Ifosfamide

Ifosfamide is a cytotoxic agent of the oxazaphosphorine group, chemically related to nitrogen mustard and a synthetic analogue of cyclophosphamide. It is inactive in vitro and has to be activated, mainly in the liver, before it can act. Its active metabolites alkylate DNA, which accounts for its cytotoxic effect.

Mechanism of Action

• Activation: liver microsomal enzymes hydroxylate ifosfamide to 4-hydroxy-ifosfamide, which is in equilibrium with its tautomer aldoifosfamide. Aldoifosfamide splits spontaneously into acrolein and the alkylating metabolite ifosfamide mustard.
• DNA alkylation: the alkylating metabolites attack the phosphodiester bridges of DNA, producing strand breaks and cross-links that lead to cell death.
• Cell-cycle effect: passage through the G2 phase is slowed. The cytotoxic effect does not depend on one particular phase of the cell cycle.
• Urotoxic metabolite: acrolein is held responsible for the bladder toxicity of ifosfamide, which is why mesna is used with high doses.
• Cross-resistance: cross-resistance cannot be ruled out, especially with structurally related cytotoxics such as cyclophosphamide and with other alkylating agents. Tumours resistant to cyclophosphamide, or recurring after it, often respond to ifosfamide.

Pharmacokinetics

• Absorption: given intravenously. The drug is detectable in organs and tissues within minutes, and the plasma concentration rises in a linear relationship with the dose.
• Distribution: volume of distribution 0.5–0.8 L/kg. Ifosfamide and its metabolites reach tissues and organs, including the brain, and unchanged ifosfamide crosses the blood–brain barrier. About 20% is bound to plasma proteins. Because the substance is teratogenic in animals and resembles cyclophosphamide, passage across the placenta and into breast milk is to be expected.
• Metabolism: starts within minutes. Hydroxylation to the active 4-hydroxy-ifosfamide in the liver is catalysed mainly by CYP3A4. Dealkylation of the chloroethyl side chains inactivates 25–60% of the drug and appears to be catalysed by CYP2B6; aldoifosfamide can also be oxidised to inactive carboxy-ifosfamide. Differences between individuals are wide.
• Elimination: mainly by the kidney. After fractionated doses of 1.6–2.4 g/m² daily for three consecutive days, 57% of the dose was eliminated within 72 hours as metabolites or unchanged drug, and after a single high dose of 3.8–5 g/m², 80%; unchanged drug accounted for up to 15% and 53% of the dose respectively. Renal clearance is 6–22 mL/min and the plasma half-life 4–7 hours.
• Special populations: reduced excretion in renal impairment can raise plasma levels of ifosfamide and its metabolites and increase toxicity; severe hepatic impairment may lower the activation of ifosfamide (see Special Instructions).

Ifosfamide is indicated in adult patients, as monotherapy or in combination with other cytotoxic medicines, radiotherapy and/or surgery, for:

• Testicular germ cell tumours: combination chemotherapy for advanced tumours of TNM stages II to IV (seminomas and non-seminomas) that do not respond, or respond insufficiently, to initial chemotherapy; or first-line treatment in patients who are not candidates for other regimens.
• Ovarian carcinoma: combination chemotherapy for advanced tumours (FIGO stages III and IV) that do not respond to initial chemotherapy, including platinum-based chemotherapy.
• Osteosarcoma, soft-tissue sarcoma, Ewing sarcoma and rhabdomyosarcoma: in combination with other chemotherapy as adjuvant or neoadjuvant treatment, and as a single agent or part of polychemotherapy regimens in advanced or metastatic disease.
• Non-Hodgkin lymphoma: combination chemotherapy in patients whose disease has relapsed or is refractory to initial treatment.
• Hodgkin lymphoma: combination chemotherapy in patients who have relapsed or are refractory and do not respond to initial treatment.

• Hypersensitivity to the active substance.
• Severely impaired bone-marrow function, especially in patients previously treated with radiotherapy or cytotoxic agents.
• Inflammation of the urinary bladder (cystitis).
• Renal impairment and/or obstruction of urinary outflow.
• Active infections.
• Pregnancy and breastfeeding.

The most frequent effects are bone-marrow suppression (leukopenia, thrombocytopenia, anaemia), nausea and vomiting, hair loss, and bladder and kidney toxicity. The frequencies below come from published clinical experience and post-marketing use of fractionated single-agent ifosfamide at a total dose of 4 to 12 g/m² per cycle; most reactions are reported with an unknown frequency.

Very common (≥1/10): myelosuppression, leukopenia, thrombocytopenia, anaemia, nausea and vomiting, alopecia, haemorrhagic cystitis (its frequency is estimated from that of haematuria), haematuria (with and without mesna), macrohaematuria (without mesna), renal dysfunction, structural renal damage.

Common (≥1/100 to <1/10): infection, febrile neutropenia, anorexia, hepatotoxicity, phlebitis, macrohaematuria (with mesna).

Uncommon (≥1/1,000 to <1/100): pneumonia, cardiotoxicity, hypotension, diarrhoea, stomatitis, fatigue.

Rare (≥1/10,000 to <1/1,000): dermatitis, papular rash.

Not known: sepsis and septic shock, reactivation of latent infections, secondary malignancies (including acute leukaemias, myelodysplastic syndrome, lymphoma, sarcomas, renal cell and thyroid cancer) and progression of the underlying cancer; agranulocytosis, febrile bone-marrow aplasia, disseminated intravascular coagulation, haemolytic uraemic syndrome and haemolytic anaemia; anaphylactic reaction, angioedema, hypersensitivity and urticaria; syndrome of inappropriate antidiuretic hormone secretion (SIADH), tumour lysis syndrome, metabolic acidosis, hypokalaemia, hypocalcaemia, hypophosphataemia and hyperglycaemia; encephalopathy and other central nervous system toxicity (confusion, coma, hallucinations, seizures including status epilepticus, ataxia, extrapyramidal and movement disorders, cranial nerve dysfunction), peripheral neuropathy and psychiatric changes; visual impairment, deafness, hearing loss, tinnitus and vertigo; cardiac arrest, atrial and ventricular arrhythmias, cardiomyopathy, myocarditis, heart failure, myocardial infarction, pericardial effusion and pericarditis; pulmonary embolism, deep vein thrombosis, capillary leak syndrome and vasculitis; acute respiratory failure, acute respiratory distress syndrome, pulmonary hypertension, pulmonary fibrosis, pneumonitis, pulmonary oedema and pleural effusion; typhlitis, colitis, pancreatitis, ileus and gastrointestinal haemorrhage; hepatic failure, fulminant hepatitis, hepatic veno-occlusive disease, portal vein thrombosis and cholestasis; toxic epidermal necrolysis, Stevens–Johnson syndrome, palmar-plantar erythrodysaesthesia and skin necrosis; rhabdomyolysis, osteomalacia, rickets and growth retardation; Fanconi syndrome, tubulointerstitial nephritis and nephrogenic diabetes insipidus; infertility, ovarian failure, premature menopause, amenorrhoea, azoospermia and oligospermia; multi-organ failure and infusion-site reactions.

Fatal outcomes have been reported for a number of these reactions, including infections, bone-marrow suppression, central nervous system toxicity, cardiotoxicity, lung toxicity, hepatic failure, kidney damage and bleeding with thrombocytopenia. Tubular kidney damage can appear months or years after treatment, and secondary cancers years after chemotherapy. The SmPC also lists class reactions reported with the related drug cyclophosphamide, such as bladder necrosis, fibrosis and contracture, haemorrhagic pyelitis and ureteritis, and cancers of the renal pelvis, ureter and bladder.

Ifosfamide is activated mainly by CYP3A4. Any combination that could add to its toxicity needs a careful individual assessment of the expected benefit and risk, with close monitoring for signs of toxicity. Patients given ifosfamide together with agents that reduce its activation should be watched for reduced efficacy and for any need to adjust the dose.

• Haematotoxicity and immunosuppression may be increased by ACE inhibitors (which can cause leukopenia), carboplatin, cisplatin and natalizumab.
• Cardiotoxicity may be increased by anthracyclines and by irradiation of the heart region.
• Pulmonary toxicity may be increased by amiodarone and by G-CSF or GM-CSF (granulocyte or granulocyte-macrophage colony-stimulating factors).
• Nephrotoxicity may be increased by aciclovir, aminoglycosides, amphotericin B, carboplatin and cisplatin.
• Haemorrhagic cystitis may be more likely with busulfan and with irradiation of the bladder.
• Additive effects on the central nervous system may occur with antiemetics, antihistamines, narcotics and sedatives.
• Enzyme inducers (carbamazepine, corticosteroids, rifampicin, phenobarbital, phenytoin, St John’s wort) can increase the formation of the metabolites responsible for cytotoxicity and other toxicities; this must be considered with earlier or concurrent treatment.
• CYP3A4 inhibitors (ketoconazole, fluconazole, itraconazole, sorafenib) reduce the activation and metabolism of ifosfamide and can alter its efficacy. They may also increase the formation of a metabolite linked to central nervous system toxicity and nephrotoxicity.
• Docetaxel: increased gastrointestinal toxicity was reported when ifosfamide was given before a docetaxel infusion.
• Coumarin derivatives: a raised INR has been reported in patients treated with ifosfamide and warfarin.
• Vaccines: a reduced response is to be expected because of immunosuppression; with live vaccines, an infection caused by the vaccine can develop.
• Tamoxifen: using tamoxifen together with chemotherapy can increase the risk of thromboembolic complications.
• Cisplatin: hearing loss caused by cisplatin can be made worse by concurrent ifosfamide.
• Irinotecan: formation of the active metabolite of irinotecan may be reduced when it is given with ifosfamide.
• Antidiabetic agents: sulfonylureas given with ifosfamide may have a stronger blood-glucose-lowering effect.
• Allopurinol: a theoretical interaction could make bone-marrow depression more severe.
• Alcohol, grapefruit and St John’s wort: alcohol can worsen nausea and vomiting. Grapefruit products inhibit CYP3A4 and may reduce activation of ifosfamide, while St John’s wort induces CYP3A4 and raises the formation of toxic metabolites, including chloroacetaldehyde, which is toxic to the kidney and nervous system; close monitoring is warranted.

Ifosfamide must be prescribed only by physicians experienced in oncology or haematology. It is given by intravenous infusion. The dose, duration and treatment intervals depend on the indication, the combination regimen, the patient’s general condition, laboratory results and recovery of blood counts. Within a combination regimen, the dosing instructions of that regimen are followed.

Recommended Dose

• Intermittent administration: 1–3 g/m² of body surface area daily, in cycles of 2 to 5 consecutive days repeated every 2, 3 or 4 weeks. The maximum dose per cycle is 12 g/m².
• Continuous administration: 5 g/m² (maximum 8 g/m², equal to 200 mg/kg) as a single dose, usually as a 24-hour continuous infusion every 3 or 4 weeks.
• Compared with fractionated dosing, single high doses can cause more severe haematotoxicity, urotoxicity, nephrotoxicity and central nervous system toxicity.
• With other cytotoxic medicines of similar toxicity, a dose reduction and/or longer treatment-free intervals may be needed. Haematopoietic growth factors (colony-stimulating factors, erythropoiesis-stimulating agents) may be considered to reduce myelosuppression and help deliver the planned dose.

Method of Administration and Mesna

• Infusion: for intravenous use only. The diluted solution must not exceed a concentration of 4%. It is given as a short infusion lasting from 30 minutes to 4 hours, depending on the volume and the regimen, or as a continuous 24-hour infusion. Reconstitution and dilution are described in section 6.6 of the SmPC.
• Fluids: during or immediately after administration, enough fluid should be drunk or infused to force diuresis and reduce the risk of urothelial toxicity.
• Mesna: at high doses, ifosfamide should be used in combination with mesna as prophylaxis against haemorrhagic cystitis. The usual mesna dose reaches or exceeds 60% of the daily ifosfamide dose, divided into 3 doses given at 0, 4 and 8 hours after ifosfamide. When ifosfamide is combined with cisplatin, which requires daily hyperhydration, the mesna dose must be increased to compensate for the greater urinary excretion.
• Inspection: parenteral medicines are checked visually for particles and discolouration, and the substance must be completely dissolved before administration.

Dose Adjustment in Myelosuppression

• Leukocytes above 4,000/µL and platelets above 100,000/µL: 100% of the planned dose.
• Leukocytes 4,000–2,500/µL and platelets 100,000–50,000/µL: 50% of the planned dose.
• Leukocytes below 2,500/µL and platelets below 50,000/µL: postpone treatment until values normalise, or decide individually.

Special Populations

• Elderly and debilitated patients: choose the dose with caution, bearing in mind the higher frequency of reduced liver, kidney or heart function and of concomitant disease or other treatment.
• Renal impairment: 75% of the dose is recommended when creatinine clearance is 10 mL/min or less. Ifosfamide and its metabolites are dialysable, so consistent intervals between ifosfamide and dialysis should be considered in patients who need dialysis.
• Hepatic impairment: the dose may need adjusting (see Special Instructions).
• Children: the authorised indications are for adult patients, and the SmPC gives no paediatric dose.

Bone Marrow Suppression, Immunosuppression and Infections

• Ifosfamide can cause myelosuppression and marked suppression of the immune response, leading to serious infections; deaths from ifosfamide-associated myelosuppression have been reported. Leukopenia, neutropenia, thrombocytopenia (with a higher risk of bleeding) and anaemia can occur.
• The white-cell count normally falls after each dose, reaching its lowest point about two weeks later, and then recovers. Myelosuppression is dose-dependent, greater after a single high dose than after fractionated dosing, greater when kidney function is reduced, and more severe in patients treated earlier or at the same time with chemotherapy, radiotherapy or other haematotoxic agents. Other immunosuppressants add to the immunosuppression.
• Severe immunosuppression has caused serious and sometimes fatal infections, including pneumonia, sepsis and septic shock and bacterial, fungal, viral and parasitic infections. Latent infections can be reactivated. Infections must be treated appropriately; antimicrobial prophylaxis may be indicated in neutropenia, and febrile neutropenia calls for antibiotics and/or antifungals.
• White-cell count, platelet count and haemoglobin should be measured before each administration and at suitable intervals afterwards. Unless it is essential, ifosfamide should not be given when counts are below 2,500 leukocytes/µL or 50,000 platelets/µL. Use it with caution in severe bone-marrow impairment, severe immunosuppression and active infection.

Encephalopathy and Central Nervous System Toxicity

• Ifosfamide can cause encephalopathy and other neurotoxic effects. Central nervous system (CNS) toxicity can appear within hours or after a few days of administration; in most cases it resolves within 48 to 72 hours of stopping ifosfamide, but symptoms can last longer and recovery has sometimes been incomplete. Fatal outcomes from CNS toxicity have been reported.
• If CNS toxicity develops, administration of ifosfamide should be stopped. Symptoms can include confusion, drowsiness, coma, hallucinations, blurred vision, psychotic behaviour, extrapyramidal symptoms, urinary incontinence and seizures.
• CNS toxicity appears to be dose-dependent. Risk factors for ifosfamide-associated encephalopathy include low serum albumin, impaired kidney function, poor performance status, pelvic disease (for example a tumour in the lower abdomen or bulky abdominal disease) and earlier or concurrent nephrotoxic treatment, including cisplatin.
• Because effects can add up, medicines that act on the CNS (for example antiemetics, tranquillisers, narcotics and antihistamines) and substances such as alcohol should be used with particular caution and, if necessary, stopped when encephalopathy develops.
• Patients should be monitored closely for symptoms of encephalopathy, especially those at higher risk. Methylene blue can be considered for treatment and prevention of ifosfamide-associated encephalopathy.

Kidney and Bladder Toxicity

• Ifosfamide is both nephrotoxic and urotoxic. Kidney function and urinary sediment should be checked regularly, with a urinalysis before each dose and blood and urine tests (for example phosphate and potassium) to detect kidney and urothelial toxicity. Appropriate supportive treatment, including phosphate and potassium, is given as needed.
• Before starting, obstruction of urinary outflow, cystitis, infections and electrolyte imbalances must be excluded or corrected. If cystitis with macroscopic or microscopic haematuria develops during treatment, treatment should be interrupted until the urine tests have returned to normal.
• Haemorrhagic cystitis can be severe, with ulceration and necrosis, and has needed blood transfusion. Bladder fibrosis, a small-capacity bladder, pyelitis and ureteritis have also been reported, and some patients needed cystectomy or died of urothelial toxicity. The risk depends on the dose, is higher with single high doses than with fractionated dosing, and is raised by earlier or concurrent bladder irradiation or busulfan. Sufficient hydration, regular emptying of the bladder and mesna are essential.
• Kidney damage includes tubular and parenchymal necrosis. Disorders of glomerular and tubular function are very common, and Fanconi syndrome, renal rickets and growth retardation in children and osteomalacia in adults have been reported. Tubular damage can show up during treatment or months to years after it; function can recover, stay stable or worsen, and acute and chronic renal failure, some fatal, have occurred.
• The risk of nephrotoxicity is higher with large cumulative doses, pre-existing renal impairment, earlier or concurrent nephrotoxic agents such as cisplatin, young age in children (especially up to about 5 years) and reduced nephron reserve (kidney tumours, kidney irradiation, one kidney removed). Glomerular and tubular function should be assessed before, during and after treatment. A syndrome resembling SIADH has been reported.
• In patients with renal impairment before treatment, or with reduced nephron reserve, the expected benefit and risk must be weighed carefully. Reduced excretion in renal impairment can raise levels of ifosfamide and its metabolites and increase toxicity (neurotoxicity, nephrotoxicity, haematotoxicity), which must be taken into account when setting the dose.

Heart, Lung and Liver

• Cardiotoxicity: reported effects include supraventricular and ventricular arrhythmias (atrial fibrillation, pulseless ventricular tachycardia), lower QRS voltage with ST-segment and T-wave changes, toxic cardiomyopathy leading to heart failure with congestion and hypotension, pericardial effusion, fibrinous pericarditis and pericardial fibrosis. Fatal cardiotoxicity has been reported. The risk is dose-dependent and rises with earlier or concurrent cardiotoxic agents, irradiation of the heart region and possibly renal impairment. Take special care in patients with cardiac risk factors or existing heart disease.
• Pulmonary toxicity: interstitial pneumonitis and pulmonary fibrosis have been reported, as have other forms of lung toxicity that can lead to respiratory failure and death.
• Hepatic veno-occlusive disease: reported with chemotherapy that included ifosfamide.
• Hepatic impairment: especially if severe, it can reduce the activation of ifosfamide and so alter its effect; this should be considered when choosing the dose and interpreting the response.

Secondary Malignancies

As with all cytotoxic treatment, there is a risk of late secondary tumours. The risk of myelodysplastic changes, some progressing to acute leukaemia, is increased, and lymphoma, thyroid cancer and sarcomas have been reported after ifosfamide-containing regimens. A secondary malignancy can develop several years after chemotherapy has ended.

Pregnancy, Breastfeeding and Fertility

• Genotoxicity and contraception: ifosfamide is genotoxic and mutagenic in male and female germ cells. Women must not become pregnant, and men must not father a child during treatment or for up to 6 months after it ends. Sexually active women and men must use effective contraception for these periods; in women of childbearing age a reliable method is needed during treatment and up to six months afterwards. In animals, exposure of oocytes during follicular development lowered implantation and viable pregnancy and raised the risk of malformations. Follicular development in humans may last longer than 12 months, which matters if conception or pregnancy is planned after treatment.
• Pregnancy: contraindicated. Ifosfamide was toxic to the foetus in rats, mice and rabbits when given during organogenesis, and foetal growth retardation and neonatal anaemia have been reported after ifosfamide chemotherapy in pregnancy. Women must be told of the risk of serious foetal harm in the first trimester. The SmPC adds that after the first trimester, if treatment cannot be delayed, chemotherapy may be started once the patient has been told of the slight but possible risk of teratogenic effects and the potential risk to the foetus.
• Breastfeeding: contraindicated. Ifosfamide may pass into breast milk, and toxicity (neutropenia, thrombocytopenia, low haemoglobin and diarrhoea) may occur in a breastfed child.
• Fertility: ifosfamide interferes with oogenesis and spermatogenesis, and amenorrhoea, azoospermia and sterility have been reported in both sexes. Sterility seems to depend on the dose, the duration of treatment and gonadal function at the time, and may be irreversible. Men may develop oligospermia or azoospermia and some testicular atrophy; azoospermia can be reversible but may take several years, and treated men have fathered children. Men should be told about sperm preservation before treatment. In women the risk of permanent amenorrhoea is higher at older ages, and girls who keep ovarian function after treatment have a higher risk of premature menopause.

Hypersensitivity, Wound Healing and Other Precautions

• Anaphylactic or anaphylactoid reactions have been reported, with cross-sensitivity between the oxazaphosphorine cytotoxics.
• Ifosfamide may interfere with normal wound healing.
• Alopecia is very common and dose-dependent and can progress to baldness; hair may grow back with a different texture or colour.
• Nausea and vomiting are common: current antiemetic guidelines should be followed, and alcohol can make them worse. Stomatitis (oral mucositis) can occur, and current guidance on prevention and relief should be followed.
• Extravasation: the cytotoxic effect appears only after activation in the liver, so the risk of tissue injury from accidental extravasation is low. If it happens, stop the infusion at once, aspirate the extravasated solution through the cannula and take other measures as appropriate.

Excipients

The vial contains no excipients.

Effect on Driving

Manifestations of central nervous system toxicity can affect the ability to drive and use machines.

Do not store above 25 °C. Keep the vial in its original pack to protect it from light. Ifosfamide is supplied as a 30 mL clear glass vial (hydrolytic class I or III) with a rubber stopper and aluminium cap, with or without a protective plastic cover that gives extra transport protection and does not touch the medicine. For storage after reconstitution, see Shelf Life.

3 years for the unopened vial. Do not use after the expiry date on the pack. The reconstituted solution should be used within 48 hours of preparation when kept at 2–8 °C. From a microbiological point of view it should be used immediately unless reconstitution took place under controlled and validated aseptic conditions; if it is not used immediately, in-use storage times and conditions are the responsibility of the user and should normally not exceed 24 hours at 2–8 °C.

Prescription only (Rx), prescribed exclusively by physicians experienced in oncology or haematology. Ifosfamide is given by intravenous infusion, so it is supplied to the hospital or clinic that administers it.