Consumer medicine information

What is in this leaflet

This leaflet answers some common questions about HOLOXAN.

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 being given HOLOXAN 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 in a safe place. You may need to read it again.

What HOLOXAN is used for

HOLOXAN is used to treat various types of cancer. These include:

• lymphoma, a cancer of the lymph glands (one type of lymphoma is also called Hodgkin’s Disease)
• a type of cancer called sarcoma
• cancer of the testes
• breast cancer
• ovarian cancer
• cervical cancer
• lung cancer

HOLOXAN belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines.

HOLOXAN works by stopping cancer cells from growing and multiplying.

Your doctor may have prescribed HOLOXAN for another reason. Ask your doctor if you have any questions about why HOLOXAN has been prescribed for you.

HOLOXAN is often used in combination with other medicines to treat cancer.

HOLOXAN is not addictive.

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

Before you are given HOLOXAN

When you must not be given it

Do not have HOLOXAN if you have an allergy to HOLOXAN (ifosfamide). Symptoms of an allergic reaction to HOLOXAN may include:

• shortness of breath, wheezing, difficulty breathing or a tight feeling in your chest
• swelling of the face, lips, tongue or other parts of the body
• rash, itching, hives or flushed, red skin
• dizziness or lightheadedness

Do not have HOLOXAN if you have, or have had, any of the following medical conditions, unless you have first discussed this with your doctor:

• severe liver problems
• kidney problems
• bladder problems, including a burning feeling when passing urine
• condition of the blood with a reduced number of white or red blood cells or platelets

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.

HOLOXAN may cause birth defects if either the male or female is using it at the time of conception. Both men and women taking HOLOXAN and their partners must use a reliable method of contraception during and for 6 months after receiving HOLOXAN.

Females: Do not have HOLOXAN if you are pregnant or intend to become pregnant. Like most medicines used to treat cancer, HOLOXAN is not recommended for use during pregnancy unless you and your doctor have discussed the risks and benefits involved.

Males: tell your doctor or pharmacist if your partner intends to become pregnant while you are having HOLOXAN or shortly after you have stopped having HOLOXAN. HOLOXAN may interfere with the reproductive system in both men and women, causing loss of ability to have children. This may be irreversible in some people.

Please discuss this with your doctor.

Do not breastfeed while you are being treated with HOLOXAN. HOLOXAN passes into the breast milk and therefore there is a possibility that the breastfed baby may be affected.

If you are not sure whether you should start having HOLOXAN, talk to your doctor or pharmacist.

Before you are given it

Tell your doctor or pharmacist if you have allergies to:

• any other medicines
• any other substances, such as foods, preservatives or dyes.

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

• liver problems
• kidney problems
• bladder problems
• heart problems
• blood disorder with a reduced number of red or white blood cells or platelets
• convulsions, fits or seizures
• sugar diabetes
• problems with too much alcohol

Tell your doctor about any previous treatments you have had for cancer, such as other medicines, or radiation therapy.

Tell your doctor if you have had any operations in the last 3 months.

If you have not told your doctor about any of the above, tell them before you start having HOLOXAN.

Taking other medicines

Tell your doctor or pharmacist if you are having any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines and HOLOXAN may interfere with each other. These include:

• other medicines used to treat cancer (eg cisplatin), radiation therapy or any other treatment which lowers your immune system
• medicines used to prevent blood clots, including warfarin
• some medicines used to treat diabetes
• allopurinol, a medicine used to treat gout
• hydrochlorothiazide, a diuretic (also called a water or fluid tablet)
• some medicines used to treat infections
• some medicines used to stop or prevent vomiting
• buproprion, a medicine to help stop smoking
• some medicines used to treat epilepsy
• some medicines used as sedatives or to relieve anxiety
• some medicines used to relieve pain
• some medicines used to help sleeping
• some anti-allergy medicines
• some vaccines

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

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while having HOLOXAN.

How HOLOXAN is given

HOLOXAN will always be given by specially trained doctors or nurses in a hospital or clinic.

How much is given

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

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

How it is given

HOLOXAN is given as an infusion (drip) into your veins.

HOLOXAN is always given with another medicine called UROMITEXAN (mesna) Injection or Tablets, to help prevent side effects on the bladder and urinary system.

How long it is given

HOLOXAN is usually given either as a continuous infusion over 24 hours, or as a short infusion on 3-5 consecutive days.

HOLOXAN may be given alone or in combination with other medicines to treat cancer. If it is given in combination with other medicines, further days of treatment may be needed.

The treatment is usually repeated every 2-4 weeks, depending on when any unwanted effects of the medicine have settled down. These are called cycles of chemotherapy.

Several cycles of HOLOXAN therapy may be needed depending on your response to treatment.

Overdose

As HOLOXAN is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

However, if you experience any side effects after being given HOLOXAN, tell your doctor immediately or go to Accident and Emergency at your nearest hospital. You may need urgent medical attention.

Symptoms of a HOLOXAN overdose include the side effects listed below in the ‘Side effects’ section, but are usually of a more severe nature.

While you are having HOLOXAN

Things you must do

Be sure to keep all your doctor’s appointments so your progress can be checked. Your doctor may want to do some blood, urine 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 HOLOXAN at the appropriate times to get the best effects from your treatments.

Be sure to follow your doctor’s instructions about other medicines you should take, and other things you should do. You may need to take other medicines to help prevent unwanted effects of HOLOXAN. You may also be advised to drink extra fluid, to help prevent damage to the bladder and urinary system.

Ask your doctor or pharmacist if you have any questions.

Tell the doctor or nurse if you experience any pain during the injection of HOLOXAN.

Tell any other doctors, dentists, and pharmacists who are treating you that you are having HOLOXAN.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are having HOLOXAN.

Both men and women taking HOLOXAN and their partners must use a reliable method of contraception during and for 6 months after receiving HOLOXAN.

If you become pregnant while having HOLOXAN, tell your doctor.

HOLOXAN 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 who have 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.
• Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist 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 you must not do

Do not drink alcohol while you are on HOLOXAN. Alcohol may worsen some side effects of HOLOXAN, such as nausea, vomiting and dizziness.

Do not eat grapefruit or drink grapefruit juice while you are on HOLOXAN. Grapefruit may interact with HOLOXAN and cause it not to work as well.

Things to be careful of

Be careful driving or operating machinery until you know how HOLOXAN affects you. As with many other medicines, HOLOXAN may cause side effects such as dizziness, drowsiness and nausea in some people. Make sure you know how you react to HOLOXAN before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive. If you drink alcohol, dizziness or light-headedness may be worse.

Side effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are having HOLOXAN. Like other medicines that treat cancer, HOLOXAN may have unwanted side effects, some of which may be serious. You may need medical treatment if you get some of the side effects.

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

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

• nausea, vomiting
• loss of appetite
• diarrhoea
• constipation
• unusual hair loss or thinning
• unusual tiredness or weakness
• no menstrual periods

These are the more common side effects of HOLOXAN.

Hair usually grows back again after treatment is stopped, although it may be of a different colour or texture.

Tell your doctor or nurse as soon as possible if you notice any of the following:

• tiredness, headaches, being short of breath when exercising, dizziness, looking pale
• bleeding or bruising more easily than normal
• frequent infections, fever, severe chills, sore throat or mouth ulcers
• changes to breathing, cough
• sore, red mouth
• inflammation of mucous membranes (eg vagina)
• skin rash
• cramps
• blurred vision, changes in vision
• severe upper stomach pain
• tingling or numbness in fingers or toes

These may be serious side effects. You may need medical attention.

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

• blood in the urine
• pain in the bladder or difficulty passing urine
• disease of the brain - symptoms include drowsiness, confusion, hallucinations, fits or seizures, loss of consciousness
• vomiting bright red blood
• heart disease - symptoms include fatigue, chest pain, palpitations, altered heart beat
• shortness of breath, swelling of feet and ankles
• swelling and redness along a vein which is extremely tender when touched
• unexpected pain, tenderness or weakness in the muscles
• sudden sign of allergy such as rash, itching or hives on the skin, swelling of face, tongue or other parts of the body, difficulty breathing, dizziness

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Other side effects not listed above may occur in some patients. Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

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

In some cases, different cancers, especially of the bladder or the bone marrow, have occurred in patients up to several years after treatment with HOLOXAN.

Discuss any concerns you have about this with your doctor.

Storage

HOLOXAN 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

HOLOXAN is a white powder in a clear glass vial. It is mixed with a liquid before use. Each vial is used only once and any leftover material is discarded.

Ingredients

Active ingredient:
ifosfamide

There are no inactive ingredients in HOLOXAN.

Sponsor

Baxter Healthcare Pty Limited
(ABN 43 000 392 781)
1 Baxter Drive
Old Toongabbie NSW 2146

HOLOXAN is available in the following sizes:
1g AUST R 43608
2g AUST R 43609

Date of preparation of this CMI:
19 September 2007

HOLOXAN and UROMITEXAN are trademarks of Baxter Healthcare S.A.

Published by MIMS October 2015

1 Name of Medicine

Ifosfamide injection 500 mg, 1 g and 2 g.

2 Qualitative and Quantitative Composition

Each vial contains 500 mg, 1 g and 2 g of ifosfamide.

3 Pharmaceutical Form

Powder for concentrate for solution for infusion. Ifosfamide is a chemotherapeutic agent related chemically to the nitrogen mustards and is a synthetic analogue of cyclophosphamide. Ifosfamide is a white crystalline powder that is soluble in water.

4 Clinical Particulars

4.1 Therapeutic Indications

Indications for the use of ifosfamide are tumours sensitive to ifosfamide either as a single agent or in combination with other chemotherapeutic agents. Tumour types that have been demonstrated to respond to ifosfamide single agent or in combination are germ cell tumours, sarcomas, lymphomas. Anti-tumour activity has been shown in ovarian and cervical cancers. Some activity has also been seen in lung and breast cancer.

4.2 Dose and Method of Administration

Ifosfamide should be administered only by physicians experienced with this drug. Dosage must be individualized. Doses and duration of treatment and/or treatment intervals depend on the therapeutic indication, the scheme of a combination therapy, the patient's general state of health and organ function, and the results of laboratory monitoring. In combination with other agents of similar toxicity, a dose reduction or extension of the therapy-free intervals may be necessary.
Where indicated, use of hematopoiesis-stimulating agents (colony-stimulating factors and erythropoiesis-stimulating agents) may be considered to reduce the risk of myelosuppressive complications and/or help facilitate the delivery of the intended dosing.
During or immediately after administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urothelial toxicity.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Before parenteral administration, the substance must be completely dissolved.
The dose of Holoxan varies considerably with the clinical indication and the regimen employed. The usual total dose for each course is either 8-10 g/m² which is fractioned equally as single daily doses over five days, or 5-6 g/m² (maximum 10 g) given as a 24 hour infusion. Courses are normally repeated at intervals of 2-4 weeks for intermittent therapy or 3-4 weeks for 24 hour infusions depending on the haematological and biochemical status of the patient. The white cell count should not be less than 4 x 10⁹/L or the platelet count less than 100 x 10⁹/L before the start of each course.
In order to prevent bladder toxicity, and for prophylaxis of haemorrhagic cystitis, Holoxan should always be given concurrently with the uroprotector Uromitexan (mesna). Although Holoxan has been administered to a small number of patients with compromised hepatic and/or renal function, studies to establish optimal dose schedules of Holoxan in such patients have not been conducted.

Method of administration.

4.3 Contraindications

Holoxan is contraindicated in patients with:
known hypersensitivity to ifosfamide;
severely impaired bone marrow function (especially in patients previously treated with cytotoxic agents or radiotherapy);
inflammation of the urinary bladder (cystitis);
impaired renal function and/or obstructions of the urine flow;
severe hepatic impairment;
acute infections;
fertility, pregnancy and lactation (see Section 4.6).

4.4 Special Warnings and Precautions for Use

In individual patients, risk factors for ifosfamide toxicities and their sequelae described here and in other sections may constitute contraindications. In such situations, individual assessment of risk and expected benefits is necessary. Adverse reactions, depending on their severity, may require dosage modification or discontinuation of treatment.
Holoxan should always be given concurrently with the uroprotector Uromitexan (mesna). Holoxan is a potent cytotoxic drug and should be used only by physicians experienced with cancer chemotherapeutic drugs.
Holoxan should be given cautiously to patients with impaired renal function and impaired hepatic function, as well to those with compromised bone marrow reserve, as indicated by leucopoenia, granulocytopenia, extensive bone marrow metastases, prior radiation therapy or prior therapy with other cytotoxic agents. Moderate to severe myelosuppression can be expected in such patients. As ifosfamide exerts an immunosuppressive action interruption or modification of dosage should be considered in those patients who develop bacterial, fungal or viral infections. Blood counts should be taken at regular intervals.
Patients with impaired immune defense (e.g. in case of diabetes mellitus or chronic liver or kidney disorders) need to be closely monitored.
Urotoxic side effects, especially haemorrhagic cystitis, have been frequently associated with the use of Holoxan. Outflow disturbances in the efferent urinary tract, cystitis, infections and electrolyte imbalances must be excluded or rectified before start of therapy. During treatment, renal function, urinary status and urinary sediment must be checked regularly. It is recommended that a urinalysis should be performed prior to each dose of Holoxan. If haematuria (greater than 10 RBCs per high power field) is present, then subsequent administration should be withheld until complete resolution.
Administration of Holoxan should be given with vigorous oral or parenteral hydration, and with the uroprotective agent mesna (Uromitexan). The use of mesna has been demonstrated to reduce the incidence of urinary tract complications from 40% - 3.5%.
Extra care is required in unilaterally nephrectomised patients, who do not tolerate high doses of the drug very well. Holoxan should not be given until three months after the nephrectomy.
Especially in the case of long-term treatment with ifosfamide, sufficient diuresis and regular monitoring of renal function is required, particularly in children. In case of onset of nephropathy, irreversible kidney damage must be expected if treatment with ifosfamide is continued. Careful appraisal of the risk-benefit ratio will be required.
Pre-disposing factors for nephrotoxicity include large cumulative doses of ifosfamide (in particular for children below 3 years of age). Therefore, glomerular and tubular kidney function must be evaluated and checked before commencement of therapy, as well as during and after treatment.
Since use of ifosfamide is associated with myelosuppression, leucocyte, erythrocyte and platelet counts should be carried out prior to each administration and at appropriate intervals, if necessary daily. There is normally a reduction in the leucocyte count beginning on approximately day 5. The nadir, depending on dosage and baseline count, tends to be reached after 8 to 10 days. Recovery occurs after 10 to 14 days and is usually complete after 2 to 3 weeks. Unless essential, ifosfamide should not be given to patients with a WBC count below 2.5 x 10⁹/L. In case of fever and/or leucopoenia, the prophylactic use of antibiotics and/or antimycotics should be considered.
Neurologic manifestations consisting of somnolence, confusion, hallucinations and in some instances, coma, have been reported following Holoxan therapy. The risk of these toxic effects on the CNS necessitates careful monitoring of the patient. The occurrence of these symptoms requires discontinuation of Holoxan therapy. The symptoms have usually been reversible and supportive therapy should be maintained until their complete resolution. Recommencement of Holoxan should only be undertaken with caution and taking into consideration the clinical situation of the patient and the risk-benefit analysis.
Administration of ifosfamide can cause CNS toxicity and other neurotoxic effects. There are some data to suggest that CNS toxicity is related to impaired renal function (creatinine > 1.5 mg/dL), pretreatment with nephrotoxic drugs (e.g. cisplatin), post-renal obstructions (e.g. pelvic tumours) and prior nephrectomy. Further risk factors for encephalopathy include a poor general state of health, old age, young age, obesity, female gender, individual predisposition, a history of alcohol abuse, decreased levels of serum albumin or serum bicarbonate, low bilirubin, low haemoglobin levels, decreased white blood cell count, acidosis, electrolyte imbalances, hyponatremia and inappropriate ADH (vasopressin) secretion, water intoxication, low fluid intake, presence of brain metastases, prior CNS disease, brain irradiation, cerebral sclerosis, peripheral vasculopathy, presence of tumour in lower abdomen, bulky abdominal disease and hepatic dysfunction. If encephalopathy develops, treatment with ifosfamide should be discontinued. The possibility to reintroduce ifosfamide should be determined after careful assessment of the benefits and risks for the individual patient. Patients with brain metastases and/or cerebral symptoms must be monitored on a regular basis.
Drugs acting on the CNS (such as antiemetics, tranquillizers, narcotics or antihistamines) are to be used with particular caution in the case of ifosfamide-induced encephalopathy or should be discontinued, if possible.
Special caution must be exercised in patients with pre-existing cardiac disorders. There is a need for regular electrolyte controls. Furthermore, there is evidence that the cardiotoxic effect of ifosfamide may be enhanced in patients who have received previous radiation treatment of the heart region and/or adjuvant treatment with anthracyclines.
To reduce stomatitis attention should be paid to thorough oral hygiene. Antiemetics must be administered prophylactically.
Close monitoring of patients with pre-existing hepatic impairment is recommended. Alcohol abuse may increase the risk of developing hepatic dysfunction.
The blood sugar level should be checked regularly in diabetic patients in order to adjust antidiabetic therapy on time (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Since ifosfamide may interfere with normal wound healing, therapy should not be initiated for at least 10 to 14 days after surgery.
Although ifosfamide is not a vesicant, in the case of extravasation, it is recommended to stop the infusion immediately, to aspirate the extravasate with the needle in place, and to irrigate with saline solution and to immobilize the extremity.

Use in patients with renal impairment.

Use in patients with hepatic impairment.

Use in elderly.

Paediatric use.

Effects on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The physician should be alert for possible combined drug actions, desirable or undesirable, involving ifosfamide even though ifosfamide has been used successfully concurrently with other drugs, including other cytotoxic drugs.
Planned co-administration or sequential administration of other substances or treatments that could increase the likelihood or severity of toxic effects (by means of pharmacodynamic or pharmacokinetic interactions) requires careful individual assessment of the expected benefit and the risks. Patients receiving such combinations must be monitored closely for signs of toxicity to permit timely intervention. Patients being treated with ifosfamide and agents that reduce its activation should be monitored for a potential reduction of therapeutic effectiveness and the need for dose adjustment.
Potentiation of the myelotoxicity due to interaction with other cytostatic agents or irradiation must be considered. Concomitant administration of ifosfamide and allopurinol or hydrochlorothiazide may also increase the myelosuppressive effect.
The nephrotoxic, haematotoxic and neurotoxic (CNS) effects associated with ifosfamide may be enhanced by prior or concomitant administration of nephrotoxic drugs, such as cisplatin, aminoglycosides, acyclovir or amphotericin B.
Holoxan therapy may exacerbate radiodermatitis.
Due to the immunosuppressant effects of ifosfamide, a reduced response to the respective vaccines can be expected. In case of live vaccines, a vaccine-induced infection may develop.
Concurrent administration of anticoagulants such as warfarin, can result in a further decrease in clotting and an increased risk of bleeding.
Concurrent administration with antidiabetic agents such as sulfonylureas may enhance the hypoglycaemic effect.
Drugs acting on the CNS (e.g. antiemetics, tranquillizers, narcotics or antihistamines) are to be used with particular caution in the case of ifosfamide-induced encephalopathy or, if possible, discontinued.
Findings from in vitro experiments indicate that bupropion is mainly catabolized via the microsomal enzyme cytochrome P450 IIB6 (CYP2B6). Therefore, caution must be exercised in case of concomitant administration of bupropion and preparations that act on the isoenzyme CYP2B6 (such as orphenadrine, cyclophosphamide and ifosfamide). In case of previous or concomitant treatment with phenobarbital, phenytoin, benzodiazepines, primidone, carbamazepine, rifampicin or chloral hydrate, there is a risk of inducing the ubiquitous microsomal CYP isoenzymes, which are particularly present in the liver.
Grapefruit contains a substance which leads to an inhibition of CYP isoenzymes and therefore may reduce metabolic activation of ifosfamide and consequently its efficacy. For this reason, patients treated with ifosfamide should avoid eating grapefruit and/or the consumption of food or beverages containing this fruit.
The following interactions are theoretically possible. The therapeutic effect and the toxicity of ifosfamide may be enhanced by the concurrent administration of chlorpromazine, triiodothyreonine or aldehyde dehydrogenase inhibitors such as disulfiram. Potentiation of the muscle-relaxant effect of suxamethonium could occur.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

4.7 Effects on Ability to Drive and Use Machines

Ifosfamide can lead to impairment of the ability to drive a vehicle or to operate machinery, directly by inducing encephalopathy and indirectly by inducing nausea and vomiting - particularly in the case of concomitant administration of medical products acting on the CNS or consumption of alcohol.

4.8 Adverse Effects (Undesirable Effects)

In individual patients, risk factors for ifosfamide toxicities and their sequelae described here and in other sections may constitute contraindications. In such situations, individual assessment of risk and expected benefits is necessary. Adverse reactions, depending on their severity, may require dosage modification or discontinuation of treatment.
In patients receiving Holoxan as a single agent, the dose-limiting toxicities are myelosuppression and urotoxicity.

Urinary.

Haematopoietic.

Gastrointestinal.

Hepatobiliary.

Integumentary.

CNS.

Cardiotoxicity.

Respiratory.

Immune system.

Endocrine system.

Musculoskeletal system.

Reproductive system.

Neoplasms.

Ocular.

Other.

Post-marketing adverse reactions.

Infections and infestations.

Neoplasms, benign and malignant and unspecified (including cysts and polyps).

Blood and lymphatic system disorders.

Immune system disorders.

Endocrine disorders.

Metabolism and nutrition disorders.

Psychiatric disorders.

Nervous system disorders.

Eye disorders.

Ear and labyrinth disorders.

Cardiac disorders.

Vascular disorders.

Respiratory, thoracic, and mediastinal disorders.

Gastrointestinal disorders.

Hepatobiliary disorders.

Skin and subcutaneous tissue disorders.

Musculoskeletal and connective tissue disorders.

Renal and urinary disorders.

Reproductive system and breast disorders.

Congenital, familial and genetic disorders.

General disorders and administrative site conditions.

Reporting suspected adverse effects.

4.9 Overdose

No specific antidote for Holoxan is known. Management of overdose would include general supportive measures to sustain the patient through any period of toxicity that might occur. Serious consequences of overdosage include manifestations of dose-dependent toxicities such as CNS toxicity, nephrotoxicity, myelosuppression and mucositis. Patients who received an overdose should be closely monitored for the development of toxicities. Ifosfamide as well as ifosfamide metabolites are dialyzable. Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with overdose. For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Clinical trials.

5.2 Pharmacokinetic Properties

Ifosfamide exhibits dose-dependent pharmacokinetics in humans. At single doses of 3.8-5.0 g/m², the plasma concentrations decay biphasically and the mean terminal elimination half-life is about 15 hours. At doses of 1.6-2.4 g/m²/day, the plasma decay is monoexponential and the terminal elimination half-life is about seven hours.
Two different dechloroethylated derivatives of ifosfamide, 4-carboxyifosfamide, thiodiacetic acid and cysteine conjugates of chloroacetic acid have been identified as the major urinary metabolites of ifosfamide in humans and only small amounts of 4-hydroxyifosfamide and acrolein are present. Small quantities (nanomol/mL) of ifosfamide mustard and 4-hydroxyifosfamide are detectable in human plasma.

5.3 Preclinical Safety Data

Genotoxicity.

Carcinogenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

None.

6.2 Incompatibilities

No data available.

6.3 Shelf Life

Five years.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Glass vial with bromobutyl rubber stopper.

6.6 Special Precautions for Disposal

The handling and preparation of ifosfamide should always be in accordance with current guidelines on safe handling of cytotoxic agents. Skin reactions associated with accidental exposure to ifosfamide may occur. To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and solutions containing ifosfamide. If ifosfamide solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water.

6.7 Physicochemical Properties

Ifosfamide is 3-(2-chloroethyl)-2-[(2-chloroethyl) amino] tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide. The molecular formula is C₇H₁₅Cl₂N₂O₂P and its molecular weight is 261.1.

Chemical structure.

CAS number.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes