting toxicities (DLTs) in this study were reversible hyperbilirubinaemia and elevated transaminase levels and skin rash, experienced at 70 mg/m2. As a result of this study, the recommended dose for subsequent study in paediatric patients was determined to be 52 mg/m2/day for 5 days.

Phase II single arm study in paediatric ALL.

Evoltra was evaluated in an open label, single arm study of 61 paediatric patients with relapsed/refractory ALL. Patients received a dose of 52 mg/m2 over 2 hours for 5 consecutive days repeated every 2 to 6 weeks for up to 12 cycles. There was no dose escalation in this study.
All patients that had disease relapsed after and/or were refractory to two or more prior therapies. Most patients, 38/61 (62%) received > 2 prior regimens and 18/61 (30%) of the patients had undergone at least 1 prior transplant. The median age of the treated patients was 12 years (range 1-20 years old), 61% were male, 39% were female, 44% were Caucasian, 38% were Hispanic, 12% were African American, 2% were Asian and 5% were of other race.
The overall remission (OR) rate (complete remission [CR] + CR in the absence of total platelet recovery [CRp]), defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow (≤ 5% blasts), and recovery of peripheral counts [platelets ≥ 100 x 109/L and absolute neutrophil count (ANC) ≥ 1.0 x 109/L] and CRp, defined as meeting all criteria for CR except for recovery of platelet counts to > 100 x 109/L was evaluated. Partial response (PR) was also determined, defined as complete disappearance of circulating blasts, an M2 bone marrow (≥ 5% and ≤ 25% blasts), and appearance of normal progenitor cells or an M1 marrow that did not qualify for CR or CRp. The remission criteria are based on those of the Children's Oncology Group. Duration of remission and overall survival was also evaluated. Transplantation rate was not a study endpoint.
Response rates for these studies were determined by an unblinded Independent Response Review Panel (IRRP).
Table 4 summarises results for the paediatric ALL study. Responses were seen in both pre-B and T-cell immunophenotypes of ALL. The median cumulative dose was 530 mg (range 29-2815 mg) in 1 (41%), 2 (44%) or 3 or more (15%) cycles. The median number of cycles was 2 (range 1-12). The median time between cycles was 28 days with a range of 12 to 55 days.
Of 35 patients who were refractory to their immediately preceding induction regimen, 6 (17.1%) achieved a CR or CRp. Of 18 patients who had at least 1 prior haematopoietic stem cell transplant (HSCT), 5 (27.8%) achieved a CR or CRp.
Among the 18 patients who achieved at least a PR, 9 patients achieved the best response after 1 cycle of clofarabine, 8 patients required 2 courses and 1 patient achieved a CR after 3 cycles of therapy. Of these 18 responding patients, 9 had postclofarabine bone marrow transplantation (3 CR, 3 CRp, 3 PR). Four of these patients who achieved CR or CRp received HSCT while in continued remission, one patient proceeded to transplant following relapse. One additional patient who achieved a CRp proceeded to transplant following alternative therapy. Duration of response was censored at the time of transplant.
The effect of clofarabine on remission duration and overall survival can only be accurately assessed for patients who did not undergo transplantation because of the confounding effect of transplantation. Of the six subjects with complete remission who did not undergo transplant, the median duration of remission was only 9 weeks (range 4 to 59). In the six who did receive transplant, the duration of remission ranged from 10 to 108+ weeks, some of the effect likely drug related since longer remission may have enabled transplant.
Median overall survival was 63 weeks (range 9 to 72) for nontransplanted responding subjects. Overall survival ranged from 42 to 145+ weeks for transplanted responding subjects. The transplanted result reflects the effects of both clofarabine and the transplant.
Achievement of complete remission appears to have translated into opportunity for transplant and longer survival, but this needs confirmation.
Table 5 lists the individual remission duration and survival data for patients who achieved a CR or CRp. Also see Figure 1.
Median overall survival for CR, CR + CRp, or CR + CRp + PR was 72.4, 69.5, 66.6 weeks respectively (Table 6). Median overall survival for all patients (n = 61) was 12.9 weeks. Seven of 61 patients were alive at the time of last follow-up (including 2 patients who achieved a PR).

5.2 Pharmacokinetic Properties

The population pharmacokinetics of Evoltra were studied in 40 paediatric patients aged 2 to 19 years (21 males/19 females) with relapsed or refractory acute lymphocytic leukaemia (ALL) or acute myelogenous leukaemia (AML). At the given 52 mg/m2 dose, similar concentrations were obtained over a wide range of body surface areas (BSAs). Clofarabine was 47% bound to plasma proteins, predominantly to albumin (27% binding). Based on noncompartmental analysis, systemic clearance and volume of distribution at steady state were estimated to be 28.8 L/h/m2 and 172 L/m2, respectively. The terminal half-life was estimated to be 5.2 hours. No apparent difference in pharmacokinetics was observed between patients with ALL and AML or between males and females.
No relationship between clofarabine or clofarabine triphosphate exposure and toxicity or response was found in this population.
Based on 24 hour urine collections in the paediatric studies, 49 - 60% of the dose is excreted in the urine unchanged. In vitro studies using isolated human hepatocytes indicate very limited metabolism (0.2%). The pathways of nonhepatic elimination remain unknown.

5.3 Preclinical Safety Data

Genotoxicity.

Clofarabine showed genotoxic activity in the in vitro mammalian cell chromosome aberration assay (CHO cells) and in the in vivo rat micronucleus assay. It did not show evidence of mutagenic activity in the bacterial mutation assay (Ames test).

Carcinogenicity.

Clofarabine has not been tested for carcinogenic potential.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, water for injections.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned, see Section 4.2 Dose and Method of Administration.

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.
For shelf life of the diluted medicinal product, see Section 4.2 Dose and Method of Administration, Stability.

6.4 Special Precautions for Storage

Store below 25°C. Do not freeze.
For storage conditions of the diluted medicinal product, see Section 4.2 Dose and Method of Administration, Stability.

6.5 Nature and Contents of Container

Strength: 20 mg/20 mL.

Pack*: 1 x 20 mL vial; 3 x 20 mL vials; 4 x 20 mL vials; 10 x 20 mL vials.
* Not all pack sizes may be marketed.
The injection is supplied in clear type I glass vials.

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

Clofarabine is a purine nucleoside anti-metabolite structurally related to marketed substances like fludarabine and cladribine. It is a white to off-white solid which is soluble in saline up to 1.5 mg/mL at room temperature. The optical rotation is + 39.93° (average; c = 5 mg/mL, 25°C) in dimethylformamide solvent. The alcohol pKa is 16, the amine pKa is 12, and the protonated base pKa is approximately 2.

Chemical structure.


Chemical Name: 2-chloro-9-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)-9H-purine-6-amine.
Molecular Formula: C10H11ClFN5O3.
Molecular Weight: 303.68.

CAS number.

123318-82-1.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes